Fatal arrythmia in a young man after COVID-19 vaccination: An autopsy report.

RATIONALE: The benefits of COVID-19 mRNA vaccination are claimed to be substantial; however, vaccination-related myocarditis and pericarditis have also been observed globally, particularly among young men. In most cases, the symptoms are mild and resolve on their own; however, fatal cases have rarely been described. PATIENT CONCERNS: A healthy 40-year-old Japanese man suddenly experienced tachycardia and lost consciousness 2 days after vaccination. Continued resuscitation recovered the spontaneous heartbeat; however, the patient did not regain consciousness and died 9 days later. Electrocardiography after resuscitation showed marked ST-segment depression and incomplete right bundle branch block. Influenza antigen and polymerase chain reaction tests for SARS-CoV-2 were negative. DIAGNOSES: Fatal arrhythmia after a second COVID-19 mRNA vaccination. INTERVENTIONS: We performed an autopsy and studied the material morphologically and immunohistochemically. OUTCOMES: At autopsy, several small inflammatory foci with cardiomyocytic necrosis were scattered in the right and left ventricles, with a propensity for the right side. Some inflammatory foci were located near the atrioventricular nodes and His bundles. The infiltrating cells predominantly consisted of CD68-positive histiocytes, with a small number of CD8-positive and CD4-positive T cells. In this case, myocarditis was focal and mild, as is mostly observed following COVID-19 mRNA vaccination. However, the inflammatory foci were close to the conduction system and were considered the cause of fatal arrhythmia. LESSONS: Although the benefits of COVID-19 vaccination appear to outweigh the side effects, it should be noted that fatal arrhythmias may rarely occur, and caution should be taken if individuals, particularly young men, complain of any symptoms after vaccination.

Gastric Juvenile Polyposis with Intramucosal Cancer Diagnosed by Magnifying Endoscopy with Narrow-band Imaging.

Although gastric juvenile polyposis (GJP) often coexists with gastric cancer, a preoperative accurate diagnosis is still difficult to obtain. A 70-year-old woman was referred for epigastralgia and anemia. Esophagogastroduodenoscopy with a conventional endoscope showed numerous gastric polyps with no cancerous findings. Magnifying endoscopy with narrow-band imaging (M-NBI) showed cancerous findings, and a target biopsy revealed adenocarcinoma. Histopathological findings after endoscopic resection confirmed a diagnosis of juvenile polyposis with intramucosal adenocarcinoma. Genetic analyses revealed a germline pathogenic variant of SMAD4. A target biopsy using M-NBI and endoscopic resection proved useful for confirming the preoperative diagnosis of coexisting cancerous lesions in GJP.

Ureteral Metastasis of Colonic Adenocarcinoma with Enteroblastic Differentiation: A Rare Case to be Distinguished from Clear Cell Adenocarcinoma of the Urinary Tract.

Adenocarcinomas with enteroblastic differentiation are rare clear cell tumors that are positive for enteroblastic markers. Enteroblastic differentiation is particularly uncommon in colorectal adenocarcinomas. Herein, we report a case of clear cell adenocarcinoma with enteroblastic differentiation in the sigmoid colon of a 38-year-old Japanese woman that metastasized to the lower left ureter. After neoadjuvant chemotherapy, the patient underwent low anterior resection. The tumor consisted of tubular, cribriform, and focal micropapillary proliferation of clear cells immunopositive for spalt-like transcription factor 4 (SALL4), glypican 3, and alpha-fetoprotein. Six months after the colonic resection, a tumor was found in the left lower ureter, which was resected. The ureteral tumor revealed clear cell adenocarcinoma, which was identical to the colonic tumor proliferating in the ureteral mucosa. Metastatic ureteral tumors are rare. We performed a literature search and found only 50 reported cases of ureteral metastases from colorectal cancer. Of these, only 10 metastatic tumors were identified in the ureteral mucosa. No case of ureteral metastasis of clear cell colorectal adenocarcinoma or colorectal adenocarcinoma with enteroblastic differentiation has been reported. Hence, it can be challenging to distinguish them from clear cell adenocarcinoma of the urinary tract and/or clear cell urothelial carcinoma. This paper discussed the differential diagnosis of these tumors and reviewed the clinicopathological features of colorectal carcinomas metastasizing to the ureter.

