Extra-ampullary duodenal adenocarcinomas are rare, and when studied, frequently have been grouped with jejunoileal adenocarcinomas. Nevertheless, anecdotal experiences suggest that these neoplasms may present 2 or more distinct phenotypes. To better characterize these neoplasms, we performed a retrospective review of 38 cases with a special focus on the morphologic and immunophenotypic characteristics and their clinicopathologic significance. Our cohort of extra-ampullary duodenal adenocarcinomas was classified on the basis of the morphologic features into gastric type (n=19, 50%), intestinal type (n=14, 37%), pancreaticobiliary type (n=2, 5%), and others (n=3, 8%). Most gastric-type adenocarcinomas (n=18, 95%) developed in the proximal duodenum, whereas the other types were located equally in the proximal and distal duodenum. Intestinal-type dysplasia was present at the periphery of 8 (57%) intestinal-type adenocarcinomas, and 8 (42%) gastric-type adenocarcinoma were associated with gastric-type dysplasia. Gastric foveolar metaplasia (n=12) and Brunner gland hyperplasia (n=10) were exclusively recognized adjacent to gastric-type adenocarcinomas. Notably, intestinal-type histology and the absence of lymph node metastasis were significantly associated with favorable disease-free survival in univariate and multivariate analyses. In summary, this study demonstrated that 2 major subsets of extra-ampullary duodenal adenocarcinoma, intestinal type and gastric type, are associated with distinct histopathologic features and clinical behavior.
Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.
In-stent restenosis (ISR) is still a recognized clinical problem in the era of drug-eluting stent (DES). Some previous studies have suggested that circulating eosinophils play an important role in both restenosis and thrombosis after DES implantation. However, the contribution of eosinophils to the pathogenesis of ISR has not yet been concisely clarified.
Persistent colonization of the gastric mucosa by Helicobacter pylori (Hp) elicits chronic inflammation and aberrant epithelial cell proliferation, which increases the risk of gastric cancer. Here we examine the ability of microRNAs to modulate gastric cell proliferation in response to persistent Hp infection and find that epigenetic silencing of miR-210 plays a key role in gastric disease progression. Importantly, DNA methylation of the miR-210 gene is increased in Hp-positive human gastric biopsies as compared with Hp-negative controls. Moreover, silencing of miR-210 in gastric epithelial cells promotes proliferation. We identify STMN1 and DIMT1 as miR-210 target genes and demonstrate that inhibition of miR-210 expression augments cell proliferation by activating STMN1 and DIMT1. Together, our results highlight inflammation-induced epigenetic silencing of miR-210 as a mechanism of induction of chronic gastric diseases, including cancer, during Hp infection.
Surgical site infections are potential complications following open myomectomy. These infections usually develop immediately after the surgery, and are most often located in the myometrium. Pyogenic cervical cysts are rare and have not been previously reported to occur at the site of myomectomy.
We describe a fatal case of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with human herpesvirus-6B (HHV-6B)-associated lymphadenitis and virus-associated hemophagocytic syndrome triggered by an over-the-counter medication to treat respiratory and influenza-like symptoms. Histologically, the structure of the lymph node was disrupted with infiltration of large lymphocytes carrying intranuclear acidophilic inclusion bodies. Immunohistochemistry and real-time PCR analysis revealed that these large lymphocytes were positive for HHV-6B. Numerous HHV-6 particles were detected in the inclusion body of the lymphocytes by electron microscopy. Interestingly, immunohistochemistry revealed that HHV-6B-infected cells in the lymph node were CD3(+), CD4(+), CD25(+), and FoxP3(+) T cells, indicating a phenotypic resemblance to regulatory T-cells. This case provides direct evidence of HHV-6 infection in CD25(+)/FoxP3(+) T cells in a case of acute lymphadenitis of DRESS syndrome, suggesting a significant role of HHV-6 infection of regulatory T-cells in the pathogenesis of DRESS syndrome.
