Integrated enhancer regulatory network by enhancer-promoter looping in gastric cancer.

Enhancer cis-regulatory elements play critical roles in gene regulation at many stages of cell growth. Enhancers in cancer cells also regulate the transcription of oncogenes. In this study, we performed a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin accessibility and expression in two gastric cancer (GC) cell lines compared to normal gastric epithelial cells. We found that GC-specific enhancers marked by histone modifications can activate a population of genes, including some oncogenes, by interacting with their proximal promoters. In addition, motif analysis of enhancer-promoter interacting enhancers showed that GC-specific transcription factors are enriched. Among them, we found that MYB is crucial for GC cell growth and activated by the enhancer with an enhancer-promoter loop and TCF7 upregulation. Clinical GC samples showed epigenetic activation of enhancers at the MYB locus and significant upregulation of TCF7 and MYB, regardless of molecular GC subtype and clinicopathological factors. Single-cell RNA sequencing of gastric mucosa with intestinal metaplasia showed high expression of TCF7 and MYB in intestinal stem cells. When we inactivated the loop-forming enhancer at the MYB locus using CRISPR interference (dCas9-KRAB), GC cell growth was significantly inhibited. In conclusion, we identified MYB as an oncogene activated by a loop-forming enhancer and contributing to GC cell growth.

Genomic Analysis of Undifferentiated Carcinoma of the Pancreas with Squamous Differentiation: A Case Report.

Pancreatic cancer is an intractable malignancy associated with a dismal prognosis. Undifferentiated carcinoma, a rare subtype, poses a clinical challenge owing to a limited understanding of its molecular characteristics. In this study, we conducted genomic analysis specifically on a case of undifferentiated carcinoma of the pancreas exhibiting squamous differentiation. An 80-year-old male, previously treated for colorectal cancer, presented with a mass with central cystic degeneration in the pancreatic tail. The mass was diagnosed pathologically as undifferentiated carcinoma of the pancreas with squamous differentiation. Despite surgical resection and chemotherapy, the patient faced early postoperative recurrence, emphasizing the aggressive nature of this malignancy. Genomic analysis of distinct histologic components revealed some common mutations between undifferentiated and squamous components, including Kirsten rat sarcoma virus (KRAS) and TP53. Notably, the squamous component harbored some specific mutations in SMARCA4 and SMARCB1 genes that code for members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. The common mutations in the undifferentiated and squamous cell carcinoma components from this analysis suggest that they originate from a common origin. The discussion also underscores the scarcity of genomic analyses on undifferentiated carcinoma of the pancreas, with existing literature pointing to SWI/SNF complex-related gene mutations. However, our case introduces chromatin remodeling factor mutations as relevant in squamous differentiation. In conclusion, this study provides valuable insights into the genomic landscape of undifferentiated pancreatic carcinoma with squamous differentiation. These findings suggest the importance of further research and targeted therapies to improve the management of undifferentiated carcinoma of the pancreas and enhance patient outcomes.

Inverse relationship between Fusobacterium nucleatum amount and tumor CD274 (PD-L1) expression in colorectal carcinoma.

Objectives: The CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence also supports an immunosuppressive effect of Fusobacterium nucleatum. We hypothesised that tumor CD274 overexpression might be inversely associated with abundance of F. nucleatum in colorectal carcinoma. Methods: We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative PCR in 812 cases among 4465 incident rectal and colon cancer cases that had occurred in two prospective cohort studies. Multivariable logistic regression analyses with inverse probability weighting were used to adjust for selection bias because of tissue data availability and potential confounders including microsatellite instability status, CpG island methylator phenotype, LINE-1 methylation level and KRAS, BRAF and PIK3CA mutations. Results: Fusobacterium nucleatum DNA was detected in tumor tissue in 109 (13%) cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue (P = 0.0077). For one category-unit increase in three ordinal F. nucleatum categories (negative vs. low vs. high), multivariable-adjusted odds ratios (with 95% confidence interval) of the low, intermediate and high CD274 categories (vs. negative) were 0.78 (0.41-1.51), 0.64 (0.32-1.28) and 0.50 (0.25-0.99), respectively (P trend = 0.032). Conclusions: Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting that different immunosuppressive mechanisms (i.e. PDCD1 immune checkpoint activation and tumor F. nucleatum enrichment) tend to be used by different tumor subgroups.

Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma.

Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.

Association of tumors having Epstein-Barr virus in surrounding lymphocytes with poor prognosis.

Infection with certain viruses is an important cause of cancer. The Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium recently analyzed the whole-genome sequencing (WGS) data from 2656 cases across 21 cancer types, and indicated that Epstein-Barr virus (EBV) is detected in many different cancer cases at a higher frequency than previously reported. However, whether EBV-positive cancer cases detected by WGS-based screening correspond to those detected by conventional histopathological techniques is still unclear. In this study, to elucidate the involvement of EBV in various cancers, we reanalyzed the WGS data of the PCAWG cohort combined with the analysis of clinical samples of gastric and pancreatic cancer in our cohort. Based on EBV copy number in each case, we classified tumors into three subgroups: EBV-High, EBV-Low, and EBV-Negative. The EBV-High subgroup was found to be EBV-positive in the cancer cells themselves, whereas the EBV-Low subgroup was EBV-positive in the surrounding lymphocytes. Further, the EBV-Low subgroup showed a significantly worse prognosis for both gastric cancer and across cancer types. In summary, we classified tumors based on EBV copy number and found a unique cancer subgroup, EBV-positive in the surrounding lymphocytes, which was associated with a poor prognosis.

Integrated environmental, lifestyle, and epigenetic risk prediction of primary gastric neoplasia using the longitudinally monitored cohorts.

BACKGROUND: DNA methylation accumulates in non-malignant gastric mucosa after exposure to pathogens. To elucidate how environmental, methylation, and lifestyle factors interplay to influence primary gastric neoplasia (GN) risk, we analyzed longitudinally monitored cohorts in Japan and Singapore. METHODS: Asymptomatic subjects who underwent a gastric mucosal biopsy on the health check-up were enrolled. We analyzed the association between clinical factors and GN development using Cox hazard models. We further conducted comprehensive methylation analysis on selected tissues, including (i) mucosae from subjects developing GN later, (ii) mucosae from subjects not developing GN later, and (iii) GN tissues and surrounding mucosae. We also use the methylation data of mucosa collected in Singapore. The association between methylation and GN risk, as well as lifestyle and methylation, were analyzed. FINDINGS: Among 4234 subjects, GN was developed in 77 subjects. GN incidence was correlated with age, drinking, smoking, and Helicobacter pylori (HP) status. Accumulation of methylation in biopsied gastric mucosae was predictive of higher future GN risk and shorter duration to GN incidence. Whereas methylation levels were associated with HP positivity, lifestyle, and morphological alterations, DNA methylation remained an independent GN risk factor through multivariable analyses. Pro-carcinogenic epigenetic alterations initiated by HP exposure were amplified by unfavorable but modifiable lifestyle choices. Adding DNA methylation to the model with clinical factors improved the predictive ability for the GN risk. INTERPRETATION: The integration of environmental, lifestyle, and epigenetic information can provide increased resolution in the stratification of primary GN risk. FUNDING: The funds are listed in Acknowledgements section.

Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein-Barr virus-positive gastric cancer.

Epstein-Barr virus (EBV) is associated with approximately 10% of gastric cancers (GCs). We previously showed that EBV infection of gastric epithelial cells induces aberrant DNA methylation in promoter regions, which causes silencing of critical tumor suppressor genes. Here, we analyzed gene expressions and active histone modifications (H3K4me3, H3K4me1, and H3K27ac) genome-widely in EBV-positive GC cell lines and in vitro EBV-infected GC cell lines to elucidate the transcription factors contributing to tumorigenesis through enhancer activation. Genes associated with "signaling of WNT in cancer" were significantly enriched in EBV-positive GC, showing increased active ß-catenin staining. Genes neighboring activated enhancers were significantly upregulated, and EHF motif was significantly enriched in these active enhancers. Higher expression of EHF in clinical EBV-positive GC compared with normal tissue and EBV-negative GC was confirmed by RNA-seq using The Cancer Genome Atlas cohort, and by immunostaining using our cohort. EHF knockdown markedly inhibited cell proliferation. Moreover, there was significant enrichment of critical cancer pathway-related genes (eg, FZD5) in the downstream of EHF. EBV protein LMP2A caused upregulation of EHF via phosphorylation of STAT3. STAT3 knockdown was shown to inhibit cellular growth of EBV-positive GC cells, and the inhibition was rescued by EHF overexpression. Our data highlighted the important role of EBV infection in gastric tumorigenesis via enhancer activation.