Clinicopathological and mutational analysis of esophageal basaloid squamous cell carcinoma.

Esophageal basaloid squamous cell carcinoma (EBSCC) is a poorly differentiated variant of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinicopathological and molecular biological characteristics of EBSCC and enrolled 58 patients with EBSCCs. Clinicopathological factors including age, sex, tumor size and location, gross tumor type (superficial, protrusive, ulcerative, and unclassifiable), lymphovascular invasion, infiltrative growth, intramural invasion, TNM stage, and dominant histological type were examined. EBSCCs were classified into four types (solid, cribri, microcystic, and tubular) according to the dominant histology. Next-generation sequencing (NGS) of a cancer hotspot panel was performed in 19 cases. NGS identified TP53 as the most frequently mutated gene, and copy number variation analysis revealed the most frequent loss of heterozygosity (LOH) at the ataxia telangiectasia mutated (ATM) and retinoblastoma 1 (RB1) loci. Target sequencing for TP53 was performed for the remaining 39 cases. We also performed LOH analysis for TP53, ATM, and RB1 and immunohistochemical staining for p53, ATM, and Rb in all cases. The rates of TP53 mutations and LOH and p53 aberrant expression were high (79.3%, 63.2%, and 72.4%, respectively); however, the frequencies were similar to those reported for ESCC. LOH rates of the RB1 and ATM loci were also high (55.3% and 67.2%, respectively). Overall survival rate was 66.5%, and recurrence-free survival rate was 55.0%. Only conventional clinicopathological factors had a prognostic impact in EBSCC; the microcystic type had the poorest prognosis. Our findings could be useful in developing novel treatment strategies for EBSCC.

Concordance of the histological diagnosis of type 1 autoimmune pancreatitis and its distinction from pancreatic ductal adenocarcinoma with endoscopic ultrasound-guided fine needle biopsy specimens: an interobserver agreement study.

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.

[Celiac disease:a case report detailing clinical and pathological improvement with a gluten-free diet].

Celiac disease has a morbidity of 0.2 to 1% in Europe and the United States (US), but appears to be extremely rare in Japan with only a few case reports. This report details a Japanese woman with celiac disease diagnosed by histopathological findings and the improvement of her clinical symptoms on a gluten-free diet. The woman was in her 60s and presented with diarrhea, abdominal pain, and vomiting which were repeatedly exacerbated over several weeks. Therefore, she was referred to our hospital for a detailed examination and treatment. Upper gastrointestinal endoscopy revealed a crude granular mucosa with an erythematous color in the duodenum. No special findings were noted on colonoscopy or capsular endoscopy. Histopathological findings of the duodenum noted villous atrophy, crypt hyperplasia, and lymphocytic infiltration within the surface epithelium, which were suspicious for celiac disease. A gluten-free diet was started which resulted in improved clinical symptoms. Repeat endoscopic imaging and histopathological findings after initiation of the gluten-free diet demonstrated improved small bowel villous atrophy. In this case, appropriate testing had ruled out inflammatory bowel disease, amyloidosis, infectious enteritis, parasitic disease, and allergies. Although anti-gliadin antibody (AGA) and anti-tissue transglutaminase antibody (ATTGA) were serologically negative, and HLA typing was HLA-DQ6, the patient was ultimately diagnosed as having celiac disease based on the characteristic pathological findings and clinical course. In many cases of celiac disease reported in Japan, serum antibodies such as AGA and ATTGA have not been detected, and HLA testing has been negative for DQ2 or DQ8. Therefore, it is possible that celiac disease in Japan might have different genetic and immunological characteristics than the disease in the US and Europe. In the future, additional cases with histology and molecular biological analysis are necessary to test this hypothesis.

