Co-occurrence of Epstein-Barr virus-positive nodal T/NK-cell lymphoma and nodal T-follicular helper cell lymphoma of different clonal origins: An autopsy case report.

Nodal T-follicular helper cell lymphoma (TFHL) is a subset of T-cell lymphoma and frequently co-occurs with Epstein-Barr virus (EBV)-positive B-cell lymphoma but not with T/NK-cell lymphoma. Recently, a new entity with a worse prognosis, called EBV-positive nodal T/NK-cell lymphoma (NTNKL) has been established. Here, we report an autopsy case of synchronous multiple lymphomas, including TFHL and NTNKL. The patient was a 78-year-old female admitted with pneumonia. Although pneumonic symptoms were improved, fever, pancytopenia, and disseminated intravascular coagulation emerged, implicating lymphoma. She died on the 21st hospital day without a definitive diagnosis. The autopsy revealed the enlargement of multiple lymph nodes throughout her body. Histological analysis revealed three distinct regions in the left inguinal lymph node. The first region consists of small-sized lymphocytes with T-follicular helper phenotype and extended follicular dendritic cell meshwork, indicating TFHL. The second region included EBV-positive large B cells. The third region comprised EBV-positive large cells with cytotoxic T/NK cell phenotype, indicating NTNKL. Clonality analysis of the first and the third regions showed different patterns. Since various hematopoietic malignancies progress from common clonal hematopoiesis according to existing literature, this case may help to understand TFHL and NTNKL.

Enterocolic granulomatous phlebitis associated with epidermal growth factor-containing fibulin-like extracellular matrix protein 1 deposition and focal amyloid properties: A case report.

A woman in her 60s with rheumatoid arthritis was admitted with fever and abdominal pain. Laparoscopic examination with the differential diagnosis of peritoneal neoplasm and infection revealed granulomatous phlebitis in the resected greater omentum. Amorphous eosinophilic deposits observed in the resected tissue exhibited focal, weak positivity for Congo red but were strongly positive for thioflavin S, confirming their focal amyloid properties. Marked degeneration of elastic fibers was also evident. Electron microscopy revealed deposits around the affected elastic fibers. Immunohistochemistry revealed the deposition of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) along with T-cell-predominant lymphocytic inflammation. The definitive diagnosis was granulomatous enterocolic lymphocytic phlebitis (ELP) associated with EFEMP1 deposition exhibiting focal amyloid properties (EFEMP1/AEFEMP1), supported by proteomics analysis. This type of vasculitis is similar to amyloid-ß-related angiitis of the central nervous system. Thus, we speculate that granulomatous ELP also results from an immune response that recognizes EFEMP1/AEFEMP1 deposits as foreign material and attempts to remove them. Confirmation of EFEMP1/AEFEMP1 deposition with Congo red staining is challenging, particularly in the presence of inflammation, and warrants comprehensive evaluation.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with neurenteric cyst. An autopsy case showing unusual fatal outcome.

A 53-year-old man with a history of an untreated brain mass was taken to Toyama Prefectural Central Hospital by emergency transport. Computed tomography revealed an intracranial hypo-attenuated lesion exhibiting mass effect. Several calcified foci were observed around the lesion. His radiographical diagnosis was meningioma with calcification and edema. He suddenly showed tonic seizure after admission; therefore an emergency craniotomy was performed. However, he unfortunately died due to advanced cerebral edema. Microscopic findings of the surgically obtained materials were consistent with neurenteric cyst (NC). Intracranial hard masses were found adjacent to NCs, and the masses were composed of fibrous cartilage-like matrix with extensive linear calcification and the presence of surrounding round-to-oval epithelioid cells. Thus, calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with NC was considered the most appropriate diagnosis of the present case. To the best of our knowledge, this is the first report of such a case. The present case suggests that delay of treatment might cause a poor outcome, at least in CAPNON associated with NC. Careful investigations, including the underlying pathology, may be essential when considering the etiology of CAPNON and its treatment strategies.

Improvement of chronic GVHD after oral treatment with Clostridium butyricum (Miya BM).

We report a case with leukoplakia of the tongue as a manifestation of chronic graft versus host disease after allogeneic stem cell transplantation for acute promyelocytic leukemia treated with Clostridium butyricum tablets. His leukoplakia subsequently disappeared and his regulatory T cells increased after three months.

Tracheobronchitis in patients with diffuse wall thickening: Three case reports.

