Extraskeletal Ewing Sarcoma of the Gastrointestinal and Hepatobiliary Tract: Deceptive Immunophenotype Commonly Leads to Misdiagnosis.

Ewing sarcoma (ES) is an uncommon mesenchymal neoplasm that typically develops as a bone mass, although up to 30% arise in extraskeletal sites. ES of the gastrointestinal (GI) and hepatobiliary tract is rare and may be misdiagnosed as other, more common neoplasms that occur in these sites. However, the correct classification of extraskeletal ES is important for timely clinical management and prognostication. We reviewed our experience of ES in the GI and hepatobiliary tract in order to further highlight the clinicopathologic features of these neoplasms and document the potential for misdiagnosis in this setting. The archives and consultation files of 6 academic institutions were retrospectively queried for cases of ES occurring in the GI and hepatobiliary tract. The histologic slides and ancillary studies were reviewed and clinical data were retrieved for each case through the electronic medical records, when available. Twenty-three patients with ES in the GI and/or hepatobiliary tract were identified from 2000 to 2022. Of these, 11 were women and 12 were men with a median age of 38 years (range, 2 to 64). Tumor locations included the pancreas (n=5), liver (n=2), stomach (n=3), colorectum (n=3), and small intestine (n=5), as well as tumors involving multiple organs, pelvis and retroperitoneum (n=5). Tumor size varied between 2 cm and 18 cm. Twenty were primary and 3 were metastases. Of the 23 cases, only 17% were initially diagnosed as ES. The most common misdiagnoses involved various forms of neuroendocrine neoplasia due to expression of synaptophysin and other neuroendocrine markers (22%). A wide variety of diagnoses including GI stromal tumor was considered due to aberrant CD117 expression (4%). The diagnosis of ES was ultimately confirmed by detection of the EWSR1 rearrangement in 22 cases. The remaining case was diagnosed using traditional immunohistochemistry. Follow-up information was available in 20 cases, with follow-up time varying between 2 and 256 months. Six patients with follow-up died of disease between 6 and 60 months following initial presentation. Our data indicate ES in the GI and hepatobiliary tract is commonly misdiagnosed leading to a delay in therapy. In light of the attendant therapeutic and prognostic implications, ES should be considered in the differential diagnosis of any GI or hepatobiliary tumor with epithelioid and/or small round cell morphology.

Arginase-1 is More Specific Than Hepatocyte Paraffin 1 for Differentiating Hepatocellular Carcinomas With Cytoplasmic Clearing from Nonhepatocellular Clear Cell Tumors in Liver Biopsies.

Arginase-1 (Arg1) and hepatocyte paraffin antigen 1 (HepPar1) are specific and sensitive markers of hepatocellular differentiation. HepPar1 is a granular cytoplasmic immunostain that may be negative in hepatocellular carcinoma (HCC) with cytoplasmic clearing. Arg1 shows uniform cytoplasmic positivity and frequent nuclear positivity. This study was undertaken to determine the staining pattern of Arg1 in HCC with cytoplasmic clearing and compare its use to HepPar1. Fifteen resected HCCs with cytoplasmic clearing and 31 biopsies of clear cell liver tumors (14 HCCs and 17 nonhepatocellular tumors) were identified. Resections were stained with Arg1 to characterize the pattern, intensity, and extent of Arg1 positivity. Biopsies were stained with Arg1 (n=31) and HepPar1 (n=28). In all, 13/15 resected and 11/14 biopsied HCCs with cytoplasmic clearing showed nuclear positivity for Arg1. Both Arg1 and HepPar1 stained significantly more HCCs than nonhepatocellular tumors (13/14 and 11/12, respectively, with P <0.0001 and P =0.0018, respectively). However, HepPar1 stained significantly more nonhepatocellular tumors (5/12) than Arg1 (0/17, P =0.0445). Arg1 frequently displayed nuclear positivity, and interobserver agreement was better for Arg1 ( K =0.93 vs. 0.79). Overall, Arg1 is more specific than HepPar1 for differentiating HCC with cytoplasmic clearing from nonhepatocellular clear cell tumors in the liver. Its staining characteristics, including nuclear positivity, make it easier to interpret in combination with morphology, improving interobserver variability, and it stains significantly fewer mimics than HepPar1.

CALFAN (Low γ-Glutamyl Transpeptidase (GGT) Cholestasis, Acute Liver Failure, and Neurodegeneration) Syndrome: A Case Report with 3-Year Follow-Up after Liver Transplantation in Early Adulthood.

