Follow-Up Biopsies in Gastrointestinal Immune Checkpoint Inhibitor Toxicity May Show Markedly Different Inflammatory Patterns Than Initial Injury.

Colitis is a common manifestation of immune checkpoint inhibitor (ICI) toxicity and can present with varied histologic patterns of inflammation, some of which have been shown to be associated with specific ICI drug types. Although the histologic features of ICI colitis seen at the time of diagnosis have been described, there have been few reports following these patients over time. We evaluated initial and follow-up biopsies in 30 patients with ICI colitis and found that 37% of patients developed a different pattern of injury on follow-up biopsy compared to the initial biopsy. Patients with a different inflammatory pattern were more likely to have restarted ICI therapy before their follow-up biopsy (64%) compared to those without a change in inflammatory pattern (11%; P < 0.01). The majority of these patients had changed ICI drug types (86%). Additionally, many cases changed to an inflammatory bowel disease (IBD)-like pattern (36%), raising a question of de novo IBD. However, all of our patients with an IBD-like pattern experienced sustained resolution of symptoms without steroids or other immunosuppressive medications following discontinuation of ICI therapy, consistent with a diagnosis of ICI toxicity. Our findings suggest that follow-up biopsies in patients with ICI colitis may show a different histology and that this does not necessarily warrant a change in the histologic diagnosis to another disease.

Adaptive Metabolic Responses Facilitate Blood-Brain Barrier Repair in Ischemic Stroke via BHB-Mediated Epigenetic Modification of ZO-1 Expression.

Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta-hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood-brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO-ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO-1 by enhancing local ß-hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO-ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

NIPBL::NACC1 Fusion Hepatic Carcinoma.

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

Histologic Features of Syphilitic Gastritis: A Rare but Resurging Imitator of Common Diseases.

OBJECTIVES: The range of histopathologic features of gastric syphilis is not well described. Here we describe the clinicopathologic findings of eight patients with syphilitic gastritis. METHODS: A search of our Pathology Data System (2003-2022) and multiple other institutions identified eight patients with syphilitic gastritis. Clinical information, pathology reports, and available slides were reviewed. RESULTS: Lesions predominated in middle-aged adults (mean age, 47.2 years; range, 23-61 years) with a propensity for men (n = 7). Three patients had a documented history of human immunodeficiency virus. Clinical presentations included weight loss, abdominal pain, hematochezia, fever, dyspepsia, nausea and vomiting, hematemesis, anemia, and early satiety. Endoscopic findings included ulcerations, erosions, abnormal mucosa, and nodularity. All specimens shared an active chronic gastritis pattern with intense lymphohistiocytic infiltrates, variable plasma cells, and gland loss. Prominent lymphoid aggregates were seen in four specimens. The diagnosis was confirmed either by immunostain for Treponema pallidum (n = 7) or by direct immunofluorescence staining and real-time polymerase chain reaction (n = 1). All patients with available follow-up data showed resolution of symptoms after antibiotic therapy (n = 4). CONCLUSIONS: Recognition of the histologic pattern of syphilitic gastritis facilitates timely treatment, prevents further transmission, and avoids unnecessarily aggressive treatment.

An update on the diagnosis of gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) arise from neuroendocrine cells found throughout the gastrointestinal tract and islet cells of the pancreas. The incidence and prevalence of GEP-NENs have been increasing each year due to higher awareness, improved diagnostic modalities, and increased incidental detection on cross-sectional imaging and endoscopy for cancer screening and other conditions and symptoms. GEP-NENs are a heterogeneous group of tumors and have a wide range in clinical presentation, histopathologic features, and molecular biology. Clinical presentation most commonly depends on whether the GEP-NEN secretes an active hormone. The World Health Organization recently updated the classification of GEP-NENs to introduce a distinction between high-grade neuroendocrine tumors and neuroendocrine carcinomas, which can be identified using histology and molecular studies and are more aggressive with a worse prognosis compared to high-grade neuroendocrine tumors. As our understanding of the biology of GEP-NENs has grown, new and improved diagnostic modalities can be developed and optimized. Here, we discuss clinical features and updates in diagnosis, including histopathological analysis, biomarkers, molecular techniques, and radiology of GEP-NENs. We review established diagnostic tests and discuss promising novel diagnostic tests that are currently in development or require further investigation and validation prior to broad utilization in patient care.

Cribriform colon cancer: a morphological growth pattern associated with extramural venous invasion, nodal metastases and microsatellite stability.