We herein report the cases of three patients with chest symptoms or fever and diffuse wall thickening of the trachea and main bronchi on chest CT. They were diagnosed with various causes of inflammations of the trachea and main bronchi using bronchial or tracheal biopsy specimens and flexible bronchoscopy.

Rare MYH9-ROS1 Fusion Gene-Positive Lung Adenocarcinoma Showing Response to Entrectinib Treatment: A Case Study.

The c-ros oncogene 1 (ROS1) fusion gene is a rare genomic alteration detected in nearly 1-2% of lung adenocarcinomas. The major partner genes of ROS1 include CD74, SDC4, and EZR. Here, we report a case of MYH9-ROS1 fusion gene-positive lung adenocarcinoma, a rare ROS1 fusion gene. The patient was a woman in her 40s who was diagnosed with advanced primary lung adenocarcinoma after a thorough examination. Initial genetic testing conducted using mediastinal lymph node biopsy specimens collected by endobronchial ultrasound-guided transbronchial needle aspiration revealed no driver gene mutations, including the ROS1 fusion gene. The patient was treated with four courses of immunochemotherapy. As the disease worsened, another genetic test was conducted using FoundationOne® CDx, and the MYH9-ROS1 fusion gene was detected. Multiple lung metastases disappeared after the administration of entrectinib; the response persisted up to a year. Adverse events of rash, dysgeusia, and peripheral edema were observed, and the patient required temporary drug interruption; however, we were able to continue entrectinib following a short-term drug interruption. This is the first report on the effectiveness of entrectinib against lung adenocarcinoma with the rare MYH9-ROS1 fusion gene.

Imaging findings of a case of intravascular large B-cell lymphoma with cardiac involvement.

Intravascular large B-cell lymphoma (IVLBCL) is a very rare subtype of malignant lymphoma that is difficult to diagnose. Cases of myocardial infarction caused by IVLBCL are even rarer. Herein, we report a case presenting with heart failure and delayed enhancement in the hypokinetic cardiac septum on contrast-enhanced cardiac magnetic resonance imaging. Myocardial biopsy showed large B-cell lymphoma cells in the microvessels within the myocardium. To the best of our knowledge, this is the first report of imaging findings of cardiac involvement in IVLBCL.

Nasal spindle cell tumor with rhabdomyoblastic features: A rare and diagnostically difficult case.

Nasal spindle cell rhabdomyosarcoma is very rare. The tumor is sometimes confused with other spindle cell tumors. We herein report a case of nasal spindle cell tumor in a 62-year-old woman. The patient first presented herself to a medical doctor's office after an episode of left epistaxis. An intranasal tumor was found and resected. The tumor was composed of spindle cells, and she was diagnosed with desmoid-type fibromatosis. Five years after the initial episode, an intranasal tumor was found again. The tumor showed a fascicular growth pattern with high cellularity and was predominantly composed of spindle cells. Scattered eosinophilic rhabdomyoblasts were also observed. She was diagnosed with spindle cell rhabdomyosarcoma. This is a unique case report not only because nasal spindle cell rhabdomyosarcoma is very rare but also because the tumor was initially diagnosed as desmoid-type fibromatosis. It is important to consider spindle cell rhabdomyosarcoma as a differential diagnosis of nasal spindle cell tumors.

Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL.

In current molecular medicine, next-generation sequencing (NGS) for transcript variant detection and multivariable analyses are valid methods for evaluating gene expression, cancer mechanisms, and prognoses of patients. We conducted RNA-sequencing on samples from patients with primary central nervous system lymphoma (PCNSL) using NGS and performed multivariable analysis on gene expression data and correlations focused on Th-1/Th-2 helper T cell balance and immune checkpoint to identify diagnosis/prognosis markers and cancer immune pathways in PCNSL. We selected 84 transcript variants to limit the analysis range for Th-1/Th-2 balance and stimulatory and inhibitory checkpoints in 31 PCNSLs. Of these, 21 highly-expressed transcript variants were composed of the formulas for prognoses based on Th-1/Th-2 status and checkpoint activities. Using formulas, Th-1low, Th-2high, and stimulatory checkpointhigh resulted in poor prognoses. Further, Th-1highTh-2low was associated with good prognoses. On the other hand, CD40-001high and CD70-001high as stimulatory genes, and LAG3-001high, PDCD1 (PD-1)-001/002/003high, and PDCD1LG2 (PD-L2)-201low as inhibitory genes were associated with poor prognoses. Interestingly, Th-1highTh-2low and Th-1lowTh-2high were correlated with stimulatory checkpointlow as CD70-001low and inhibitory checkpointlow as HAVCR2 (TIM-3)-001low and PDCD1LG2-001/201low, respectively. Focused on the inhibitory checkpoint, specific variants of CD274 (PD-L1)-001 and PDCD1-002 served severe hazard ratios. In particular, PDCD1-002high by a cut off score was associated with poor prognoses, in addition to PDCD1-001/003high, PDCD1LG2-201low, and LAG3-001high. These results mainly suggest that expression of transcript variants of PDCD1 and PDCD1LG2 on the Th-1/Th-2 balance enable prognostic prediction in PCNSL. This study provides insights for development of molecular target therapies and identification of diagnosis/prognosis markers in PCNSL.