CALFAN syndrome is an extremely rare disease consisting of recurrent pediatric acute liver failure (PALF), neurodegenerative diseases, and skeletal abnormalities associated with SCYL1 gene mutation. To date, three of 18 patients reported underwent liver transplantation in infancy and early childhood (7-23 months). Here, we report a case of CALFAN syndrome with infantile onset, recurrent jaundice/PALF requiring liver transplantation in early adulthood. At the most recent follow-up, 3 years after transplantation, the patient is doing well.

Pathologic Diagnosis of Well-differentiated Hepatocellular Lesions: A Practical Approach to Diagnosis With Particular Focus in Core Needle Biopsies and Utilization of Ancillary Techniques.

Common well-differentiated hepatocellular lesions include focal nodular hyperplasia, focal nodular hyperplasia-like lesions, large regenerative nodule, hepatocellular adenoma, dysplastic nodule, and hepatocellular carcinoma. The term atypical hepatocellular neoplasm/hepatocellular neoplasm of uncertain malignant potential can be used especially in needle core biopsies when a well-differentiated hepatocellular lesion is either histologically atypical (focal reticulin loss, focal cytologic/architectural atypia) or is clinically atypical (male sex or female >50 y) and cannot be confidently classified as adenoma or hepatocellular carcinoma. These are resected in an attempt for more definite classification. Although radiology can suggest the diagnosis in some of the entities mentioned above, needle core biopsies are often performed to confirm the diagnosis and plan therapy. Diagnosis of these lesions on needle core biopsies can be challenging and may have overlapping histologic and sometimes even immunohistochemical features. Herein, we review the histologic, immunohistochemical, and molecular features of well-differentiated hepatocellular lesions, along with recent advances in this area. We also provide the best approach for the diagnosis of well-differentiated hepatocellular lesions with ancillary testing, especially on needle core biopsies, and discuss the pitfalls. Accurate recognition of well-differentiated hepatocellular lesions is essential as some of them have excellent prognosis and may not require resection, while others have histologic prognostic information that is key for management.

Immunophenotypic profiles and prognosis for colorectal mucinous adenocarcinomas are dependent on anatomic location.

BACKGROUND: The prognostic value of mucinous adenocarcinomas (MCAs, exhibiting >50% extracellular mucin) of the colorectum, in relation to their anatomic location is not well studied. MATERIALS AND METHODS: We compared MCAs (n = 175) with non-MCAs (NMCAs, n = 1015) and the cancer-specific survival rates were evaluated, based on their anatomic site, by univariate Kaplan-Meier and multivariate Cox methods. Subsets of these tumors were immunostained for MUC1, MUC2, Bcl-2, and p53. RESULTS: MCAs were more commonly found in the right colon, were of high-grade, and were more prevalent in younger patients (<40 years). They exhibited strong expression of MUC2 and Bcl-2 and showed less p53 nuclear staining. In contrast, most NMCAs were low-grade with high expression of MUC1. MCAs of the rectum were associated with poorer outcomes relative to NMCAs (HR 1.85, CI 95% 1.15-2.97), even though the distributions of advanced-stage tumors were similar. CONCLUSION: Late-stage disease and age were poor independent prognostic indicators of cancer-specific deaths across all tumor locations. In summary, rectal MCAs have a poor prognosis.

Molecular characterization of visible low-grade dysplastic lesions in patients with inflammatory bowel disease.

We studied pathogenic gene mutations and tumor mutation burden (TMB) in visible low-grade dysplastic lesions in patients with inflammatory bowel disease (IBD). The dysplastic lesions with histologically normal mucosa in the background (group 1) were compared with dysplastic lesions occurring either in a background of chronic active colitis (group 2) or associated with synchronous carcinomas regardless of the status of the background mucosa (group 3). The TMB in group 3 was consistently higher in comparison to the group 1 and group 2 lesions, although the difference was not statistically significant. There also seem to be different mutation profiles between the groups, indicating different pathways of tumor pathogenesis. More frequent APC mutations were seen in group 1 as compared to other groups and TP53 mutations were seen in groups 2 and 3, but none in group 1. Molecular characterization could potentially be used as an ancillary prognostic marker in challenging cases to guide the further management of IBD patients with visible dysplastic lesions.

Claudin-18.