BACKGROUND: Cribriform comedo-type adenocarcinoma was a colon cancer subtype recognised in the previous WHO classification of tumours that is no longer included in the recent edition. Previous reports have described colon cancers with cribriform growth as having worse overall survival and being associated with microsatellite stability. We sought to validate whether cribriform carcinoma (CC) is a distinct morphological subtype with clinical relevance in the context of modern colon cancer diagnosis. METHODS: Consecutive cases of non-neoadjuvantly treated colon cancer resections were identified (n=177) and reviewed to evaluate for CC and other histopathological and clinical features. CC was defined as solid nests of cancer with round, 'punched out' spaces and intraluminal bridges, reminiscent of ductal carcinoma in situ of the breast. RESULTS: CC was present in 18.6% of the consecutive case cohort. Compared with all other cases, CC was associated with positive lymph nodes, increased depth of invasion, extramural venous involvement (EMVI), and microsatellite stability, and was less likely to have tumour infiltrating lymphocytes (p<0.05). In contrast to previous reports, we did not find significantly worse overall, disease-specific or recurrence-free survival for CC. Morphological features mimicking CC occurred in 33.3% of all other colon cancer cases. CONCLUSION: Identifying CC may be useful due to its association with worse stage at presentation and EMVI, but given that cribriform-like appearance may be found in many colon cancer cases and that we did not find a survival difference for CC, CC may not necessitate its own subtype classification.

Sinusoidal Growth Pattern of Hepatic Melanoma Metastasis: Implications for Histopathologic Diagnosis.

Metastatic tumors interface with liver in multiple patterns, of which, the rare "sinusoidal" growth pattern can be subtle and easily overlooked on biopsy. We sought to characterize the metastasis-to-liver interface patterns of melanoma compared with other tumor types and assess the incidence of metastatic melanoma in histologically normal-appearing targeted liver lesion biopsies. Liver lesion samples from 54 melanoma patients were assessed. Nearly normal-appearing cases, defined as no obvious malignancy on routine hematoxylin and eosin stain (n=24), were stained with SOX10 and confirmed with MelanA. Tumor-to-liver interface patterns were determined in biopsies overtly positive for metastatic melanoma (n=30) versus other hepatic metastases as controls (colon, n=28; breast, n=20; pancreaticobiliary, n=20; and neuroendocrine, n=28). Of the 24 nearly normal-appearing liver biopsies from melanoma patients, 3 had subtle melanoma cells detected in sinusoids, confirmed with immunohistochemistry. Of 30 livers overtly positive for melanoma, 8 showed the sinusoidal pattern, compared with none in other metastases. In total, 11/33 (33%) cases of metastatic melanoma liver biopsies demonstrated the sinusoidal pattern. We describe 11 metastatic melanoma cases in liver with the rare sinusoidal pattern, 3 of which were subtle and easy to miss on routine hematoxylin and eosin stain. Given that sinusoidal metastasis does not elicit a tissue reaction, it is prudent for the pathologists to be aware of this pattern of metastases and have a low threshold to order immunostains for accurate diagnosis and optimal patient care.

De Novo Inflammatory Bowel Disease Rarely Occurs During Posttransplant Immunosuppression.

OBJECTIVES: De novo chronic idiopathic inflammatory bowel disease (CIIBD) is reported to occur at higher rates in posttransplant patients than that of the general population. The previous reports, however, included patients with primary sclerosing cholangitis (PSC), a known association with CIIBD. Hence, we investigated how often posttransplant de novo CIIBD occurs in the absence of PSC. METHODS: We identified 185 posttransplant adults without a history of PSC or CIIBD, who had undergone colonoscopy between July 2013 and June 2020. Biopsies were reviewed and clinical data were gathered. RESULTS: CIIBD-like colitis accounted for 1.1% (2/185) of our cohort. The 2 affected patients were already taking multiple immunosuppressive therapies. They were initially placed on standard CIIBD maintenance therapy, but then required escalation therapy. One patient had persistent active colitis despite escalation therapy, while the other subsequently had resolution of symptoms and developed quiescent disease. CONCLUSIONS: The incidence of CIIBD-like colitis in our study population was lower than what has been previously described. Both patients had a poor response to standard CIIBD therapy, raising the question whether their diagnosis is truly de novo CIIBD or another immunologic process.

Transient elastography versus liver biopsy: discordance in evaluations for fibrosis and steatosis from a pathology standpoint.

Vibration-controlled transient elastography (VCTE) is a non-invasive method of evaluating liver fibrosis and steatosis. It can easily be performed in the outpatient setting and has been suggested as an alternative to liver biopsy. However, VCTE and biopsy discrepancies commonly occur. Patient characteristics, procedure performance, and liver features can impact the reliability of VCTE results. We identified 82 patients who received VCTE and biopsy within one month to assess how frequently major discrepancies occur and to determine the role of the liver biopsy in this workup. In our study, 35.4% of patients had a major fibrosis discrepancy, which was defined as advanced fibrosis or cirrhosis by VCTE and no to minimal fibrosis on biopsy. This was significantly associated with increased BMI, and liver features including steatohepatitis, inflammation, congestion, and cholestasis were important contributors to discrepancies. All patients with advanced fibrosis or cirrhosis on liver biopsy were appropriately detected by VCTE (n = 28). Detection of steatosis was less sensitive as 19% (n = 4 of 21) of patients with moderate to severe steatosis on biopsy were missed by VCTE. Liver biopsy has been traditionally performed for diagnosis, but with the emergence of non-invasive tools to evaluate for liver fibrosis and steatosis, biopsies are now additionally being performed to confirm findings from noninvasive procedures. Although VCTE is a highly sensitive tool for liver fibrosis, it is not as specific, and therefore, the liver biopsy remains the gold standard for accurate fibrosis assessment.

