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Next-generation sequencing of oral squamous cell carcinoma (OSCC) has revealed TP53 as the most frequently mutated gene in OSCC mutually exclusive with human papillomavirus infection. Oral epithelial dysplasia (OED) is defined as a precancerous lesion of OSCC by the current World Health Organization (WHO) classification; therefore, it is assumed that TP53 mutations occur in early precancerous conditions such as OED. Here, we conducted an integrated analysis of TP53, including whole coding sequencing of TP53, FISH analysis of the 17p13.1 locus, and immunohistochemical analysis for p53 (p53-IHC), in 40 OED cases. We detected 20 mutations in 16 (40%) OED cases, and four cases, each harbored two mutations. FISH analysis revealed six of 24 cases (25%) had a deletion on 17p13.1, and four cases had concurrent TP53 mutations and 17p13.1 deletion (2-hit). Also, the increased frequency of TP53 mutations in higher degrees of OED implies acquisition of the mutation is a major event toward OSCC. p53-IHC revealed that overall cases could be categorized into four patterns that correlate well with the mutational status of TP53. Especially, two patterns, broad p53 expression type (pattern HI) and p53 null type (pattern LS), strongly correlated with a missense mutation and nonsense mutation, respectively. Furthermore, seven of the 40 cases progressed to SCC, and six of these seven cases presented pattern HI or LS. Therefore, patterns HI and LS have a high risk for malignant transformation if excisional treatment is not performed irrespective of the dysplasia grade. Although the current WHO classification mainly focuses on morphological criteria for the diagnosis of OED, interobserver discrepancy appears in some instances of the OED diagnosis. Our immunohistochemical analysis supports a more accurate pathological diagnosis for OED in cases of low dysplastic changes or of differential diagnosis with non-dysplastic lesions.

The current World Health Organization (WHO) classification defines a new disease entity of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, making fluorescence in situ hybridization (FISH) screening for these genes mandatory. In addition, the prognostic significance of MYC expression was reported, with a cut-off value of 40%. However, interobserver discrepancies arise due to the heterogeneous intensity of MYC expression by immunohistochemistry. Moreover, a cut-off value of positivity for MYC protein in diffuse large B-cell lymphoma (DLBCL) varies among studies at present. Here, we applied a high-sensitivity semiquantitative immunohistochemical technique using fluorescent nanoparticles called phosphor-integrated dots (PID) to evaluate the MYC expression in 50 de novo DLBCL cases, and compared it with the conventional diaminobenzidine (DAB)-developing system. The high MYC expression detected by the PID-mediated system predicted poor overall survival in DLBCL patients. However, we found no prognostic value of MYC protein expression for any cut-off value by the DAB-developing system, even if the intensity was considered. These results indicate that the precise evaluation of MYC protein expression can clarify the prognostic values in DLBCL, irrespective of MYC rearrangement.

Background The prevalence and molecular characteristics of deficient mismatch repair prostate cancer in the Japanese population have scarcely been investigated. Methods Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary prostate cancers in patients who underwent prostatectomy at our institution between January 2001 and May 2016. Genetic and/or epigenetic alterations of mismatch repair genes were investigated in patients with any loss of mismatch repair protein expression in the tumour. Results Of the 337 patients, four (1.2%) showed loss of mismatch repair protein expression on immunohistochemistry. All four patients showed loss of both MSH2 and MSH6 protein expression. Genetic testing was performed in two of the four patients, demonstrating no pathogenic germline alterations were present. In each of these two patients, at least one somatic alteration inactivating MSH2 without MSH2 hypermethylation was identified, leading to the diagnosis of supposed ‘Lynch-like syndrome’. Patients with deficient mismatch repair prostate cancer were at a significantly higher stage (pT2pN0 vs. pT3-4pN0/pTanypN1, P = 0.02) and had a greater Gleason score ( Conclusions The prevalence of deficient mismatch repair prostate cancer in the Japanese hospital-based prostatectomized population was extremely low. To improve screening efficacy for deficient mismatch repair prostate cancer, screening candidates can be limited to patients with locally advanced, node-positive and/or Gleason score of 8 or greater prostate cancer. Universal tumour screening for Lynch syndrome seems ineffective in patients with prostate cancer.

Duodenal cancer is a leading cause of death after colectomy in patients with familial adenomatous polyposis (FAP). Detailed endoscopic evaluation of duodenal lesions with potential for carcinoma development is therefore mandatory. Here we investigated the features of duodenal lesions in FAP patients using an endocytoscopy system (ECS). We retrospectively reviewed duodenal lesions in 15 cases of FAP using an ECS (GIF-H290EC) with methylene blue (MB) as the vital dye. With reference to the Spigelman classification, we investigated the number of lesions using white light (WL), narrow-band imaging (NBI), and MB staining. Using the maximum magnification power of the ECS we investigated the histology (duct openings or finger-like projections) and grade of dysplasia (presence or absence of enlarged oval-shaped nuclei) of the lesions. The number of duodenal lesions increased in ascending order of WL, NBI, and MB (P

MYC-associated factor X (MAX) is a protein in the basic helix-loop-helix leucine zipper family, which is ubiquitously and constitutively expressed in various normal tissues and tumors. MAX protein mediates various cellular functions such as proliferation, differentiation, and apoptosis through the MYC-MAX protein complex. Recently, it has been reported that MYC regulates the proliferation of anaplastic large cell lymphoma. However, the expression and function of MAX in anaplastic large cell lymphoma remain to be elucidated. We herein investigated MAX expression in anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and found 11 of 37 patients (30%) with ALCL lacked MAX expression, whereas 15 of 15 patients (100%) with PTCL-NOS expressed MAX protein. ALCL patients lacking MAX expression had a significantly inferior prognosis compared with patients having MAX expression. Moreover, patients without MAX expression significantly had histological non-common variants, which were mainly detected in aggressive ALCL cases. Immunohistochemical analysis showed that MAX expression was related to the expression of MYC and cytotoxic molecules. These findings demonstrate that lack of MAX expression is a potential poor prognostic biomarker in ALCL and a candidate marker for differential diagnosis of ALCL and PTCL-NOS.