CONTEXT.­: Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target. OBJECTIVES.­: To evaluate claudin-18 expression in intestinal metaplasia, dysplasia, and adenocarcinoma of the distal esophagus/gastroesophageal junction and stomach and to evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin. DESIGN.­: Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarcinoma (n = 25). Additionally, gastric (n = 40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria (≥2+ intensity in ≥50% of tumor). RESULTS.­: Claudin-18 staining was not significantly different across dysplasia categories in the gastroesophageal junction (P = .11) or stomach (P = .12). The rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 samples without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastroesophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001). CONCLUSIONS.­: Claudin-18 staining was similar in intestinal metaplasia, dysplasia, and adenocarcinoma. Claudin-18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors.

Gastrointestinal Manifestations of COVID-19 Infection: Clinicopathologic Findings in Intestinal Resections Performed at Single Institution.

It is now known that COVID-19 not only involves the lungs, but other organs as well including the gastrointestinal tract. Although clinic-pathological features are well-described in lungs, the histopathologic features of gastrointestinal involvement in resection specimens are not well characterized. Herein, we describe in detail the clinicopathologic features of intestinal resection specimens in four patients with COVID-19 infection. COVID-19 viral particles by in situ hybridization and immunofluorescence studies are also demonstrated. All four patients were males, aged 28-46 years, with comorbidities. They initially presented with a severe form of pulmonary COVID-19 and showed gastrointestinal symptoms, requiring surgical intervention. Histopathologic examination of resected GI specimens, mostly right colectomies, revealed a spectrum of disease, from superficial mucosal ischemic colitis to frank transmural ischemic colitis and associated changes consistent with pneumatosis cystoides intestinalis. Three patients were African American (75%), and one was Caucasian (25%); three patients died due to complications of their COVID-19 infection (75%), while one ultimately recovered from their GI complications (25%), but experienced prolonged sequela of COVID-19 infection including erectile dysfunction. In conclusion, COVID-19 infection, directly or indirectly, can cause ischemic gastrointestinal complications, with predilection for the right colon.

High-grade Transformation in Adult Granulosa Cell Tumor: Potential Diagnostic Challenges and the Utility of Molecular Testing.

Adult granulosa cell tumor (AGCT) is the most common sex cord-stromal tumor, accounting for about 1% of all ovarian tumors. It has a propensity for recurrences, especially late in the disease course. High-grade or sarcomatoid transformation has been rarely described in AGCT. We present a case of a 65 year old woman who presented with hemodynamic shock and bowel obstruction from a large pelvic mass. Histologic examination revealed predominantly high-grade epithelioid and spindled cells with high mitotic activity and necrosis. A minor component suggestive of AGCT was also identified. Molecular analysis confirmed the diagnosis of AGCT by revealing FOXL2 C134W mutations. Additionally, TP53 mutations were also detected which may contribute to the high-grade transformation. Our case is unique because the high-grade sarcomatous component constituted most of the tumor and the areas of "typical" AGCT were minor. Also, the clinical and operative findings did not suggest a specific site of origin leading to a broad differential diagnosis. High-grade transformation in AGCT is a rarely described phenomenon. The awareness of this presentation is helpful in reaching the correct diagnosis. Molecular analysis may be an extremely helpful adjunct in challenging cases.

The Use of Intraoperative Frozen Sections in Guiding the Extent of Pancreatic Resections for Intraductal Papillary Mucinous Neoplasms: A Single Institution Experience and Review of the Literature.

OBJECTIVES: The utility of frozen section evaluation of the pancreatic parenchymal resection margin(s) in the surgical management of intraductal papillary mucinous neoplasm (IPMN) remains controversial. We investigated the frequency of its use in IPMN resections and its impact on achievement of negative final parenchymal margin(s). METHODS: Sixty-two IPMN resections (11 with invasive carcinoma) performed over a 12-year period were studied. RESULTS: Frozen sections of the parenchymal margin(s) were performed on 44 of the 62 resections (71%), 30 (68%) of which had 10 positive and 22 indefinite margins on frozen section. Additional margin resections were performed in 14 of these 30 cases (47%), boosting the complete resection rate from 14% (2 of 14) on the initial margin(s) to 71% (10 of 14) on the final margin(s) (P = 0.002). Overall, negative final parenchymal margin(s) were achieved more frequently when evaluation of the initial margin(s) by frozen section was performed (35 of 44; 80%) than when it was not (11 of 18; 61%) (P = 0.13). CONCLUSIONS: In the intraoperative management of IPMN, frozen sections are highly reliable for margin evaluation and are useful for guiding the extent of pancreatic resection.

Under-Representation of Racial Groups in Genomics Studies of Gastroenteropancreatic Neuroendocrine Neoplasms.