Metastases can occur in cirrhotic livers with patent portal veins.

OBJECTIVES: Metastases are common in non-cirrhotic livers but are considered unlikely in the setting of cirrhosis. However, the degree of fibrosis in cirrhosis may vary; thus metastases may still access the liver vasculature and present as a mass in cirrhotic livers. This possibility may affect pathologists' diagnostic algorithms when faced with a liver mass biopsy. METHODS: We hypothesized that metastases can occur in cirrhotic livers if fibrous remodeling is not severe or abnormal veno-arterial shunting exists to override an obstructed portal system. We searched departmental archives for cirrhotic livers with masses, categorizing fibrosis by Laennec staging: 4A = mild cirrhosis, 4B = moderate, 4 C = severe. RESULTS: Of 1453 cirrhotic livers with masses, 1429 were primary tumors and 24 were metastases (1.7 %). Of livers with metastases, most had 4A or 4B cirrhosis by Laennec staging (n = 17; 71 %). Eleven patients were evaluated by ultrasound Doppler; 2 of 5 with Laennec 4 C had reversal of portal vein flow, but all 4A & 4B patients had patent portal veins without reversed flow. Echocardiograms (13 patients) showed no ventricular or atrial septal defects or arteriovenous shunts. CONCLUSIONS: Metastases are uncommon in cirrhotic livers, accounting for 1.7 % of masses. Most involved livers had mild or moderate cirrhosis (Laennec 4A/4B) and patent portal veins; however, as some Laennec 4 C cases also contained metastases, obstructed portal access may not be enough to deter metastatic access.

A Clinicopathologic and Molecular Update of Pancreatic Neuroendocrine Neoplasms With a Focus on the New World Health Organization Classification.

CONTEXT.­: According to the 2017 World Health Organization classification, pancreatic neuroendocrine neoplasms (PanNENs) include a new category of pancreatic neuroendocrine tumor, grade 3, which is often difficult to differentiate from pancreatic neuroendocrine carcinoma. However, pancreatic neuroendocrine tumor grade 3 and pancreatic neuroendocrine carcinoma are distinct entities with very different clinical presentation, prognosis, and therapeutic strategies. Recent discoveries on the molecular characteristics of pancreatic neuroendocrine tumors also play an essential role in the pathologic differential diagnosis of PanNENs. In addition, the histopathologic varieties of PanNENs bring in many differential diagnoses with other pancreatic neoplasms, especially acinar cell carcinoma, solid pseudopapillary neoplasm, and ductal adenocarcinoma. OBJECTIVE.­: To provide a brief update of the World Health Organization classification; the clinical, histopathologic, immunohistochemical, and molecular characteristics; and the differential diagnoses and biological behavior of PanNENs. DATA SOURCES.­: Analysis of the pertinent literature (PubMed) and authors' clinical practice experience based on institutional and consultation materials. CONCLUSIONS.­: The evolving clinical, histopathologic, immunohistochemical, and molecular features of PanNENs are reviewed. Important differential diagnoses with other neoplasms of the pancreas are discussed.

Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells.

BACKGROUND: Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases. METHODS: Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival. RESULTS: High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1+ expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%, p = 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance. CONCLUSION: Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.

Clear Cell Myoepithelial Carcinoma Arising from the Hard Palate with Metastasis to the Lungs.

Myoepithelial carcinoma is an uncommon tumor of the salivary glands, most commonly the parotid gland. Clear cell myoepithelial carcinoma is a rare variant with an aggressive behavior. Here, we describe a case of clear cell myoepithelial carcinoma arising from the hard palate in an elderly male who underwent resection of the tumor and postop radiation. Posttreatment imaging demonstrated bilateral pulmonary nodules and a C2 body lesion concerning for metastasis. Biopsy of the lung lesions revealed a monomorphous population of optically clear cells with hyperchromatic and pleomorphic nuclei which were morphologically similar to the prior resection specimen. There are few reported cases of clear cell myoepithelial carcinoma arising from the hard palate, and there are even fewer reports on metastases to the lungs. Due to the low number of reported cases, prognosis and treatment of this neoplasm is not well defined.