DNA Methylation and Genetic Aberrations in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. SUMMARY: Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows CDKN2A silencing, PIK3CA mutations, PD-L1/2 overexpression, and lack of TP53 mutations. MSI, exhibiting high DNA methylation, often has MLH1 silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows CDH1/RHOA mutations or CLDN18-ARHGAP fusion. CIN is generally an intestinal-type GC and frequently has TP53 mutations and genomic amplification of receptor tyrosine kinases. Key Messages: The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.

Relationship between time-varying status of reflux esophagitis and Helicobacter pylori and progression to long-segment Barrett's esophagus: time-dependent Cox proportional-hazards analysis.

BACKGROUND: Reflux esophagitis (RE) and absence of Helicobacter pylori (non-H. pylori) are considered to be associated with the progression to long-segment Barrett's esophagus (LSBE). However, it is difficult to assess this association because RE and H. pylori status can change during follow-up. Additionally, the association between H. pylori eradication and LSBE remains unclear. METHODS: A total of 11,493 asymptomatic Japanese subjects who underwent medical check-ups and were endoscopically diagnosed with short-segment Barrett's esophagus (SSBE) between May 2006 and December 2015 were enrolled. The hazards of progression to LSBE were compared between time-varying RE and H. pylori infection/eradication by time-dependent multivariable Cox proportional hazards models. RESULTS: A total of 7637 subjects who underwent additional medical check-ups after being diagnosed with endoscopic SSBE were analyzed. Subjects with RE and without current/past H. pylori infection were strongly associated with a higher rate of progression to LSBE (adjusted hazard ratio [HR]: 7.17, 95% confidence interval [CI]: 2.48-20.73, p < 0.001 for RE and non-H. pylori vs. non-RE and H. pylori groups). Subjects with H. pylori had a lower rate of progression to LSBE (adjusted HR: 0.48, 95% CI: 0.22-1.07, p = 0.07 for H. pylori vs. non-H. pylori). Hazards of progression to LSBE were still lower in the H. pylori eradication group than that of the non-H. pylori group (adjusted HR: 0.51, 95% CI: 0.18-1.46, p = 0.21). CONCLUSIONS: RE and non-H. pylori were associated with the progression to LSBE, considering the changes in exposures. H. pylori infection was associated with the prevention of the development of LSBE irrespective of RE. The environment preventive of the development of LSBE persists for at least a few years after H. pylori eradication.

Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma.

Epstein-Barr virus (EBV) is associated with several human malignancies including 8-10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human-viral interactions with non-integrated EBV episomes. EBV infection in vitro suffices to remodel chromatin topology and function at EBV-interacting host genomic loci, converting H3K9me3+ heterochromatin to H3K4me1+/H3K27ac+ bivalency and unleashing latent enhancers to engage and activate nearby GC-related genes (for example TGFBR2 and MZT1). Higher-order epigenotypes of EBV-positive GC thus signify a novel oncogenic paradigm whereby non-integrative viral genomes can directly alter host epigenetic landscapes ('enhancer infestation'), facilitating proto-oncogene activation and tumorigenesis.

Association Between Helicobacter pylori Infection and Short-segment/Long-segment Barrett's Esophagus in a Japanese Population: A Large Cross-Sectional Study.

