Variability in morphology and immunohistochemistry of Crohn's disease-associated small bowel neoplasms: implications of Claudin 18 and Cadherin 17 expression for tumor-targeted immunotherapies.

AIMS: Inflammatory bowel disease-associated colorectal carcinomas are known to have different morphology, immunoprofile, and genetic findings from sporadic colorectal carcinomas; however, little is known for Crohn's disease-associated small bowel neoplasms (CD-SBNs). Cadherin 17 is a useful biomarker of adenocarcinomas with intestinal phenotype and recently reported as an ideal target for chimeric antigen receptor T-cells (CAR-T) therapy for gastrointestinal carcinoma. Claudin 18 is a cell adhesion protein, and Claudin18 isoform 2 (CLDN18.2) is frequently expressed at high levels in gastric-type adenocarcinoma. Zolbetuximab, a targeted monoclonal antibody, has been developed for CLDN18.2-positive gastroesophageal adenocarcinoma. We examined a series of CD-SBNs for both Cadherin 17 and Claudin 18, and also hypothesized that expression of Claudin 18 was associated with gastric phenotype. METHODS AND RESULTS: We performed histological and immunohistochemical examinations on 25 CD-SBNs. Most of adenocarcinomas showed tubular morphology as seen in gastric carcinomas, whereas a subset of dysplasia was morphologically similar to that of the large bowel. Cadherin17 and Claudin 18 expression was identified in 93% and 57% CD-associated adenocarcinomas respectively. In Cadherin 17-positive CD-SBNs, frequent MUC5AC, MUC6, and Claudin18 expression was identified (61%, 57%, and 57%, respectively). Claudin 18-positive CD-SBNs showed significantly more MUC5AC and MUC6 expression than Claudin 18-negative CD-SBNs (P = 0.005, < 0.001 respectively). CONCLUSION: In CD-associated small bowel adenocarcinomas, Cadherin 17 expression was frequently retained and Claudin 18 was frequently co-expressed. Claudin 18 had a positive correlation with the expression of gastric mucins. These results suggest that CD-associated small bowel adenocarcinomas may be candidates for Cadherin 17- and Claudin 18-targeted immunotherapies.

[Malignant transformation of Ollier disease-related multiple glioma with IDH1 p.R132C mutation].

A 21-year-old man who was diagnosed with Ollier disease at the age of 1 year developed incidental multiple gliomas at the age of 15 years. Subsequently, the multiple gliomas enlarged and the patient underwent three surgical removals. Genetic analysis revealed the IDH1 p.R132C mutation in the gliomas, and histopathology showed malignant transformation. Despite multimodality treatment, the gliomas could not be controlled, and the patient died at the age of 23 years. Ollier disease is a rare disease with IDH1/2 mutations and is often associated with gliomas. However, there are very few reports on genetic analysis of IDH1/2 mutations and long-term follow-up in Ollier disease-related gliomas. Genetic analysis of IDH mutations may contribute to the elucidation of its pathogenesis. The cross-departmental collaboration is required for long-term follow-up of Ollier disease-related gliomas.

Improving intraoperative diagnosis of spread through air spaces: A cryo-embedding-medium inflation method for frozen section analysis.