Chest tightness is relieved with the use of asthma drugs except bronchodilators.

Objective: Many patients with a chief complaint of chest tightness are examined in medical facilities, and a lack of diagnosis is not uncommon. We have reported that these patients often include those with chest tightness relieved with bronchodilator use (CTRB) and those with chest tightness relieved with the use of asthma drugs except bronchodilators (CTRAEB). The purpose of this study was to demonstrate the clinical characteristics of the patients with CTRAEB and compare them with data from patients with CTRB. Methods: Patients with CTRB (n = 13) and CTRAEB (n = 7) underwent a bronchodilator test, assessments of airway responsiveness to methacholine, bronchial biopsy, and bronchial lavage under fiberoptic bronchoscopy before receiving treatment. In all, 10 healthy subjects, 11 bronchial biopsy control patients, and 10 asthmatic patients were recruited for comparison. Results: Inhalation of a short-acting ß2-agonist (SABA) increased the forced expiratory volume in one second (FEV1) by 5.1% ± 4.0% in patients with CTRB and by 1.3% ± 3.5% in patients with CTRAEB, and the difference was statistically significant (p = 0.0449). The bronchial biopsy specimens from the patients with CTRB and CTRAEB exhibited significant increases in T cells (p < .05) compared with those of the control subjects. The bronchial responsiveness to methacholine was increased in only a minor portion of patients with CTRB and CTRAEB. Conclusions: We hypothesized that the clinical condition of patients with CTRAEB involves chest tightness arising from inflammation alone, and this chest tightness is mostly associated with airway T cells, without constriction of the airways. There is little to distinguish CTRAEB from CTRB aside from the response to bronchodilator treatment. This clinical trial is registered at www.umin.ac.jp (UMIN13994, 13998, and 16741).

Fetal closed head injuries following maternal motor vehicle accident: A clinicopathologic case report.

RATIONALE: The clinicopathologic appearance of fetal closed head injury (FCHI) due to a maternal motor vehicle accident has not been fully investigated because of its extreme rarity. PATIENTS CONCERN: A 22-year-old woman at 31 weeks of gestation was riding in the front passenger seat of a car, and another rightward-turning car struck the right side of her vehicle. DIAGNOSIS: Uterine injury with placental abruption was strongly suspected. INTERVENTION: A live female infant in breech presentation was delivered by emergency caesarean section. OUTCOMES: Although the female infant was and showed no evidence of trauma on her body surface. She exhibited a convulsion on the day of birth, and subsequent ultrasonography revealed possible intracranial hemorrhage. Although laboratory parameters associated with circulatory and respiratory function suggested a good response to the intensive care administered during the treatment course, the infant died 6 days later despite intensive care. Autopsy showed severe brain softening, subarachnoid hemorrhage with cerebral and cerebellar contusion, and bilateral thalamic hemorrhage. No hypoxic/ischemic changes of the thoracoabdominal organs were evident at autopsy. LESSONS: This was a clear case of FCHI by both shear and tensile forces. Multiple factors including the structural vulnerability of the fetal brain, the head posture of the fetus, the crash location and direction of force on the vehicle, and the employment of safety equipment may have contributed to the occurrence of FCHI in the present case.

Sudden unexpected death with primary adrenal lymphoma.

An 82-year-old man was found dead on the road near his home with unwitnessed interval of 3 h from final witness. He had been diagnosed with hypertension and mild aortic stenosis (AS) 13 years before death, and was continuously followed up with medication. Although a recent medical check-up related to cardiac function was stable and consistent with moderate AS, he sometimes complained of general fatigue, anorexia associated with intermittent mild fever and rare vomiting in the weeks before death. At autopsy, no lethal injury or drug intoxication was found, but congenital bicuspid aortic valve (BAV) with central rache was found. Although calcification was found in a restricted area of one cusp, valvular structural deformity was clearly milder than in typical severe AS cases. Moderate left ventricular hypertrophy without coronary disease was found. A brownish-red, soft nodular lesion was found in both adrenal glands, but no other tumorous focus was evident in any other organs. Immunohistochemical examination showed that B-lymphocyte-derived markers (CD20, melanoma associated antigen (mutated) 1, and CD79a) were exclusively positive. Therefore, we diagnosed primary adrenal lymphoma (PAL), diffuse large B-cell lymphoma phenotype. We concluded that the cause of sudden unexpected death (SUD) was adrenal insufficiency associated with PAL, with a background of moderate AS related to BAV.

Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma.

Exome-sequencing for somatic mutation detection and copy number variation analysis are effective and valid methods for evaluating human cancers in current molecular medicine. We conducted target amplicon exome-sequencing analyses using PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Twenty-seven primary central nervous system lymphoma (PCNSL) specimens and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverages of the entire coding regions of 409 cancer-related genes. The average of the total numbers of somatic mutations including single-nucleotide variations and insertion/deletion mutations in each specimen was 13.3. Of these, the average of the ratios of nonsynonymous substitutions in each specimen was 74.8%. The most frequent mutations in 27 specimens were in PIM1, MYD88, CD79B, DST, IRF4, ERBB3, MYH11, DCC, and KMT2D. Furthermore, somatic mutations of MYH11 were related to poor prognoses in PCNSL patients. Copy number variations were also duplicated and/or deleted from deep-sequencing in segmental genomic islands. In addition to these prognostic marker candidates, analysis of RTK-RAS-MAPK signaling and the PTEN-PI3K-AKT proapoptotic pathway showed that somatic activations and aberrations, respectively, may be involved in a promising central oncopathway harboring mTOR, c-Myc, FOXO1, and p53. This study provides a foundation for molecular targeted therapies based on genome diagnostics and prognosis in PCNSL.

Characteristic Distribution Pattern of CD30-positive Cytotoxic T Cells Aids Diagnosis of Kikuchi-Fujimoto Disease.

INTRODUCTION: Histiocytic necrotizing lymphadenitis (or Kikuchi-Fujimoto disease) frequently occurs in Asian young adult females and typically presents as cervical lymphadenopathy with unknown etiology. Although large immunoblasts frequently appear in Kikuchi-Fujimoto disease, the diffuse infiltration of these cells can cause difficulty in establishing a differential diagnosis from lymphoma. In such cases, CD30 immunostaining may be used; however, the extent or distribution pattern of CD30-positive cells in Kikuchi-Fujimoto disease remains largely unknown. Here we investigated the expression of CD30 and its clinicopathologic significance. MATERIALS AND METHODS: We investigated 30 Kikuchi-Fujimoto disease and 16 control [6, systemic lupus erythematosus (SLE); 10, reactive lymphoid hyperplasia (RLH)] cases. RESULTS: The number of CD30-positive cells in Kikuchi-Fujimoto disease was significantly more than that in SLE and RLH, and majority of these cells were located around necrotic areas. Moreover, double immunohistochemical staining showed these CD30-positive cells to be CD8-positive cytotoxic T cells, suggesting that activated cytotoxic T cells around necrotic areas are a characteristic feature of this disease. Clinicopathologic analysis showed that cases with abundant CD30-positive cells were predominantly female with only mild symptoms and normal laboratory data. CONCLUSIONS: In Kikuchi-Fujimoto disease cases, CD30-positive cytotoxic T cells were abundant around necrotic areas; this histologic feature may be helpful to differentiate this disease from SLE and RLH.

Programmed Cell Death Ligand 1 Expression in Primary Central Nervous System Lymphomas: A Clinicopathological Study.

BACKGROUND/AIM: Programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) have been shown to predict response to PD-L1/PD-1-targeted therapy. We analyzed PD-L1 expression in primary central nervous system lymphomas (PCNSLs). MATERIALS AND METHODS: PD-L1 protein and mRNA expression were evaluated in 64 PCNSL tissue samples. IFN-γ, IL-10, CD4, and CD8 mRNA expression was also evaluated. RESULTS: PD-L1 protein was detected in tumor cells in 2 (4.1%) cases and in tumor microenvironments in 25 (52%) cases. PD-L1 mRNA positively correlated with IFN-γ (p=0.0024) and CD4 (p=0.0005) mRNA expression. IFN-γ mRNA positively correlated with CD8 mRNA expression (p=0.0001). Furthermore, tumor cell PD-L1 expression correlated positively with overall survival (p=0.0177), whereas microenvironmental PD-L1 expression exhibited an insignificant negative trend with overall survival (p=0.188). CONCLUSION: PD-L1 was expressed on both tumor and/or tumor-infiltrating immune cells in PCNSL. The biological roles of this marker warrant further investigation.