GOAL: The goal of this study was to investigate the relationship between Helicobacter pylori (H. pylori) infection and short-segment and long-segment Barrett's esophagus (SSBE and LSBE). BACKGROUND: H. pylori infection is reported to be inversely associated with Barrett's esophagus (BE) in western countries. However, the impact of BE segment length on the association between BE and H. pylori infection has scarcely been investigated. MATERIALS AND METHODS: The study subjects were 41,065 asymptomatic Japanese individuals who took medical surveys between October 2010 and September 2017. Using this large database of healthy Japanese subjects, we investigated the association between H. pylori infection and SSBE/LSBE. We used multivariable logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the study subjects, 36,615 were eligible for the analysis. H. pylori seropositivity was significantly associated with a lower rate of LSBE (OR: 0.42; 95% CI: 0.16-0.91) and a higher rate of SSBE (OR: 1.66; 95% CI: 1.56-1.78) after multivariate adjustment. In the subgroup analysis, H. pylori seropositivity was significantly associated with a high rate of SSBE in subjects without reflux esophagitis (RE) (OR: 1.73; 95% CI: 1.61-1.85). However, H. pylori seropositivity was not associated with SSBE in subjects with RE (OR: 1.07; 95% CI: 0.84-1.37). CONCLUSION: In a Japanese population, H. pylori infection was inversely associated with LSBE but significantly associated with SSBE only in subjects without RE. H. pylori may be a risk factor for SSBE, especially in individuals without RE.

Association between visceral abdominal obesity and long-segment Barrett's esophagus in a Japanese population.

BACKGROUND: Visceral abdominal obesity is associated with Barrett's esophagus (BE), especially long-segment BE (≥ 3 cm) (LSBE), in white individuals. However, the association between central obesity and LSBE has not been well investigated in Asia. The aim of this study was to investigate the association between central obesity and LSBE in the Japanese population. METHODS: A total of 38,298 healthy subjects who took medical surveys between April 2006 and November 2018 were enrolled. We investigated the association between LSBE and central obesity indices [visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and the VAT to SAT ratio (VAT/SAT)] using a multivariable logistic regression model. RESULTS: A total of 37,686 subjects were eligible for the analysis. LSBE rates in the middle and high VAT/SAT groups were higher than those in the low VAT/SAT group [odds ratio (OR) 1.70, 95% confidence interval (CI) 1.07-2.69 for middle vs low; OR 2.02, 95% CI 1.17-3.49 for high vs low). These associational trends between VAT/SAT and LSBE remained in subgroups with and without reflux esophagitis. From subgroup analyses by SAT, we found that the OR between VAT and LSBE is higher in the low SAT subgroup (OR 2.43, 95% CI 1.34-4.40 for middle vs low; OR 2.55, 95% CI 1.01-6.40 for high vs low); but not large or imprecise due to limited event numbers in the middle and high SAT subgroups. CONCLUSIONS: VAT was associated with LSBE, especially among subjects with low SAT accumulation, who are seemingly not obese. VAT/SAT was associated with LSBE regardless of the presence of reflux esophagitis in a Japanese population.

Arteritis and Plexiform Lesion in Intralobar Pulmonary Sequestration: The First Case With Such Two Distinct Complex Lesions Associated With Local Pulmonary Hypertension.

In intralobar pulmonary sequestrations, vascular changes similar to those in pulmonary hypertension (PH) are generally observed, such as intimal proliferation and plexiform lesions. However, to our knowledge, a sequestrated lung manifesting vascular changes with both arteritis and a plexiform lesion has never been reported. A 25-year-old man was diagnosed with intralobar pulmonary sequestration. Pathologically, both arteritis and a plexiform lesion were observed in the sequestrated lung. Systemic vasculitis syndrome was clinically excluded, and the pathological findings appeared to be associated with local PH. Arteritis is an extremely rare finding; only one case of arteritis associated with local PH has been reported in intralobar sequestration. In this case, the artery near the plexiform lesion had milder inflammation and fibrosis, suggesting that the arteritis formed prior to the plexiform lesion. This is the first case of arteritis and a plexiform lesion co-occurring in intralobar pulmonary sequestration associated with local PH. This case may shed light on the formation of plexiform lesions and their association with arteritis.

Myocardial calcification in a patient with B-lymphoblastic leukemia accompanied by tumor lysis syndrome.