Regressive lymphoproliferative disorders (R-LPD) after methotrexate (MTX) withdrawal are one of the specific features of methotrexate - associated lymphoproliferative disorders (MTX-LPD). Although the impact of the absolute lymphocyte count (ALC) on the pathogenesis of R-LPD has been recently emphasized, understanding relapse/regrowth events (RRE) and differences among LPD subtypes is necessary. In this study, we confirmed ALC recovery in the regressive group (R-G; R-LPD without RRE) and relapse/regrowth group (R/R-G; R-LPD with RRE). The increase in ALC lasted at least 2 years in R-G, whereas it decreased within 3 years in R/R-G, supporting the better overall survival (OS) in R-G, as previously reported. In addition, our study suggested that an ALC of 1000/µL at the time of development of LPD is a significant predictor for treatment-free survival (TFS). Furthermore, an ALC of 1000/µL at 6 months after MTX withdrawal was found to be a significant indicator of TFS and OS for R-G and R/R-G. The ALC decreased gradually before LPD development in R/R-G, whereas it decreased 6 months before LPD development in R-G, confirming the important role of ALC in the pathogenesis of MTX-LPD such as regressive events and RRE. In addition to ALC, other predictive factors, such as serum C-reactive protein and soluble interleukin-2 receptors, may be helpful in the management of MTX-LPD, including the decision making for an additional chemotherapy for regressive LPD after MTX withdrawal.

Background Chronic spinal epidural hematomas (SEHs) are rare clinical entities. SEH with vertebral scalloping is extremely rare, with only a few cases having been reported to date. We report a unique case of spontaneous chronic SEH in the lumbar spine with severe vertebral scalloping mimicking an epidural tumor. Case presentation A 71-year-old man presented with a 2-month history of lumbar pain and a 3-week history of paresthesia and pain in the right lower extremity, hypesthesia in the perineal and perianal regions, and bladder dysfunction. Computed tomography following myelography revealed an epidural mass lesion on the right side that compressed the dural sac and was associated with severe bony scalloping on the posterior wall of the L4 vertebral body. Magnetic resonance imaging (MRI) on T1- and T2-weighted images revealed a space-occupying lesion with heterogeneous intensity, and T1-gadolinium images showed an intralesional heterogeneous enhancement effect. A tumoral lesion in the spinal canal was suspected, based on preoperative imaging; therefore, a total spinal tumor resection was planned. Intraoperative findings revealed that the brownish lesion adhered to the dura and epidural tissues in the spinal canal, and the space-occupying mass in the scalloped cavity of the posterior wall of the L4 vertebra was encapsulated in red-brownish soft tissues. The lesion was totally resected in a piecemeal fashion, and pathological examination revealed a mixture of tissues that contained a relatively new hematoma with hemoglobin, as well as an obsolete hematoma with hemosiderin and amyloid deposits. The mass was diagnosed as a chronic epidural hematoma with recurrent hemorrhage. The postoperative course was uneventful, and the preoperative neurological symptoms immediately improved. Conclusions The preoperative diagnosis of chronic SEHs is challenging, as MRI results may not be conclusive, particularly in patients with scalloping of bony structures. Thus, chronic SEHs should be considered as a differential diagnosis in cases of suspected tumoral lesions in the spinal canal. To the best of our knowledge, this is the first reported case of acute exacerbation of chronic SEH with cauda equina syndrome and severe vertebral scalloping.

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoma characterized by the selective growth of lymphoma cells within the lumen of vessels. We describe the case of a 69-year-old male who presented with marked pain in the left facial region. Gadolinium-enhanced magnetic resonance imaging revealed a swollen left trigeminal nerve (TN) and positron emission tomography/computed tomography demonstrated fluorodeoxyglucose-only uptake at the same site. The patient had high serum lactate dehydrogenase and soluble interleukin-2 receptor levels. As random skin biopsy and bone marrow biopsy detected no abnormal pathogenesis, open biopsy of the TN was performed, revealing diffuse large B-cell lymphoma (DLBCL). However, ground glass opacities rapidly developed in both lung fields with severe respiratory failure. The patient died of progressive disease before the initiation of chemotherapy. Postmortem examination revealed widespread lymphoma cells in the lumen of vessels in multiple organs, including the lungs, excluding the bone marrow and skin. Lymphoma cells formed a mass in the TN and left lumbar plexus. A diagnosis of IVLBCL was made based on the postmortem pathological analysis. DLBCL of abnormal sites, such as the peripheral nervous system, should be considered in cases of IVLBCL as a differential diagnosis.

The tumor microenvironment (TME) is a critical regulator of the development of malignant lymphoma. Therapeutics targeting the TME, especially immune checkpoint molecules, are changing the treatment strategy for lymphoma. However, the overall response to these therapeutics for diffuse large B-cell lymphoma (DLBCL) is modest and new targets of immunotherapy are needed. To find critical immune checkpoint molecules for DLBCL, we explored the prognostic impact of immune checkpoint molecules and their ligands using publicly available datasets of gene expression profiles. In silico analysis of three independent datasets (GSE117556, GSE10846, and GSE181063) revealed that DLBCL expressing CD24 had a poor prognosis and had a high frequency of MYC aberrations. Moreover, gene set enrichment analysis showed that the 'MYC-targets-hallmark' (false discovery rate [FDR] = 0.024) and 'inflammatory-response-hallmark' (FDR = 0.001) were enriched in CD24-high and CD24-low DLBCL, respectively. In addition, the expression of cell-specific markers of various immune cells was higher in CD24-low DLBCL than in CD24-high DLBCL. CIBERSORT analysis of the datasets showed fewer macrophages in CD24-high DLBCL than in CD24-low DLBCL. Additionally, immunohistochemical analysis of 335 cases of DLBCL showed that few TME cells were found in CD24-high DLBCL, although statistical differences were not observed. These data indicate that CD24 expression suppresses immune cell components of the TME in DLBCL, suggesting that CD24 may be a target for cancer immunotherapy in aggressive large B-cell lymphoma.

Background Desmoplastic fibroblastoma (also known as collagenous fibroma) is a benign, slowly growing soft-tissue tumor. Most desmoplastic fibroblastomas develop in the limbs, neck, or trunk. A mediastinal origin is quite rare. Case presentation A 32-year-old Asian female was referred to us for the diagnosis and treatment of an anterior mediastinal tumor. The tumor was 80 mm in the largest diameter and was located on the pericardium. No invasion was evident. She underwent resection of the tumor via video-assisted thoracoscopic resection. The tumor was totally encapsulated, and its pedicle was on the pericardium. The resected specimen was very rigid, making it difficult to remove from the intercostal space. Histologically, the tumor was composed of a paucicellular dense collagenous tissue. Mitosis was rarely observed, and cellular atypia was not evident, suggesting that the tumor was benign. We diagnosed the tumor as a desmoplastic fibroblastoma by morphology and immunohistochemistry. Conclusions Desmoplastic fibroblastoma of the mediastinum is an extremely rare disease. Preoperative diagnosis is difficult. Early surgical resection is suitable for diagnosis and treatment planning.