Bronchial biopsy and reactivity in patients with chest tightness relieved with bronchodilator.

OBJECTIVE: It has been hypothesized that some patients with chest tightness of unknown origin can be successfully treated with a bronchodilator and that they should be diagnosed with chest pain variant asthma. We conducted a prospective study to characterize newly diagnosed patients with chest tightness relieved with bronchodilator use and without characteristic bronchial asthma attacks. METHODS: Eleven patients were registered following recurrent positive responses of chest tightness to inhalation of a ß2-agonist. These patients underwent assessments of airway responsiveness to methacholine, bronchial biopsy and bronchial lavage under fiber-optic bronchoscopy before receiving treatment. RESULTS: For the patients with chest tightness relieved with bronchodilator use, the bronchial biopsy specimens exhibited significant increases in lymphocyte and macrophage infiltration (p < 0.05) and no significant increase in eosinophils (p = 0.2918) compared with the control subjects. The bronchial responsiveness to methacholine was increased in two of the patients with chest tightness, and it was not increased in seven; in addition, increased percentages of eosinophils were detected in bronchial lavage fluid (5% or more) from two patients, but no increase was detected in eight patients. CONCLUSIONS: We suspect that the chest tightness was induced by airway constriction in these patients, but further study is necessary to validate this hypothesis. We propose that the chest tightness relieved with bronchodilator use was attributed to airway constriction resulting from inflammation with lymphocytes and macrophages and/or that the chest tightness was directly attributed to airway inflammation. This clinical trial is registered at www.umin.ac.jp (UMIN13994 and UMIN 16741).

Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia.

Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas-Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4-repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDP Type B. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD.

An autopsy case of pneumococcal Waterhouse-Friderichsen syndrome with possible functional asplenia/hyposplenia.

We report an autopsy case of rapid progressive Waterhouse-Friderichsen syndrome (WFS) associated with Streptococcus pneumonia infection in a previously healthy man. Although he once visited a hospital about 6 hours before death, the both physical and serological examination did not show any sign of overwhelming infection. Autopsy showed massive adrenal hemorrhage without inflammation, and showed proliferation of gram positive cocci and microthrombosis in the vessels of many organs. The pathological change of respiratory tract was extremely minimal. Size and weight of the spleen possible decreased than normal. However, histological examination showed that obscuration of germinal center and decreasing the immunological cells of mantle and marginal zone. Immunohisitochemically, marked decreasing the marginal zone macrophages, which are positive for specific intercellular adhesion molecule grabbing nonintegrin receptor-1 (SIGN-R1) and macrophage receptor with collagenous structure (MARCO), were decreased comparing with age-matched control case. Polymerase chain reaction (PCR) assay using each DNA, extraction from formalin-fixed paraffin-embedded specimen (FFPE) samples of lung, adrenal gland, heart, spleen, and kidney showed positive the ply gene and the lytA gene specific for Streptococcus pneumonia. Present case showed possible acquired atrophy of spleen, especially decreasing marginal zone macrophage may correlate with rapid progression of sepsis of Streptococcus pneumonia with massive adrenal hemorrhage. In addition, present case showed the usefulness of PCR using FFPE for the postmortem diagnosis of WFS.

Family with MSH2 mutation presenting with keratoacanthoma and precancerous skin lesions.

Muir-Torre syndrome (MTS) is a familial cancer syndrome characterized by a predisposition to keratoacanthoma (KA) and sebaceous tumors. Although MTS and hereditary non-polyposis colorectal cancer (HNPCC) share the same genetic alterations in mismatch repair (MMR) genes, the other skin lesions in MTS or HNPCC have been only rarely reported. We report a family with an MSH2 mutation c.1126_1127delTT (p.Leu376Thrfs*12). A 46-year-old male proband developed KA with sebaceous differentiation, colon cancer and gastric cancer, and fulfilled the diagnostic criteria for MTS. His 80-year-old mother, diagnosed with HNPCC, presented with multiple gastrointestinal tract cancers, Bowen's disease and actinic keratosis. Immunostaining revealed attenuated MSH2 protein expression in KA, as well as in Bowen's disease and actinic keratosis lesions. These findings suggest that MMR gene abnormality is also critical in the development of benign or malignant cutaneous tumors such as actinic keratosis and Bowen's disease in MTS/HNPCC patients.