Myocardial calcification, a rare disease that leads to chronic or acute heart failure and with a poor prognosis, occurs in patients with abnormal calcium-phosphorus metabolism. The association between myocardial calcification and tumor lysis syndrome has not been reported to date. A 50-year-old man with hyperthermia and general malaise presented to our hospital and was clinically diagnosed with B-lymphoblastic leukemia (B-ALL) and febrile neutropenia accompanied by septic shock. Prednisolone was administered for tumor reduction. Two to three hours later, electrocardiography demonstrated ST elevation in V4-6, and blood tests showed elevated levels of cardiac enzymes. Transthoracic echocardiogram revealed diffuse severe hypokinesis with decreased left ventricular ejection fraction. Additionally, blood tests showed that serum phosphorus level increased to 8.0 mg/dl, which was likely due to tumor lysis syndrome. Circulatory and respiratory failure due to left heart failure progressed, and he died 3 days after administration of prednisolone. Pathological autopsy revealed diffuse proliferation of atypical B-lymphoblasts in the bone marrow, which led to the pathological diagnosis of B-ALL, accompanied by necrosis. On the cut surface of the heart, the left ventricle was dilated, and patchy yellowish-brown areas were present in the epicardial-side of the myocardium and spread through the circumferential wall of the left ventricle and interventricular septum. Microscopically, myocardial fibers were granularly basophilic in that area and were revealed as calcium deposits by Von Kossa staining. He was diagnosed with myocardial calcification. The drastic increase in the serum phosphorus level caused by tumor lysis syndrome seemed to be associated with myocardial calcification.

Aortogenic Embolic Stroke Diagnosed by a Pathological Examination of Endovascularly Removed Thrombus: An Autopsy Report.

Complex aortic atheroma is a high-risk factor for recurrent embolic stroke. An accurate identification of stroke etiology is clinically important; however, it can be challenging. A 91-year-old man with atrial fibrillation was diagnosed with cardioembolic stroke and treated with mechanical thrombectomy. The removed thrombus microscopically contained foamy cells, suggesting an atheroembolism. An autopsy revealed an atherosclerotic lesion with ulceration, located in the aortic arch. At the lesion, the plaque had microscopically ruptured into the lumen. We therefore concluded that the aortic atherosclerotic lesion was the embolic source. Removed thrombi should be pathologically examined even if a cardioembolic stroke is clinically suspected.

Intrahepatic Carcinosarcoma With Cholangiocarcinoma Elements and Prominent Bile Duct Spread.

Carcinosarcomas with elements of cholangiocarcinoma and sarcoma are rare and have a poor prognosis. The spreading pattern and radiological findings of these lesions remain unclear. A 74-year-old man presented with a high γ-glutamyl transferase level. Magnetic resonance imaging revealed dilation of the right intrahepatic and common bile ducts, consistent with an intraductal papillary neoplasm of the bile duct (IPNB), and diffusion-weighted imaging (DWI) indicated an area of high signal intensity in the intrahepatic bile duct. Bile duct biopsy yielded a small amount of atypical spindle cells, and the patient underwent a right hepatectomy. Microscopically, the tumor contained cholangiocarcinoma and sarcomatous components, including osteosarcoma and leiomyosarcoma, leading to a diagnosis of intrahepatic carcinosarcoma. The tumor spread primarily through the intrahepatic bile duct. An accurate radiological diagnosis of carcinosarcoma was challenging, given the apparent similarities with IPNB. The findings from DWI and pathology of a bile duct biopsy may assist with preoperative diagnosis.

Cerebral amyloid-ß-related angiitis without cerebral microbleeds in a patient with subarachnoid hemorrhage.