Objective: Accurate intraoperative diagnosis of spread through air spaces (STAS), a known poor prognostic factor in lung cancer, is crucial for guiding surgical decision-making during sublobar resections. This study aimed to evaluate the diagnostic sensitivity of STAS using frozen section (FS) slides prepared with the cryo-embedding medium inflation technique. Methods: In this prospective study at Shinshu University Hospital, 99 patients undergoing lung resection for tumors <3 cm in size were included, a total of 114 lesions. FS slides were prepared with injecting diluted cryo-embedding medium into the lung parenchyma of resected specimens. The diagnostic performance of these FS slides for STAS detection was evaluated by comparing FS-STAS results with the gold-standard STAS status. Results: The incidence of STAS, determined by the gold standard, was 43 (38%) of 114 lesions, including 31 (37%) of 84 primary lung cancers and 12 (40%) of 30 metastatic lung tumors. The sensitivity, specificity, positive and negative predictive values, and accuracy of FS slides for STAS detection were 81%, 89%, 81%, 89%, and 86%, respectively. Specifically, in primary lung cancers, these values were 90%, 89%, 82%, 94%, and 89%, respectively. Regarding metastatic lung tumors, the corresponding values were 58%, 89%, 78%, 76%, and 77%, respectively. Conclusions: Our adapted cryo-embedding medium inflation method has demonstrated enhanced sensitivity in detecting STAS on FS slides, providing results similar to the gold-standard STAS detection. Compared with historical benchmarks, this technique could show excellent performance and be readily incorporated into clinical practice without requiring additional resources beyond those used for standard FS analysis.

Case of severe alcoholic hepatitis following acute pancreatitis.

This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5-7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory-Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient's hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis.

Leucine-rich repeat-containing G protein-coupled receptor 5 expression in lymph node metastases of colorectal cancer: Clinicopathological insights and prognostic implications.

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a significant cancer stem cell marker in colorectal cancer (CRC), lacks lymph node (LN) expression studies. In this study, we identified LGR5 expression by RNAscope, a highly sensitive RNA in situ method, and analyzed its association with clinicopathological characteristics. Tissue microarrays were generated from primary tumors (PTs) and LN metastases in paraffin-embedded blocks of 38 CRC surgical resection materials. LGR5 expression by RNAscope was evaluated by dividing the expression levels into negative and positive expression. In all but two cases of LN metastasis, LGR5-positive dots were detected in tumor cells, and there was a wide range of LGR5-positive cells. More LGR5-positive dots were identified in the gland-forming region. Twenty-three cases were classified into a high LGR5-expression group, and 15 cases were classified into a low LGR5-expression group. In the high LGR5-expression group, the histological grade was lower than in the low LGR5-expression group (p = 0.0159), while necrosis was significantly more prevalent (p = 0.0326), and the tumor, node, metastasis stage was significantly lower (p = 0.0302). There was no association between LGR5 expression levels in LN metastases and LGR5 expression levels in PT tissue. LGR5 expression in LN metastases may influence prognosis. Further analysis may lead to new therapeutic strategies.

An Immunohistochemical Analysis of Osteopontin and S100 Calcium-binding Protein P is Useful for Subclassifying Large- and Small-duct Type Intrahepatic Cholangiocarcinomas.

Intrahepatic cholangiocarcinoma (iCCA) has been newly subclassified into two different subtypes: large-duct (LD) type and small-duct (SD) type. However, many cases are difficult to subclassify, and there is no consensus regarding subclassification criteria. LD type expresses the highly sensitive diagnostic marker S100 calcium-binding protein P (S100P), while SD type lacks sensitive markers. We identified osteopontin (OPN) as a highly sensitive marker for SD type. This study aimed to develop new subclassification criteria for LD-type and SD-type iCCA. We retrospectively investigated 74 patients with iCCA and subclassified them based on whole-section immunostaining of S100P and OPN. Of the 74 cases, 41 were subclassified as LD type, 32 as SD type, and one was indeterminate. Notably, all S100P-negative cases had OPN positivity. Seventy-three of the 74 cases (98.6%) were clearly and easily subclassified as LD or SD type using only these 2 markers. We also determined the value of immunohistochemistry in cases that were difficult to diagnose based on hematoxylin-eosin and Alcian blue-periodic acid-Schiff staining. Furthermore, we analyzed the clinicopathological characteristics and prognoses of these 2 subtypes. LD type was a poor prognostic factor on univariate analysis; it had significantly worse overall survival ( P = 0.007) and recurrence-free survival ( P < 0.001) than the SD type. In conclusion, we propose new subclassification criteria for iCCA based on immunostaining of S100P and OPN. These criteria may help pathologists to diagnose subtypes of iCCA, supporting future clinical trials and the development of medications for these 2 subtypes as distinct cancers.