Not all populations are poised to benefit from advancing genomics in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), as genomics have focused on White patients. This study aimed to evaluate racial populations represented in genomic studies of GEP-NENs and to provide evidence of differential genomic findings between racial groups in GEP-NENs. Manuscripts analyzing DNA, RNA, or DNA methylation in GEP-NENs were queried using PUBMED and EMBASE. NIH race/ethnicity term frequency was then determined by Natural Language Processing, followed by manual evaluation of tumor types and subjects by racial group. IHC of institutional tissue micro-arrays and analysis of AACR GENIE data analyzed was performed to determine mutational differences between Black and White pancreatic NEN (pNEN) patients. 313 manuscripts conducted the requisite genomic analyses, 16 of which included subject race data. Race data were included in 13/184 DNA, 4/107 RNA, and 1/54 DNA Methylation analyses. These studies included 89% White subjects (n = 2032), 5.8% Asian subjects (n = 132), 4.0% "Other" subjects (n = 93), and 1.2% Black subjects (n = 27). No Native American/Alaska Native, Native Hawaiian/Pacific Islander, or ethnically Hispanic/Latinx subjects were represented. There were significant differences in MEN1 mutations among Black and White patients in immunohistochemical (13:40) and GENIE data (24:268 patients per group, respectively), with 9 additional genes differentially mutated in the GENIE dataset. Genomic sequencing data for GEP-NENs is almost racially homogenous. Differences in pNEN genomics may exist between racial groups, highlighting a need for diversity in future genomic analyses of GEP-NENs to understand the putative influence of interracial genomic variation on GEP-NEN prevention, diagnosis, and therapy. Significance: There is little diversity in genomic studies of GEP-NENs, which may exhibit clinically impactful variation in their tumor biology among racial groups. Improved diversity in such studies is imperative for understanding this variation and its potential impacts on disease prevention, diagnosis, therapeutic targeting, and clinical outcomes.

Hepatic macrosteatosis in the US pediatric deceased liver donor population.

INTRODUCTION: The pediatric obesity epidemic is associated with early development of hepatic macrosteatosis, a hallmark of non-alcoholic fatty LI disease, which is thought to be more rapidly progressive in children than adults. Macrosteatosis in adult allografts is associated with allograft loss, but this has not been examined in pediatric donors. METHODS: We studied all pediatric potential whole LI donors (2005-2018) who had a LI biopsy in the SRTR (n = 862) and whose LI was transplanted (n = 862). Macrosteatosis was abstracted from biopsy reports and compared to values in the SRTR standard analytic file. Recipients of macrosteatotic pediatric allografts were matched 1:1 to recipients of non-macrosteatotic pediatric allografts by propensity score matching on donor/recipient variables. All-cause allograft loss was estimated via Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: From 2005 to 2018, the proportion of pediatric donors (age ≥2 years) with obesity increased (14.8% to 21.7%; p < .001), as did the proportion of pediatric deceased whole LI-only donor allografts with macrosteatosis (n = 10 648; 1.8% to 3.9%; p < .001). The median degree of macrosteatosis among macrosteatotic donors was 10% (IQR 5-30). There were no significant differences in all-cause allograft loss between recipients of pediatric LI allografts with and without macrosteatosis at 90 days (p = .11) or 1 year (p = .14) post-transplant in Kaplan-Meier analysis or a Cox proportional hazards model (p > .05). CONCLUSION: Obese pediatric LI donors have increased over time and were more likely to have hepatic macrosteatosis; however, pediatric macrosteatosis did not appear to adversely affect recipient outcomes.

Lack of uniformity in reporting autoimmune gastritis among a diverse group of pathologists.

Autoimmune gastritis (AIG) is a clinicopathologic diagnosis requiring characteristic histopathology and correlation with laboratory work-up. To better understand how the diagnosis of AIG is made and reported in the pathology community, we conducted an anonymous web-based survey which was circulated among a diverse group of pathologists. Excluding trainees there were 64 respondents: 25 academic gastrointestinal pathologists (AGI, 39%), 22 academic general pathologists (AGP, 34%), 17 private general pathologists (PP, 27%). Our survey results highlighted variations in work-up and sign-out practices. The type of metaplasia needed to diagnose AIG lacked consensus. There was variation in accurate interpretation of immunostains with a trend towards more accurate diagnosis of enterochromaffin-like (ECL) cell hyperplasia by AGI (92%) and AGP (95%) than PP (71%) (p = 0.07). G-cells in antrum on neuroendocrine immunostain, a mimicker of ECL cell hyperplasia, was more frequently misdiagnosed by PP/ AGP (44%), versus AGI (12%) (p = 0.02). A triple immunostain panel (H. pylori, neuroendocrine, gastrin) was used in the work-up of AIG by 72% of AGI versus 23% AGP and 12% PP (p = 0.000061). The less-specific term "atrophic gastritis" was used in the diagnostic line more by respondents with >10 years sign-out experience compared with others (p = 0.04). In conclusion, the survey results highlighted deficiencies in the interpretation of neuroendocrine immunostains which is crucial for AIG diagnosis, as well as variation in reporting practices and definitions. Uniform criteria and terminology are needed in this field to improve communication with clinicians, resulting in appropriate testing and follow-up.

Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations From the Pancreatobiliary Pathology Society.

Currently, there are no internationally accepted consensus guidelines for pathologic evaluation of posttherapy pancreatectomy specimens. The Neoadjuvant Therapy Working Group of Pancreatobiliary Pathology Society was formed in 2018 to review grossing protocols, literature, and major issues and to develop recommendations for pathologic evaluation of posttherapy pancreatectomy specimens. The working group generated the following recommendations: (1) Systematic and standardized grossing and sampling protocols should be adopted for pancreatectomy specimens for treated pancreatic ductal adenocarcinoma (PDAC). (2) Consecutive mapping sections along the largest gross tumor dimension are recommended to validate tumor size by histology as required by the College of American Pathologists (CAP) cancer protocol. (3) Tumor size of treated PDACs should be measured microscopically as the largest dimension of tumor outer limits that is bound by viable tumor cells, including intervening stroma. (4) The MD Anderson grading system for tumor response has a better correlation with prognosis and better interobserver concordance among pathologists than does the CAP system. (5) A case should not be classified as a complete response unless the entire pancreas, peripancreatic tissues, ampulla of Vater, common bile duct, and duodenum adjacent to the pancreas are submitted for microscopic examination. (6) Future studies on tumor response of lymph node metastases, molecular and/or immunohistochemical markers, as well as application of artificial intelligence in grading tumor response of treated PDAC are needed. In summary, systematic, standardized pathologic evaluation, accurate tumor size measurement, and reproducible tumor response grading to neoadjuvant therapy are needed for optimal patient care. The criteria and discussions provided here may provide guidance towards these goals.

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in ß-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

Towards a More Standardized Approach to Pathologic Reporting of Pancreatoduodenectomy Specimens for Pancreatic Ductal Adenocarcinoma: Cross-continental and Cross-specialty Survey From the Pancreatobiliary Pathology Society Grossing Working Group.

In recent literature and international meetings held, it has become clear that there are significant differences regarding the definition of what constitutes as margins and how best to document the pathologic findings in pancreatic ductal adenocarcinoma. To capture the current practice, Pancreatobiliary Pathology Society (PBPS) Grossing Working Group conducted an international multispecialty survey encompassing 25 statements, regarding pathologic examination and reporting of pancreatic ductal adenocarcinoma, particularly in pancreatoduodenectomy specimens. The survey results highlighted several discordances; however, consensus/high concordance was reached for the following: (1) the pancreatic neck margin should be entirely submitted en face, and if tumor on the slide, then it is considered equivalent to R1; (2) uncinate margin should be submitted entirely and perpendicularly sectioned, and tumor distance from the uncinate margin should be reported; (3) all other surfaces (including vascular groove, posterior surface, and anterior surface) should be examined and documented; (4) carcinoma involving separately submitted celiac axis specimen should be staged as pT4. Although no consensus was achieved regarding what constitutes R1 versus R0, most participants agreed that ink on tumor or at and within 1 mm to the tumor is equivalent to R1 only in areas designated as a margin, not surface. In conclusion, this survey raises the awareness of the discordances and serves as a starting point towards further standardization of the pancreatoduodenectomy grossing and reporting protocols.

Positivity for SATB2 distinguishes Islet1 positive rectal neuroendocrine tumours from pancreaticoduodenal neuroendocrine tumours.