We compared the two methods of assessing CD30 protein expression in DLBCL and TCL specimens routinely employed at our hospital, immunohistochemistry (IHC) and flow cytometry (FCM), using the same clone of the anti-CD30 antibody (Ber-H2) in 123 patients with DLBCL and 28 patients with TCL. FCM was more sensitive than IHC, especially in cases with low expression. In three cases of TCL and two cases of DLBCL, there was discordance between these two methods. Two of these TCL cases were ALCL and one was peripheral T-cell lymphoma, NOS, but ALCL was unable to be excluded. One of two cases of DLBCL was an anaplastic variant of DLBCL. The data suggested that CD30 was undetectable, though rare, by FMC in several cases. Based on this study, a combination of IHC and FCM is recommended for the reliable and quantitative detection of CD30.

BackgroundThe prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet.MethodsA total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated.ResultsThe frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that ageConclusionsThe prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.

Background A hydatidiform mole with a coexisting fetus is a rare condition that commonly occurs as either a partial mole with fetus or a twin pregnancy comprising a complete mole and normal fetus. In the former case, the fetus is triploid, and in the latter case, the fetus is diploid with different alleles from those of the mole. Because there is a difference in the persistent trophoblastic disease incidence between the two, an accurate diagnosis is required. Case presentation We present a case of a 34-year-old Japanese woman who was pregnant with a hydatidiform mole and two coexisting fetuses. At 17 weeks of gestation, hemorrhage-induced progressive anemia in the mother prompted the decision to terminate the pregnancy, after which no complications occurred. Molecular cytogenetic analysis revealed that one of the fetuses was a normal diploid fetus with the same allele in the fetus and placenta. The hydatidiform mole was revealed to be a mosaic of two diploids, and the other coexisting fetus was a normal diploid that shared one of the mole alleles. Conclusions This was presumed to be a rare case of twin pregnancy by triploid embryo formation, followed by loss of an allele due to postzygotic diploidization, development of a diploid fetus, and development of another fetus from a separate embryo. Because of the existence of cases such as this one with a diploid fetus, but without a normal pregnancy coexistent with a complete hydatidiform mole, diagnosis by genetic analysis is required for prognosis.

Methotrexate (MTX) is one of the potent drugs for autoimmune diseases (ADs), especially for rheumatoid arthritis. Recent studies suggest that MTX should be immediately withdrawn when patients with AD develop lymphoproliferative disorder (LPD). However, biopsy cannot be performed for diagnosis because LPD regresses quickly after MTX withdrawal, thus making clinical MTX-LPD (c-MTX-LPD) challenging to diagnose. In this study, among the 28 patients with c-MTX-LPD, seven developed a proven LPD (p-LPD) after suspicious LPD (s-LPD) regression, six of which were Hodgkin lymphoma. Four of seven patients with p-LPD + died, whereas all patients with p-LPD- survived. The clinical manifestations indicative of p-LPD include fever, elevated serum C-reactive protein level, and soluble interleukin-2 receptor level. Anti-AD drugs did not appear to affect the pathogenesis of p-LPD development. P-LPD was not observed after 3 years from the time of s-LPD regression.

We describe the case of an elderly Japanese female who had experienced diabetic nephropathy since the year 20xx and had been undergoing dialysis treatment while receiving vascular access interventional therapy (VAIVT) for arteriovenous fistula (AVF) occlusion. The patient visited the clinic/hospital in 20xx+10 with the AVF occlusion; emergency VAIVT was performed but blood flow could not be resumed. The patient was not admitted and was treated as an outpatient, and thus a cuff catheter (Split stream catheter: SST28 cm, Medcomp) was inserted. An infection developed and was successfully treated with antibiotics. The dialysis treatment continued without issue. One year after the cuff catheter’s insertion, the patient was admitted due difficulty breathing. Despite continued dialysis treatment with the catheter, the patient died 15 days post-admission. The removal of the catheter proved to be difficult. An autopsy was approved, and the area around the catheter was examined. The adhesion of the catheter to the right atrium was observed, but no infection was detected in the bloodstream. This case illustrates that dialysis with the use of a cuff catheter can be effective.

Background The attention on mismatch repair-deficient (dMMR) gastric cancer has increased in this era of anti-PD-1 blockade therapy; however, the prevalence and molecular genetics of patients with dMMR gastric cancer have not been completely investigated. Methods Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary gastric cancers of 513 consecutive patients. Genetic and/or epigenetic alterations of the MMR genes were also investigated. Results Loss of expression of one or more MMR proteins was observed in 58 patients (11.3%); 54 patients showed loss of MLH1/PMS2, 3 patients showed loss of MLH1/PMS2/MSH6 and 1 patient showed loss of PMS2 alone. Among these 58 patients, 55 showed hypermethylation of the promoter region of MLH1. Genetic testing revealed that the remaining three patients had Lynch syndrome (n = 1) or Lynch-like syndrome (n = 2). A total of 15 patients (25.9% of all patients with dMMR gastric cancer and 2.9% of all patients with gastric cancer), including 11 patients with stage I–III dMMR gastric cancer who had recurrence and 4 patients with stage IV dMMR gastric cancer, are potential candidates for the use of anti-PD-1 blockades. Conclusions This is the first study to investigate the frequency and molecular genetic mechanisms of dMMR gastric cancer comprehensively, focusing on the benefit of using PD-1 blockades. Our observations will be beneficial in the clinical practice of metastatic gastric cancer.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD), a category of immunodeficiency-associated LPD according to the World Health Organization classification, is associated with immunosuppressive drugs (ISDs). Several factors, including autoimmune disease (AID) activity, Epstein-Barr virus (EBV) infection, ISD usage, and aging, influence the development of OIIA-LPD, resulting in complicated clinical courses and outcomes. Most OIIA-LPD develops in patients with rheumatoid arthritis using methotrexate (MTX-LPD). The management of MTX-LPD is based on the clinical course, i.e., with/without regression, with/without relapse/regrowth event (RRE), LPD subtype, and ISDs for AIDs after LPD development. There are three clinical courses after ISD withdrawal: regressive LPD without relapse/regrowth (R-G), regressive LPD with RRE (R/R-G), and persistent LPD (P-G). The majority of EBV+ diffuse large B-cell lymphomas are classified in R-G, whereas classic Hodgkin lymphoma is generally classified in R/R-G. Polymorphic LPD (P-LPD) in MTX-LPD develops with heterogeneous pathological features similar to monomorphic LPD. Chemotherapy for MTX-LPD is selected according to that for de novo LPD, although the strategy for aggressive P-LPD and non-specific LPD is not well established. The absolute lymphocyte count in the peripheral blood has been suggested as a candidate marker for MTX-LPD development and RRE. Several clinical issues, including correct diagnosis among overlapping clinicopathological features in MTX-LPD and clinical management of LPD by ISDs other than MTX, require further investigation.