Genetic mutations in pancreatic ductal adenocarcinoma (PDAC) with critical roles have been well examined. The recent discovery of alterations in genes encoding histone modifiers suggests their possible roles in the complexity of cancer development. We previously reported loss of heterozygosity of the KDM6B gene, which encodes a histone demethylase for trimethylated histone H3 lysine 27, a repressive chromatin mark, in PDAC cells. In this study, we demonstrated that loss of KDM6B enhanced aggressiveness of PDAC cells. KDM6B has been regarded as a tumor suppressor that mediates oncogenic KRAS-induced senescence. Consistently, KDM6B was highly expressed in pancreatic precancerous lesions (pancreatic intraepithelial neoplasms); then, the expression decreased as the malignant grade progressed. We found that knockdown of KDM6B in PDAC cells promoted tumor sphere formation and increased peritoneal dissemination and liver metastasis in vivo. Microarray and chromatin immunoprecipitation analysis implicated CEBPA for aggressiveness induced by KDM6B knockdown. CEBPA knockdown recapitulated the phenotypic change of PDAC cells after KDM6B knockdown, which was reversed by forced expression of C/EBP?. Moreover, similar protein expression patterns of KDM6B and C/EBP? in human PDAC emphasized their functional correlation. Notably, pharmacological inhibition of the H3K27 methylase EZH2 in PDAC cells inhibited tumor sphere formation along with the upregulation of CEBPA expression, and this effect was impaired in KDM6B knockdown cells, highlighting the role for KDM6B in the activation of CEBPA. Together, our results propose a significant role for the KDM6B-C/EBP? axis in the PDAC phenotype.
We sought to evaluate whether pancreatic elasticity, measured using acoustic radiation force impulse (ARFI) imaging, can determine the degree of pancreatic fibrosis and risk of pancreatic fistula (PF) in patients undergoing pancreatic resection. Although soft pancreatic texture is a reliable predictor of postoperative PF, noninvasive, quantitative methods of assessing pancreatic hardness have not been established.
Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.
Although cervical pregnancy and placenta previa, in which the embryo and placenta embed in or adjacent to the cervix, are life-threatening complications that result in massive bleeding and poor pregnancy outcomes in women, the incidence of these aberrant conditions is uncommon. We hypothesized that a local molecular mechanism is normally in place to prevent embryo implantation in the cervix. The ovarian hormones progesterone (P(4)) and estrogen differentially direct differentiation and proliferation of endometrial cells, which confers the receptive state for implantation: P(4) dominance causes differentiation of the luminal epithelium but increases stromal cell proliferation in preparation of the uterus for implantation. In search for the cause of cervical nonresponsiveness to implantation, we found that the statuses of cell proliferation and differentiation between the uterus and cervix during early pregnancy are remarkably disparate under identical endocrine milieu in both mice and humans. We also found that cervical levels of progesterone receptor (PR) protein are low compared with uterine levels during this period, and the low PR protein levels are attributed to elevated levels of microRNA(miR)-200a in the cervix. These changes were associated with up-regulation of the P(4)-metabolizing enzyme 20?-hydroxysteroid dehydrogenase (200?-HSD) and down-regulation of its transcriptional repressor signal transducer and activator of transcription 5 in the cervix. The results provide evidence that elevated levels of miR-200a lead to down-regulation of P(4)-PR signaling and up-regulation of (200?-HSD) in the cervix, rendering it nonresponsive to implantation. These findings may point toward not only the physiological but also the pathological basis of the cervical milieu in embryo implantation.
Xanthogranulomatous inflammation is an uncommon form of chronic inflammation that is destructive to the normal tissue of affected organs. Although xanthogranulomatous endometritis and xanthogranulomatous salpingitis of the female genital tract has been described previously, to the best of our knowledge, this is the first report of xanthogranulomatous inflammation with infiltration into the uterine myometrium from the perimetrium without endometritis.
Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important phenomenon in gene regulation. APA is involved in development, cancer and cell proliferation. APA may lead to disruption of microRNA-mediated gene silencing in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer. We selected the top 10 genes showing significant 3'UTR shortening in lung cancer, using the package of the Bioconductor for probe-level analyses of expression microarrays. We established and evaluated the APA score by quantitative RT-PCR in 147 clinical specimens of non-small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA-related genes, including PABPN1, CPEB1, E2F1 and proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and a poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both lower expression of PABPN1 and higher expression of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001). Our results indicate that the loss of PABPN1, a suppressor of APA, might promote tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation.