Amyloid-ß-related angiitis (ABRA), a subtype of cerebral amyloid angiopathy (CAA), is vasculitis occurring in relation to amyloid-ß (Aß) deposition in the walls of intracranial blood vessels. ABRA is presumed to be caused by some immune response to the deposited Aß. An 81-year-old man on oral anticoagulant therapy complained of headache, nausea, and difficulty with standing after a head injury. Head computed tomography revealed subcortical bleeding in the right temporoparietal lobe, and 3 days after admission, magnetic resonance imaging (MRI) showed subarachnoid hemorrhage (SAH) around the hematoma. Cerebral microbleeds, a characteristic of CAA, were not detected on MRI. On worsening of his symptoms, intracranial brain biopsy and hematoma removal were performed. Intraoperative rapid diagnosis with a frozen section suspected vasculitis, which enabled the prompt initiation of steroid therapy. He was pathologically diagnosed with ABRA (granulomatous angiitis) using a formalin-fixed paraffin-embedded section. Vasculitis was prominent around blood vessels in the pia matter covering the cerebrum. In this case, the inflammatory cells seemed to appear via the subarachnoid space following cerebral hemorrhage and SAH. ABRA seemed to be developed by intracranial hemorrhage in this case.

Cerebral Thromboembolism after Lobectomy for Lung Cancer: Pathological Diagnosis and Mechanism of Thrombus Formation.

Lung cancer is the leading cause of cancer-related deaths worldwide. Although molecular therapies have emerged as efficacious strategies for the treatment of lung cancer, surgical resection is still recommended as a radical therapeutic option. Currently, lobectomy is regarded as the most reliable radical treatment of primary lung cancer. Among the various complications after lobectomy, cerebral thromboembolism requires attention as a life-threatening complication during the early postoperative period. It occurs in 0.2⁻1.2% of surgical cases of lung cancer and typically develops following left upper lobectomy with a long pulmonary vein stump (PVS). PVS-associated thrombosis is known to cause cerebral thromboembolism after such procedures; however, distinguishing this specific complication from that caused by postoperative atrial fibrillation is challenging. We summarize herein the diagnostic pathology of thrombus formation in accordance with its thrombogenic mechanism. We focus on the potential utility of the pathological assessment of thrombectomy specimens. The morphological information obtained from these specimens enables the presumption of thrombogenic etiology and provides useful clues to both select an appropriate pharmacotherapy and determine a follow-up treatment for cerebral thromboembolism.

Enterocolic lymphocytic phlebitis with marked myointimal hyperplasia and perivenous concentric fibrosis.

Enterocolic lymphocytic phlebitis (ELP) is a rare enteropathy characterized by lymphocytic phlebitis of the mesenteric veins without arteritis. Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare disease similar to ELP, characterized by myointimal hyperplasia that constricts the lumen of veins, causing mucosal injury. A 62-year-old man with chief complaint of abdominal pain was treated by partial resection of the ileum after 3 months of conservative therapy. The pathologic diagnosis was ELP with prominent myointimal hyperplasia. Histologically, the lesion consisted of lymphocytic infiltration into the vein accompanied by prominent myointimal hyperplasia and perivenous concentric fibrosis, which are characteristics shared by ELP and IMHMV. The observations in this case suggest that some of ELP and IMHMV may belong to the same disease spectrum. Furthermore, perivascular concentric fibrosis was a remarkable observation that may contribute to differential diagnosis between ELP and "true" IMHMV.

Colon Metastasis From Microscopic Serous Carcinoma of the Fallopian Tube Fimbria Mimicking a Primary Colon Cancer.

Metastatic diseases rarely develop in the colorectum, and diagnosing colorectal metastasis by biopsy without history of a malignant tumor or clinical information of a primary tumor is challenging. A 65-year-old woman with a 6-month history of constipation and diarrhea was admitted to our hospital and diagnosed with rectosigmoid colonic micropapillary carcinoma. Low anterior resection was performed after neoadjuvant chemotherapy. Because the lipoleiomyoma in the uterus obstructed the operator's vision, total hysterectomy and bilateral salpingo-oophorectomy were performed. Examination of the colon and adnexa, together with immunohistochemical studies, revealed that the colonic tumor was actually serous carcinoma that had metastasized from the left fimbria of the fallopian tube. Retrospective immunohistochemical examination of the colon biopsy specimen suggested carcinoma with a Müllerian immunophenotype. When a colon biopsy reveals carcinoma with an invasive micropapillary pattern without a component of conventional tubular adenocarcinoma, immunohistochemical examination should be performed to rule out the possibility of metastasis.