In the current revised 4th edition of the World Health Organization (WHO) classification, ‘other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPDs)’ is listed in the last section in the chapter on immunodeficiency-associated lymphoproliferative disorders. Oii-LPDs cover a broad spectrum from benign lesions to lymphoma, and correspond to one of the subtypes in the WHO classification for immunocompetent patients. The WHO classification does not clearly indicate the histological subtype of this disease category; however, the framework of subtype classification is similar to the classification of post-transplant lymphoproliferative disorders, and recent studies have attempted to subcategorize Oii-LPDs that fit this unique disease type. In this review, we provide an overview of B-cell-type Oii-LPDs regarding their histopathology and immunophenotype, genetics and clinical behaviors.

BackgroundThe prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking.MethodsImmunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated.ResultsLoss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01).ConclusionsThis study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

The endocytoscopic system (ECS) helps in virtual realization of histology and can aid in confirming histological diagnosis in vivo. We propose replacing biopsy-based histology for esophageal squamous cell carcinoma (ESCC) by using the ECS. We applied deep-learning artificial intelligence (AI) to analyse ECS images of the esophagus to determine whether AI can support endoscopists for the replacement of biopsy-based histology. A convolutional neural network-based AI was constructed based on GoogLeNet and trained using 4715 ECS images of the esophagus (1141 malignant and 3574 non-malignant images). To evaluate the diagnostic accuracy of the AI, an independent test set of 1520 ECS images, collected from 55 consecutive patients (27 ESCCs and 28 benign esophageal lesions) were examined. On the basis of the receiver-operating characteristic curve analysis, the areas under the curve of the total images, higher magnification pictures, and lower magnification pictures were 0.85, 0.90, and 0.72, respectively. The AI correctly diagnosed 25 of the 27 ESCC cases, with an overall sensitivity of 92.6%. Twenty-five of the 28 non-cancerous lesions were diagnosed as non-malignant, with a specificity of 89.3% and an overall accuracy of 90.9%. Two cases of malignant lesions, misdiagnosed as non-malignant by the AI, were correctly diagnosed as malignant by the endoscopist. Among the 3 cases of non-cancerous lesions diagnosed as malignant by the AI, 2 were of radiation-related esophagitis and one was of gastroesophageal reflux disease. AI is expected to support endoscopists in diagnosing ESCC based on ECS images without biopsy-based histological reference.

Background Muir-Torre syndrome (MTS) is currently considered as a clinical variant of Lynch syndrome (LS). The clinical significance of the screening of patients with MTS-associated cutaneous tumors for the identification of LS has not yet been established. In addition, the prevalence and molecular characteristics of mismatch repair (MMR) protein deficiency in such tumors has scarcely been investigated in the Japanese population. Methods Immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from 16 sebaceous neoplasms (SNs) resected from 13 patients and 32 keratoacanthomas (KAs) resected from 31 patients at our institution between January 2005 and March 2014. Tumors showing MMR protein loss were further subjected to genetic analysis for detecting the presence of germline and/or somatic alterations of the MMR genes to identify the precise molecular mechanisms underlying the protein loss. Results Among the 16 SNs resected from 13 patients, eight SNs resected from five patients (38.5%) showed loss of expression of MMR proteins (MLH1/PMS2 loss, one patient; MSH2/MSH6 loss, four patients). Genetic analyses showed a pathogenic germline MSH2 mutation in one patient, somatic hypermethylation of the MLH1 promoter region in one patient, and somatic alterations of MSH2 without detectable germline mutations of MSH2 in three patients. None of the KAs examined in the study showed any loss of MMR protein expression. Conclusions The efficacy of routine screening of cutaneous neoplasms known to be associated with MTS by IHC for MMR proteins to identify LS may be fairly limited. MMR protein loss as determined by IHC in SNs is not always diagnostic of LS, and appears, in most cases, to be a result of somatic inactivation of the MMR genes.

The relationship between thymidine phosphorylase (TP) and angiogenesis at the early stage of esophageal squamous cell carcinoma has been unclear. Using 14 samples of normal squamous epithelium, 11 samples of low-grade intraepithelial neoplasia, and 64 samples of superficial esophageal cancer, microvessel density (MVD) was estimated using immunostaining for CD34 and CD105. TP expression was also evaluated in both cancer cells and stromal monocytic cells (SMCs). We then investigated the correlation between MVD and TP expression in both cancer cells and SMCs. On the basis of the above parameters, MVD was significantly higher in cancerous lesions than in normal squamous epithelium. In terms of CD34 and CD105 expression, MVD showed a gradual increase from normal squamous epithelium, to low-grade intraepithelial neoplasia, and then to M1 and M2 cancer, and M3 or deeper cancer. M1 and M2 cancer showed overexpression of TP in both cancer cells and SMCs. There was no significant correlation between TP expression in cancer cells and MVD estimated from CD34 (rS = 0.16, P = 0.21) or CD105 (rS = 0.05, P = 0.68) expression. Significant correlations were found between TP expression in SMCs and CD34-related (rS = 0.46, P

To clarify the prevalence and clinicopathologic/molecular characteristics of mismatch repair (MMR)-deficient colorectal cancer in the young Japanese population. Immunohistochemical analyses for MMR proteins (MLH1, MSH2, MSH6, and PMS2) were performed in formalin-fixed paraffin-embedded sections prepared from the resected CRC specimens of 119 consecutive patients aged

The revised WHO classification newly defined the entities “High‐grade B‐cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL‐DH/TH)” and “HGBL, NOS.” Standard immunochemotherapy for diffuse large B‐cell lymphoma (DLBCL), R‐CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)‐derived B‐cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC‐derived B‐cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B‐cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC‐derived B‐cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B‐cell (ABC)‐like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B‐cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GC‐derived B‐cell lymphomas., The effects of CDK4/6 inhibitors on cell proliferation in aggressive B‐cell lymphoma cell lines were investigated. Abemaciclib completely suppressed cell growth irrespective of the CCND3 mutation status in GCB‐like DLBCL cell lines. Abemaciclib has potential as a therapeutic agent for aggressive GC‐derived B‐cell lymphomas, including high‐grade B‐cell lymphomas.

Patient: Female, 2 Final Diagnosis: Abdominal compartment syndrome Symptoms: Abdominal distention • fever • respiratory distress Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Unusual clinical course Background: Abdominal compartment syndrome (ACS), characterized by an increased intra-abdominal pressure and new-onset organ dysfunction, is a critical and potentially fatal condition, with no case of ACS caused by intestinal gas without intestinal lesion being reported to date. Case Report: A 2-year-old girl with a chromosomal abnormality of 1p36 deletion presented with fever and diarrhea following upper-gastrointestinal series for the evaluation of gastroesophageal reflux. After 20 days, she experienced septic shock and multiple-organ failure, accompanied with rapidly growing, severe abdominal distension. A marked increase in the intra-abdominal pressure was indicated by the complete loss of elasticity in the extremely hard and distended abdomen. She died 14 h after the onset of shock. Her autopsy examination revealed extensive pneumonia and excessive intestinal gas, despite no occlusive intestinal lesion present. Conclusions: It is critical to be aware that secondary ACS can occur following sepsis due to the accumulation of extensive intestinal gas, without an occlusive intestinal lesion.

Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P

Recently, attention has been focused on methotrexate-induced lymphoproliferative disease (MTX-LPD), and atypical phenotypes are occasionally documented. We encountered two patients with rheumatoid arthritis (RA) who were diagnosed with non-specific LPD (LPD-nos). Biopsy samples were not obtained during the initial examination when the LPD development was discovered, and the patients achieved a complete response after MTX cessation (case 1) or steroid pulse therapy (case 2). However, the tumors flared up 1.5 years later, and LPD-nos was determined following biopsies of the lymph node (LN, case 1) and liver (case 2). Prednisolone was subsequently administered instead of chemotherapy; however, multiple masses, including in the spine (case 1), and severe icterus with liver dysfunction (case 2) were exacerbated within a few months. Although the re-biopsy of LN proved the presence of HL and radiation followed by aggressive chemotherapy rescued the patient (case 1), the superficially accessible biopsy site was not found, and autopsy finally revealed HL (case 2). In both cases, the underlying pathogenesis along with the B symptoms and laboratory abnormalities suggested MTX-LPD, HL in particular. Therefore, even if the pathological diagnosis does not confirm the specific LPD subtype, the administration of aggressive chemotherapy should be considered if the LPD activity flares severely.

Although intravascular large B-cell lymphoma (IVLBCL) is an extranodal lymphoma characterized by the selective growth of lymphoma cells within the lumina of small vessels, we here report three autopsy cases of IVLBCL characterized by the proliferation within large blood vessels. These three cases were diagnosed as IVLBCL of the bone marrow or skin biopsy. Two cases died suddenly before treatment, whereas the other died during treatment. Autopsies showed a large embolus of dense lymphoma cells extending from the truncus pulmonalis to the pulmonary arteries in Case 1, emboli of lymphoma cells in the aorta and carotis in Case 2, and a mass of lymphoma cells blocking the lumen of the aortic arch in Case 3. This is the first report of IVLBCL involving large blood vessels, and it is essential to note that this type of IVLBCL might cause sudden death because of tumor emboli within large blood vessels.

Human parvovirus B19 (HPV-B19) causes hemophagocytic lymphohistiocytosis (HLH). Here we describe a 35-year-old female with hereditary spherocytosis (HS) who developed HLH due to HPV-B19 infection. Upon admission, she had high fever and diarrhea. Laboratory findings included severe pancytopenia and elevated serum triglyceride and ferritin levels. Moreover, high HPV-B19 levels in the peripheral blood and increased reactive lymphocytosis in the bone marrow led to a diagnosis of HLH due to HPV-B19 infection. With supportive therapy and a blood transfusion, HLH symptoms, including fever and myelosuppression, improved in 1 week. However, symptoms of heart failure (HF) suddenly developed, and an echocardiography revealed diffuse systolic dysfunction, suggesting viral myocarditis due to HPV-B19 infection. Conservative management with diuretics gradually improved HF symptoms over a period of 2 weeks. HPV-B19 infection in adult patients with HS rarely results in severe HLH, but conservative therapy may improve the symptoms. Nonetheless, a careful follow-up is required after HLH improves because viral myocarditis can develop, as was seen in our patient.

Background: Lymphoproliferative disorders (LPD), including malignant lymphoma, is a relatively rare but life-threatening complication in RA patients under methotrexate (MTX) therapy. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct characteristic in part of such LPDs. Objective: The present study aimed to investigate the immunological difference in regressive LPD and persistent LPD. Methods: We studied RA patients who developed LPD during MTX administration (n = 35) and clinically matched controls (n = 35). The time of MTX cessation was defined as week 0, and LPD patients were divided into two groups according to LPD status at week 12: regressive group (n = 22) and persistent group (n = 13). Flow cytometric analysis of whole blood samples and serum cytokine assays were conducted for LPD (n = 10) and control patients (n = 10) at weeks 0, 4 and 12. Results: There was a significant decrease in peripheral lymphocytes and the proportion of T helper 1 cells (Th1 cells), effector memory CD8+ T cells (EMCD8+ T) and Epstein–Barr virus (EBV)-specific CD8+ T cells at the time of LPD diagnosis, and a significant increase after MTX cessation was observed in the regressive group but not in the persistent group. The expansion of Th1 cells and EMCD8+ T cells significantly correlated with an increase in serum interferon (IFN)-γ concentration. Conclusion: Changes in Th1 cells, EMCD8+ T cells and EBV-specific CD8+ T cells, which coincided with an increase in IFN-γ, were significantly different between regressive LPD and persistent LPD after MTX cessation.

Using immunohistochemical staining, the present study was conducted to examine whether cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) affect angiogenesis in early-stage esophageal squamous cell carcinoma (ESCC). We also analyzed the correlation between these two factors. Cyclooxygenase 2, iNOS, and angiogenesis in early-stage ESCC are unclear. Using 10 samples of normal squamous epithelium, 7 samples of low-grade intraepithelial neoplasia (LGIN), and 45 samples of superficial esophageal cancer, we observed the expression of COX-2 and iNOS. We then investigated the COX-2 and iNOS immunoreactivity scores and the correlation between COX-2 or iNOS scores and microvessel density (MVD) using CD34 or CD105. The intensity of COX-2 or iNOS expression differed significantly according to histological type (P < 0.001). The scores of COX-2 and iNOS were lowest for normal squamous epithelium, followed in ascending order by LGIN, carcinoma in situ and tumor invading the lamina propria mucosae (M1-M2 cancer); and tumor invading the muscularis mucosa (M3) or deeper cancer. The differences were significant (P < 0.001). Cancers classified M1-M2 (P < 0.01 and P < 0.05, respectively); M3; or deeper cancer (P < 0.01) had significantly higher COX-2 and iNOS scores than normal squamous epithelium. There was a significant correlation between COX-2 and iNOS scores (P < 0.001, rs = 0.51). Correlations between COX-2 score and CD34-positive MVD or CD105-positive MVD were significant (rs = 0.53, P < 0.001; rs = 0.62, P < 0.001, respectively). Inducible nitric oxide synthase score was also significantly correlated with CD34 MVD and CD105 MVD (rs = 0.45, P < 0.001; rs = 0.60, P < 0.001, respectively). Chemoprevention of COX-2 or iNOS activity may blunt the development of ESCC from precancerous lesions.