AIMS: Determining the site of origin of a metastatic neuroendocrine tumour (NET) can be challenging and has important prognostic and therapeutic implications. An immunohistochemical (IHC) panel consisting of TTF1, CDX2, PAX8/PAX6 and Islet1 is often employed. However, there can be a significant IHC overlap among different primary sites. Herein, we sought to determine the utility of including Special AT-rich sequence binding protein-2 (SATB2) in the IHC panel that is used for determining the site of origin of a metastatic NET. METHODS: Paraffin tissue microarrays consisting of 137 primary NETs (26 lung, 22 jejunoileal, 8 appendix, 5 stomach, 4 duodenum, 17 rectum and 55 pancreas) were stained for SATB2, in addition to the well-described lineage-associated markers, such as TTF1, CDX2, PAX6 and Islet1. Additionally, a tissue microarray consisting of 21 metastatic NETs (1 lung, 1 stomach, 8 jejunoileal and 11 pancreas) was stained for TTF1, CDX2, SATB2 and Islet1. The results were recorded as no staining, weak staining and moderate to strong staining. RESULTS: All appendiceal NETs and majority (88%) of the rectal NETs were positive for SATB2. All primary foregut NETs (stomach, pancreas, duodenum and lung) were negative for SATB2, except for one pulmonary NET with weak staining. However, among the metastatic tumours, 5 of 11 pancreatic NETs, 1 stomach NET, 1 lung NET and 2 of 8 jejunoileal NETs showed weak staining. Receiver operating characteristic analysis incorporating sensitivity and specificity data of IHC panel, considering moderate to strong staining as truly positive cases, showed that inclusion of SATB2 to the previously described NET IHC panel outperformed the panel without SATB2, raising the specificity for pancreaticoduodenal NETs from 81.2% to 100%, with a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 82.22% (p<0.0001); for appendiceal NETs the specificity changed from 99.1% to 98.5% and sensitivity increased from 11.8% to 80%, with a PPV and NPV of 66.67% and 99.26%, respectively (p<0.0001); and for rectal NETs the specificity increased from 97.6% to 99.3% and sensitivity raised from 7.1% to 66.7%, with a PPV and NPV of 80% and 98.53%, respectively (p<0.0001). CONCLUSIONS: SATB2 stain is useful in differentiatingIslet1/PAX6 positive pancreatic and rectal NETs, as rectal NETs are typically moderately to strongly positive for SATB2 and pancreatic NETs are usually negative or weakly positive for SATB2. Moderate to strong staining for SATB2 is suggestive of an appendiceal or a rectal primary. SATB2 may complement the panel of CDX2, TTF1 and Islet1 in determining the site of origin of an NET in a metastatic setting.

Acute Liver Failure in a Healthy Young Female With COVID-19.

Several well-described manifestations of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported. Among them, a transient elevation of liver enzymes is the typical presentation of coronavirus disease 2019 (COVID-19) liver-related injury. The mechanism of liver involvement is likely a combination of viral injury and immune-mediated inflammation. In contrast, acute liver failure in the setting of COVID-19 has rarely been reported. Herein, we report a case of pediatric acute liver failure in a previously healthy female adolescent infected with SARS-CoV-2 with biopsy evidence of replicating virus in hepatocytes, which has not been previously reported.

T3 versus T4a staging challenges in deeply invasive colonic adenocarcinomas and correlation with clinical outcomes.

Despite the latest 8th edition American Joint Committee on Cancer Staging Manual guidelines, disagreement still exists among pathologists regarding staging deeply invasive colonic adenocarcinomas ≤1 mm to the serosal surface. In this retrospective study, 151 untreated colonic adenocarcinomas staged initially as either pT3 or pT4a and with available 5-year follow-up data were retrieved and re-categorized: Group 1 (38 cases): pT4a with tumor at the serosa; Group 2 (49 cases): tumor ≤1 mm from the serosa, with intervening reactive fibrosis (40/49) or inflammation (9/49); Group 3 (64 cases): pT3 tumor >1 mm from the serosa. Clinical outcomes were analyzed. Groups 1 and 2 tumors showed significantly lower 5-year recurrence-free survival and lower overall survival rates (log-rank p < 0.001 for both), when compared with Group 3 tumors. Even after adjusting for adjuvant therapy and nodal metastases, the proportional hazards ratios for the risk of death (p < 0.001) and risk of recurrence (p = 0.005) showed significantly higher risk in Groups 1 and 2 compared with Group 3. The synchronous nodal (p = 0.012) and metachronous distant metastases (p = 0.004) were also significantly more in Groups 1 and 2 versus Group 3. Colonic adenocarcinomas ≤1 mm from the serosal surface behaved more akin to "bona fide" pT4a tumors at the serosal surface in our study with regards to clinical outcomes. We recommend these tumors be staged as pT4a rather than pT3, as supported by outcome data in our study. We hope this will also ensure reproducibility and consistency in staging these tumors across institutions.