Gastric epithelial neoplasm of fundic-gland mucosa lineage: proposal for a new classification in association with gastric adenocarcinoma of fundic-gland type.

BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. METHODS: One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. RESULTS: GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. CONCLUSIONS: We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.

Does previous biopsy lead to cancer overdiagnosis of superficial non-ampullary duodenal epithelial tumors?

Background and study aims We aimed to evaluate the diagnostic performance of magnifying endoscopy with narrow-band imaging (M-NBI) in superficial non-ampullary duodenal epithelial tumors (SNADETs) regarding the absence or presence of biopsy before M-NBI diagnosis. Patients and methods Clinicopathological data were retrospectively reviewed for 99 SNADETs from 99 patients who underwent endoscopic resection. The 99 tumors were divided into the non-biopsy group (32 lesions not undergoing biopsy before M-NBI examination) and the biopsy group (67 lesions undergoing biopsy before M-NBI examination). We investigated the correlation between the M-NBI diagnosis and the histopathological diagnosis of the SNADETs in both groups. Results According to the modified revised Vienna classification, 31 tumors were classified as category 3 (C3) (low-grade adenoma) and 68 as category 4/5 (C4/5) (high-grade adenoma/cancer). The accuracy, sensitivity, and specificity of preoperative M-NBI diagnoses in the non-biopsy group vs the biopsy group were 88 % (95 % confidence interval: 71.0 - 96.5) vs 66 % (51.5 - 75.5), P  = 0.02; 95 % (77.2 - 99.9) vs 89 % (76.4 - 96.4), P  = 0.39; and 70 % (34.8 - 93.3) vs 14 % (3.0 - 36.3), P  < 0.01, respectively. Notably, in the biopsy group, the specificity of M-NBI in SNADETs was low at only 14 % because we over-diagnosed most C3 lesions as C4/5. M-NBI findings might have been compromised by the previous biopsy procedure itself. Conclusions In the non-biopsy group, the accuracy of M-NBI in SNADETs was excellent in distinguishing C4/5 lesions from C3. The M-NBI findings in SNADETs should be evaluated while carefully considering the influence of a previous biopsy.

Molecular and clinicopathological features of appendiceal mucinous neoplasms.

Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.

Comprehensive clinicopathological and molecular analysis of primary malignant melanoma of the oesophagus.

AIMS: This study was performed to elucidate the clinicopathological characteristics, genetic alterations and therapeutic targets of primary malignant melanoma of the oesophagus (PMME). METHODS AND RESULTS: The clinicopathology and molecular pathology of 13 PMME cases and 10 skin malignant melanoma (SKMM) cases were analysed with next-generation sequencing (NGS) and immunohistochemistry. The 3-year overall survival rate and the median survival time for PMME patients were 23.1% and 11.9 months, respectively. Three (23.1%) and eight (61.5%) PMME cases showed a papillary structure and lymph node metastasis, respectively. DNA and RNA hybridization capture-based NGS analysis revealed that NF1 was the most frequently mutated gene (30%) in 10 of the PMME cases. Other mutations detected in PMME included SF3B1 (20%), KRAS (10%), BRCA2 (10%), KIT (10%) and TP53 (10%) mutations. Commonly detected BRAF mutations in SKMM were not detected in PMME. Immunohistochemistry and mutation status were concordant between p53/c-Kit and TP53/KIT, respectively. Focal expression of programmed death-ligand 1 was observed in one PMME sample. The tumour mutation burden in PMME was significantly lower than that in SKMM (P = 0.030). No PMME case showed high microsatellite instability. RNA sequencing revealed a distinctive pattern with respect to RNA expression. T-cell co-stimulation differed between PMME and SKMM. CONCLUSIONS: The RAS-mitogen-activated protein kinase pathway is one of the main pathways involved in PMME. The genetic profile of PMME was similar to that of mucosal/acral melanoma, but differed from the SKMM profile. A subset of PMMEs may contain actionable mutations. Immunotherapy seemed to be less effective for most PMMEs in this series.