Background The prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancers in the Japanese population have scarcely been investigated. Methods Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary epithelial ovarian cancers in patients who underwent oophorectomy at our institution between April 2005 and September 2014. Genetic and/or epigenetic alterations of the mismatch repair genes were investigated in patients with loss of any mismatch repair proteins in the tumor. Results There were 305 patients with a median age of 54 years (range, 18-83 years). Loss of expression in the ovarian tumor of one or more mismatch repair proteins was observed in 3 of the 305 patients (0.98%): 2 patients MLH1/PMS2 loss and 1 patient showed MSH2/MSH6 loss. Genetic testing of these three patients failed to reveal any pathogenic germline mutations of MLH1 or MSH2. One patient with MLH1/PMS2 loss showed hypermethylation of the promoter region of MLH1. Somatic mutations were found in each of the alleles of MLH1 (c.545dupG and deletion of exons 2-19) in the other patient with MLH1/PMS2 loss. In the patient with MSH2/MSH6 loss, two somatic mutations were detected in MSH2 (c.229_230delAG and c.1861C>T), although we could not determine whether these mutations were biallelic or not. Conclusions The prevalence of defective mismatch repair epithelial ovarian cancer in the Japanese hospital-based population was extremely low. Molecular mechanism involved in such defective mismatch repair ovarian cancers seems to be epigenetic events through MLH1 promotor hypermethylation or somatically mutated mismatch repair genes without germline mismatch repair mutation.

The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms have been published in "Blood" as a review form. A major revision is being published that will be an update of the current fourth edition and not a truly new fifth edition. Because it is considered a part of the fourth edition, while some provisional entities will be promoted to definite entities and a small number of new provisional entities added, there will be no new definite entities. As with the 2001 and 2008 classifications, an all-important Clinical Advisory Committee meeting was held to obtain the advice and consent of clinical hematologists/oncologists and other physicians critical to the revision. The classification maintains the goals of helping to identify homogeneous groups of well-defined entities and facilitating the recognition of uncommon diseases that require further clarification. Some provisional or variant entities; EBV-positive large B-cell lymphoma, elderly and Pediatric follicular lymphoma focused on the age of onset, in situ lesions, and gray zone lymphomas, recognized in the 2008 WHO classification, were revised. This will review the major areas in mature B-cell lymphoid and mature T/NK-cell lymphoid neoplasms and Hodgkin lymphoma where changes from the 2008 WHO classification.

Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.

OBJECTIVE This study was performed to clarify whether size criteria could be applied to the prediction of metastasis to the mesorectal, internal iliac and obturator lymph nodes in patients with lower rectal cancer. METHODS A total of 915 lymph nodes (416 mesorectal, 199 internal iliac and 300 obturator) from 53 patients with lower rectal cancer who underwent a curative resection were examined; 83 lymph nodes were positive. The sizes of the lymph nodes immediately after removal and those of paraffin-embedded sections were compared for 175 lymph nodes. Then, size criteria for discriminating the status of metastasis were evaluated in 915 paraffin-embedded lymph nodes. RESULTS Regardless of the metastatic status and the site of the lymph nodes, a positive relationship was observed between the sizes of the lymph nodes immediately after removal and those of paraffin-embedded sections (P < 0.01). The area under the curve generated by a receiver-operating characteristics curve showed no significant differences between the short-axis diameter and the long-axis diameter, regardless of the lymph node location. Specifically, the optimal cutoff value of the short-axis diameter for discriminating the status of metastasis in mesorectal, internal iliac and obturator lymph nodes extrapolated to the living body was set at 6.2, 5.0 and 4.8 mm, with accuracies of 72.4, 63.8 and 59.3% and with positive predictive values of 29.9, 16.3 and 7.1%, respectively. CONCLUSIONS Size criteria were applicable for discriminating the metastatic status of lymph nodes from three different locations, although the positive predictive values of the size criteria for the internal iliac and obturator lymph nodes were lower than that for the mesorectal lymph nodes.

Objective: The esophagus is the only organ where changes in the superficial microvasculature from normal squamous epithelium to invasive cancer are evident by magnifying endoscopy. We investigated in detail the features of angiogenesis in early-stage esophageal cancer using CD34 and CD105 immunostaining, and also the correlation between angiogenesis and mononuclear cell infiltration. Materials and methods: Using 10 samples of normal squamous epithelium, 7 samples of low-grade intraepithelial neoplasia, and 45 samples of superficial esophageal cancer, we determined the microvessel density at hot spots showing positive staining for CD34 and CD105. We observed the histological features of CD34- and CD105-positive microvessels that corresponded to observations made by magnifying endoscopy. We then investigated the correlation between microvessel density and each histological situation or the grade of mononuclear cell infiltration. Results: The histological features of CD34- and CD105-positive microvessels were able to explain the morphological changes in the microvasculature during cancer progression observed by magnifying endoscopy. The microvessel density for CD34 or CD105 was significantly correlated with each of the histological types (P , 0.001, rS ¼ 0.51 and 0.76, respectively). Mononuclear cell infiltration at CD105 hot spots was most frequent in M1 and M2 cancer (94.7%). The correlation between the degree of mononuclear cell infiltration and microvessel density for CD105 staining was also significant (P , 0.001, rS ¼ 0.49). Conclusions: The microvessel density based on CD34 and CD105 immunostaining can be used to corroborate observations of superficial esophageal squamous cell carcinoma made by magnifying endoscopy. Mononuclear cell infiltration may play an important role in angiogenesis at the early stage of cancer progression.

Granulocyte colony-stimulating factor (G-CSF) induces the mobilization of leukocytes from the bone marrow (BM) to the circulation by a yet incompletely understood mechanism. Here, we describe that the membrane-bound receptor LR11 is highly expressed in human myeloid cells and that the shed soluble form of LR11 (sLR11) is a modifier of myeloid cell migration. In the process of leukocyte mobilization by G-CSF treatment, circulating sLR11 levels are transiently elevated in humans and mice. Moreover, following G-CSF treatment, the sLR11 levels in patients show significant positive correlation with the numbers of mobilized leukocytes. The changes of LR11 levels in BM cells and of sLR11 released into the BM fluid of mice correlate tightly with the changes in circulating sLR11 levels. G-CSF dose-dependently enhanced sLR11 release from HL-60 cells, which in turn accelerated cell migration. Finally, cooperatively with tumor necrosis factor-α (TNF-α) and G-CSF, sLR11 increased the attachment of floating cells (HL-60 and U937) to endothelial cells. We propose that sLR11 is a novel candidate modifier of G-CSF-mediated mobilization of hematologic cells. Identification of sLR11 as a regulatory component of G-CSF-mediated hematologic cell mobilization may facilitate further improvement of hematologic stem cell collection for clinical applications.

Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 high-grade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum α-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of α-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity.