A preliminary study of IgG4 expression and its prognostic significance in oral squamous cell carcinoma.

BACKGROUND: IgG4, which plays a pivotal role in the progression of phenotypically diverse tumors, serves as a prognostic marker because of its influence on cancer immunity. Nevertheless, the functions of IgG4 in tongue squamous cell carcinoma (TSCC) remained to be identified. METHODS: To evaluate the significance of IgG4 expression in TSCC, we performed immunohistochemical analysis of patients with TSCC (n = 50) to evaluate the correlation of IgG4 expression with patients' clinicopathological features and prognoses. RESULTS: Higher IgG4 expression detected in TSCC tissues was associated with the less advanced mode of invasion (Yamamoto-Kohama [YK] 1-3) (P = 0.031) and with well-differentiated TSCC (P = 0.077). Kaplan-Meier analyses revealed that the higher IgG4 expression group exhibited better prognosis indicated by overall survival (OS) (P = 0.04) and recurrence-free survival (RFS) (P = 0.016). Univariate analysis of OS indicated that IgG4 expression was associated with longer OS (P = 0.061), and multivariate analysis of RFS revealed that IgG4 expression served as an independent prognostic factor for longer RFS (P = 0.005). CONCLUSION: These results indicate that relatively higher IgG4 levels serve as a favorable prognostic factor for TSCC.

Identification of Terminal ßGlcNAc on Brachyspira Species in Human Intestinal Spirochetosis.

Human intestinal spirochetosis (HIS) is a colorectal bacterial infection caused by the Brachyspira species. Griffonia simplicifolia-II (GS-II) is a lectin specific to terminal α/ßGlcNAc residues. Here, we investigated terminal ßGlcNAc residues in the context of HIS infection using GS-II-horseradish peroxidase staining and HIK1083 immunostaining specific to terminal αGlcNAc residues. Fourteen of 15 HIS cases were GS-II-positive on the bacterial body. No cases showed HIK1083 positivity. The percentage of bacterial bodies staining positively for GS-II based on comparison with anti-Treponema immunostaining was ≤30% in seven cases, 30-70% in two, and >70% in six. Of 15 HIS cases analyzed, none were comorbid with tubular adenomas, and three were comorbid with sessile serrated lesions (SSLs). To determine the species of spirochete infected, the B. aalborgi-specific or B. pilosicoli-specific NADPH oxidase genes were amplified by PCR. After direct sequencing of the PCR products, all nine cases in which PCR products were observed were found to be infected with B. aalborgi alone. These results indicate that the HIS bacterial body, especially of B. aalborgi, is characterized by terminal ßGlcNAc and also indicate that terminal ßGlcNAc on the HIS bacterial body is associated with HIS preference for SSLs.

Mucosal damage in pancreaticobiliary maljunction is stronger in the gallbladder than in the bile duct.

BACKGROUND: The frequency of gallbladder carcinoma is high in pancreaticobiliary maljunction (PBM), and the mechanism of carcinogenesis is not well understood. METHODS: The expression of γH2AX, the most sensitive marker for detecting DNA damage, was analyzed using immunohistochemistry in patients with PBM, in which the gallbladder and bile duct were simultaneously resected. Gallbladder and bile ducts were evaluated in non-neoplastic regions in 13 cases of PBM without cancer in the gallbladder and bile ducts. RESULTS: The median frequencies of γH2AX expression in the bile duct and gallbladder within the same case were 5.9% (range 1.7-12.05%) and 9.9% (range 2.8-25%), respectively, and were significantly higher in the gallbladder mucosa (P < 0.0004). γH2AX expression strongly correlated in the bile duct and gallbladder (r = 0.9436, P < 0.0001). PBM caused marked mucosal damage to the gallbladder. CONCLUSIONS: Mucosal damage may be involved in carcinogenesis, which may be useful for predicting malignant transformation.