The development and acquisition of multiple drug resistance in cancer cells remain a major obstacle in the treatment of bladder cancer. Nuclear translocation of Y box binding-1 (YB-1), which is a member of a family of DNA-binding proteins that contain a cold shock domain, plays a significant role in the acquisition of drug resistance by upregulating expression of the multidrug resistance-1 (MDR-1) gene product, p-glycoprotein. The tumor suppressor protein p53 is thought to be essential for nuclear translocation of YB-1. We hypothesized that nuclear translocation of YB-1 might be associated with drug resistance of bladder cancer with an abnormality of the TP53 gene that results in a mutated p53 protein. To test this hypothesis, we analyzed the association of YB-1 with drug resistance of TP53-mutated bladder cancer, including immunohistochemical analysis of YB-1, p-glycoprotein and p53 in vivo as well as the function of YB-1 nuclear translocation and regulation of its translocation by p53 in vitro. Additionally, we examined the association between the nuclear translocation of YB-1 and gemcitabine, a major anticancer-drug for bladder cancer, in cancer cell lines. Nuclear expression of YB-1 was correlated with the expression of p-glycoprotein and p53 in bladder cancer cases (p

Objective We investigated the prevalence of Lynch syndrome and Lynch-like syndrome among Japanese colorectal cancer patients, as there have been no credible data from Japan. Methods Immunohistochemical analyses for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were carried out in surgically resected, formalin-fixed paraffin-embedded specimens obtained from 1,234 newly diagnosed colorectal cancer patients between March 2005 and April 2014. The presence/absence of the BRAF V600E mutation and hypermethylation of the MLH1 promoter was analyzed where necessary. Genetic testing was finally undertaken in patients suspected as having Lynch syndrome. Results By the universal screening approach with immunohistochemical analysis for mismatch repair proteins followed by analyses for the BRAF V600E mutation and MLH1 promoter methylation status, 11 (0.9%) of the 1,234 patients were identified as candidates for genetic testing. Out of the 11 patients, 9 (0.7%) were finally diagnosed as having Lynch syndrome; the responsible genes included MLH1 (n = 1), MSH2 (n = 4), EPCAM (n = 1) and MSH6 (n = 3). The remaining two patients (0.2%) were regarded as having Lynch-like syndrome, since biallelic somatic deletion of the relevant mismatch repair genes was detected in the absence of germline mismatch repair alterations. None of the cases was identified as having germline MLH1 epimutation. Conclusions The prevalence of Lynch syndrome among all newly diagnosed cases of colorectal cancer in Japan is in the same range as that recently reported by studies in Western population. The prevalence of Lynch-like syndrome seems to be extremely low.

We herein describe a case of somatostatinoma coexisting with a gastrointestinal stromal tumor (GIST) in the duodenum of an 81-year-old woman with Von Recklinghausen's disease (VRD) and common bile duct stone who presented with diarrhea of three months in duration. Gastroduodenoscopy revealed an ulcer on the second part of the duodenum. A 2.1-cm enhancing tumor was observed to extend from the ulcer on an abdominal computed tomography scan. Subtotal stomach-preserving pancreaticoduodenectomy revealed a somatostatinoma on the papilla of the vater and duodenal GIST. There have been only eight reports on VRD associated with ampullary somatostatinoma and GIST. An awareness of this possibility in patients with gastrointestinal lesions is necessary for proper treatment and patient management.

Background Classical Hodgkin’s lymphoma is characterized by Hodgkin and Reed Sternberg cells, which are of B-cell origin in many cases. We recently highlighted the adverse prognostic significance of cytotoxic molecule expression in patients with classical Hodgkin’s lymphoma. However, the clinical characteristics of cytotoxic molecule-positive classical Hodgkin’s lymphoma remain controversial. Design and Methods We investigated the clinicopathological profiles of 32 patients with cytotoxic molecule-positive Hodgkin’s lymphoma, comprising 23 with nodular sclerosis and 9 with mixed cellularity, and compared these profiles with those of 55 patients with cytotoxic molecule-positive nodal peripheral T-cell lymphoma, not otherwise specified and 439 patients with cytotoxic molecule-negative Hodgkin’s lymphoma. Results The patients with cytotoxic molecule-positive Hodgkin’s lymphoma consisted of 20 men and 12 women with a median age of 50 years (range, 19 to 81). All these patients had lymphadenopathy at presentation, and 14 showed mediastinal involvement. Physical findings included hepatomegaly and splenomegaly in six patients each. Four patients had a bulky mass, and nine showed stage IV disease. The tumor cells of patients with cytotoxic molecule-positive Hodgkin’s lymphoma had a prototypic immunophenotype of CD15+ CD30+ CD45RO− fascin+, with positivity for Epstein-Barr virus in 39% of cases. All patients were negative for Pax5. In comparison with patients with cytotoxic molecule-positive nodal peripheral T-cell lymphomas, not otherwise specified, patients with cytotoxic-positive Hodgkin’s lymphoma had relatively mild clinical symptoms, similar to those of patients with cytotoxic molecule-negative Hodgkin’s lymphoma. Regarding prognosis, the survival of patients with cytotoxic molecule-positive Hodgkin’s lymphoma was worse than that of patients with cytotoxic molecule-negative Hodgkin’s lymphoma ( P =0.0003) but better than that of patients with cytotoxic molecule-positive peripheral T-cell lymphomas, not otherwise specified ( P =0.002). Conclusions Cytotoxic molecule-positive Hodgkin’s lymphoma is characterized by an unfavorable prognosis, even if its clinicopathological features are within the boundaries of classical Hodgkin’s lymphoma. More effective chemotherapy for cytotoxic molecule-positive Hodgkin’s lymphoma is clearly required.

The expression of YB-1 has been reported to predict poor clinical outcome in many human malignancies, including hematopoietic malignancies. In this study, we investigated the correlations between YB-1 expression and the clinicopathological features of patients with diffuse large B-cell lymphoma (DLBCL) in a single institution. The expression of YB-1 was analyzed in 168 cases by immunohistochemistry. Fifteen out of 168 cases (8.9%) showed cytoplasmic expression of YB-1. The expression of YB-1 was significantly associated with 5-year overall survival (OS) (p = 0.023). Rituximab plus CHOP therapy (n = 94) improved the 5-year survival rate in both YB-1-positive and -negative patients. In conclusion, the data presented in this report provide evidence that the cytoplasmic expression of YB-1 is a poor prognosis factor in DLBCL treated with CHOP therapy, whereas rituximab improves the survival of both YB-1-positive and -negative patients with DLBCL.

In our previous study on nm23-H1 expression with diffuse large B-cell lymphoma (DLBCL), we found that patients with positive nm23-H1 had significantly poorer prognosis than patients with negative nm23-H1. We examined whether nm23-H1 is a prognostic factor of DLBCL in the rituximab era. The subjects were 101 DLBCL patients who underwent R-CyclOBEAP (rituximab, cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone) therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, MUM1, and nm23-H1 expression by immunohistochemistry. Ninety-four DLBCL patients who underwent CyclOBEAP therapy were assumed as historical controls. Among DLBCL patients who underwent CyclOBEAP therapy, BCL2 positivity, MUM1 positivity, non-germinal center B-cell (non-GCB), and nm23-H1 positivity were associated with significantly shorter overall survival (OS) and progression-free survival (PFS). On the other hand, among DLBCL patients who underwent R-CyclOBEAP therapy, the 5-year OS rates of the nm23-H1-positive DLBCL (n = 32) and nm23-H1-negative DLBCL groups (n = 69) were 65% and 97%, respectively (p = 0.001), with 5-year PFS rates of 51% and 89%, respectively (p = 0.001). In the rituximab era, BCL2, MUM1, and non-GCB were not prognostic factors. We demonstrated that among patients with DLBCL who underwent R-CyclOBEAP therapy, patients with nm23-H1 expression had a significantly poorer prognosis than patients without nm23-H1 expression. These results suggest an important role for nm23-H1 in malignant progression and a potential therapeutic target for DLBCL.

Background: We carried out immunohistochemistry to examine the expression of nm23-H1 in Hodgkin and Reed–Sternberg cells in patients with classical Hodgkin’s lymphoma (CHL). Patients and methods: We evaluated 128 patients with CHL [87 patients with nodular sclerosis (NS) and 41 patients with mixed cellularity (MC)] for CD15, CD20, Ki-67, EBER, TIA-1, and nm23-H1 by immunohistochemistry. Results: CD15 was expressed in 79%, CD20 in 11%, Ki-67 in 93%, EBER in 34%, TIA-1 in 11%, and nm23-H1 in 60% of the CHL patients. NS patients showed a significantly higher rate of nm23-H1 expression than MC patients (P < 0.001). The serum nm23-H1 level was significantly higher in patients with positive nm23 expression. Univariate analysis showed that stage IV, poor performance status, low hemoglobin level, low serum albumin level, age of 45 years or older, TIA-1-positive status, and nm23-H1-positive status were associated with significantly shorter progression-free survival. Multivariate analysis with these factors showed TIA-1 and cytoplasmic nm23-H1 expression to be significant and independent prognostic factors. Conclusions: Our results indicate that nm23-H1 expression is a prognostic factor for CHL and that it is as important as serum nm23-H1, both of which are useful for planning the treatment strategy.

Background De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5−) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5+ DLBCL. Design and Method From 1984 to 2002, 120 patients with CD5+ DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. Results Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5+ DLBCL was more frequent than in CD5− DLBCL ( p =0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5+ DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5+ DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants ( p =0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. Conclusions Our study revealed the morphological spectrum of CD5+ DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5+ DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

We here report the case of a young Japanese woman diagnosed with chronic active Epstein-Barr virus (EBV) infection. Intensive therapy with the CHOP regimen was partially able to control virus expansion, but various central nervous system symptoms appeared and gradually progressed. EBV-encoded RNA, detected using in situ hybridization, disclosed the presence of EBV in liver and bone marrow tissue, and real-time PCR revealed the presence of EBV in the cerebrospinal fluid (CSF) and serum. CD3+CD4+CD8-CD56- T-cell expansion in the peripheral blood (PB) and CSF was also observed. Atrophic brain changes were progressive, and the patient died of central nervous system disturbance and pulmonary hemorrhage a year after diagnosis. Autopsy revealed that EBV-infected T lymphocytes with a phenotype similar to those seen in PB and CSF had infiltrated multiple organs: the lymph nodes, bone marrow, endocardium, pericardium, myocardium, spleen, liver, and spinal cord. There have been few previous reports of severe degenerative changes in the myocardium, liver, and spinal cord in patients with EBV infection. Although EBV occasionally infiltrates the central nervous system and brain, atrophic changes mediated by EBV are rare. The autopsy results of this case suggest the possibility of EBV-mediated, severe degenerative changes in multiple organs.

Rhabdomyosarcoma is exceedingly rare in adults. A 62-year-old woman was referred to our hospital because of general pain. Computed tomography revealed a solid tumor in the right nasal cavity. Histopathological examination showed solid proliferation of atypical small round cells, having cytologic features reminiscent of lymphomas, and lacking the fibrovascular stroma. The cells were CD56(+), desmin(+), vimentin(+), HHF35(+), myogenin(+) and MyoD1(+). The patient was positive for the PAX3-FKHR fusion gene. The patient was diagnosed as having alveolar rhabdomyosarcoma. We conclude that rhabdomyosarcoma should be included in the differential diagnoses of CD56(+) small round cell tumor, and immunohistochemical and cytogenetic studies should be performed.

Aims: The Revised European American Lymphoma classification uses the term Hodgkin's-like anaplastic large cell lymphoma (HD-like ALCL) for borderline cases with features of both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (HL). The aim of this study was to clarify the association between cytotoxic molecule (CM) expression and clinical outcome in HD-like ALCL. Methods and results: Subjects were 59 patients with HD-like ALCL, defined by nodal presentation without mediastinal bulky lesions, T- or null-cell phenotype, CD30+ anaplastic lymphoma kinase (ALK)– phenotype and by confluent sheets or nodules of large cells mimicking classic Hodgkin and Reed–Sternberg cells. We evaluated the presenting features and prognosis of subjects on categorization into two defined groups, namely CM (TIA1 and/or granzyme B)-positive (n = 21) and CM-negative (n = 38). The series consisted of 18 women and 41 men ranging from 16 to 88 years of age (median 59 years). The CM+ group had poorer disease-specific survival than the CM– group (P = 0.02) despite the absence of differences in other clinical characteristics. Multivariate analysis confirmed that CM expression was an independent prognostic factor, in contrast to phenotypic categorization (T-cell vs. null-cell group), which had no prognostic impact on disease-specific survival. Conclusion: CM expression is predictive of prognosis in HD-like ALCL.

We report on a patient of rheumatoid arthritis (RA) who sequentially developed an axillary mass and a fatal interstitial pneumonia during a 2-year course of methotrexate (MTX) therapy. Autopsy revealed a systemic lymph node involvement and the diagnosis of Epstein-Barr virus (EBV)-related lymphoproliferative disease (LPD) with the features of lymphomatoid granulomatosis was made. The lung tissue specimens revealed a typical diffuse alveolar damage (DAD), and small nodules consisting of atypical B lymphocytes showing positive staining for EBV were sparsely recognized only in basal lungs. This is the first report of a RA patient receiving MTX therapy sequentially developing MTX-associated lymphomatoid granulomatosis and DAD.