To evaluate radiographic features of endotracheal/endobronchial fluid in the airway (FA) observed on postmortem computed tomography (PMCT). We studied 164 subjects who died at our hospital between April 2009 and September 2012. Fluid in the airway was considered positive when fluid was identified in the lumen of 1 of the 2 main bronchi in continuity with a segmental bronchus. Pleural effusion and atelectasis/consolidation of the lung lower lobes were also evaluated. Fluid in the airway was observed in 60 (71%) of 84 subjects with unilateral or bilateral pleural effusion, and in 44 (55%) of 80 subjects without pleural effusion (P = 0.029). Of the latter, 41 (93%) had atelectasis/consolidation of the lower lung lobes. Among subjects without pleural effusion, average times after death to PMCT of subjects with and without FA were 501 and 314 minutes, respectively (P = 0.01). Time-course analysis showed that cases with FA on PMCT largely correlated with time after death (R = 0.7966). Fluid in the airway is frequently observed on PMCT in subjects with pleural effusion or atelectasis/consolidation of the lung. No FA in subjects without pleural effusion correlated to shorter times after death. In addition, FA frequency on PMCT increased over time after death.
Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction. We performed whole-exome sequencing on 30 DGC cases and found recurrent RHOA nonsynonymous mutations. With validation sequencing of an additional 57 cases, RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein. These positions are highly conserved among RHO family members, and Tyr42 and Arg5 are located outside the guanine nucleotide-binding pocket. Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner. Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs, the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa. Our findings identify a potential therapeutic target for this poor-prognosis subtype of gastric cancer with no available molecularly targeted drugs.
The importance of Notch signaling in colorectal cancer (CRC) tumorigenesis has been recently recognized. However, the significance of Notch3 expression and its association with Notch1 expression in CRC is unclear. In the present study, we investigated Notch1 and Notch3 expression in Stage II and III CRC to assess their association with clinicopathological characteristics.
We aimed to confirm whether postmortem adrenal volumetric changes occur by measuring adrenal volumes on computed tomography (CT). Fifty-five adrenal glands from 28 subjects who died were included. All subjects underwent antemortem CT (AMCT) and postmortem CT (PMCT) within 94-1,191 min after death, followed by conventional autopsy. CT volumetry was performed using freely-available software. Differences between AMCT and PMCT adrenal volumes were evaluated statistically along with differences in the degree of volume change, elapsed time to PMCT, and presence of underlying malignant disease. The mean volume of the right adrenal gland decreased from 3.8 cm(3) on AMCT to 2.6 cm(3) on PMCT (P < 0.001); the left adrenal gland decreased from 4.2 cm(3) on AMCT to 3.1 cm(3) on PMCT (P < 0.001). Conventional autopsy revealed decreased intracellular lipid components in portions of the adrenal glands. No correlation between the adrenal gland reduction rate and the elapsed time from AMCT to death or from death to PMCT was observed (P = 0.99 and 0.79; P = 0.28 and 0.59 for the right and left adrenal glands, respectively). Significant differences in both the bilateral adrenal gland reduction rates and underlying malignant disease were found for the left adrenal gland (P = 0.015), but not for the right (P = 0.74). Adrenal volume reduction was observed on PMCT compared to AMCT. This highlights the need to further elucidate the mechanism of adrenal shrinkage during the agonal stage and after death. This may be explained by pathological findings of intracellular lipid depletion.
Heat shock protein 105 (Hsp105) is one of the cancer/testis antigens, which is overexpressed in a variety of cancer cells, including urinary bladder cancer, and has been investigated as a target molecule for immunotherapy due to its immunogenicity. In this study, we assessed the expression of Hsp105 in primary bladder cancer samples from 84 patients treated with radical cystectomy, using immunohistochemical analysis, and investigated its correlation with clinicopathological characteristics and cancer-specific survival. The immunoreactivity of Hsp105 expression was evaluated as a score of 0-3, according to the intensity of the signal. The Hsp105 expression was high (score 2 or 3) in 31 cases and low (score 0 or 1) in 53 cases; however, it was not significantly correlated with age, nuclear grade, pathological tumor stage and previous intravesical Bacillus Calmette-Guérin immunotherapy. Female gender, lymphovascular invasion and lymph node metastasis were associated with low Hsp105 scores, although the differences were not statistically significant (P=0.071, 0.061 and 0.175, respectively). However, a high Hsp105 score was significantly associated with a favorable prognosis (P=0.017) and was identified as an independent prognostic factor by multivariate analysis (P=0.032; hazard ratio, 2.34). These findings suggested that the expression of Hsp105 may be a novel indicator of a favorable prognosis in bladder cancer.
Kaposiform hemangioendothelioma is a vascular tumor categorized as intermediate malignancy. We experienced an autopsy of a female baby with kaposiform hemangioendothelioma with Kasabach-Merritt syndrome. She died of systemic bleeding tendency following disseminated intravascular coagulation at the age of 9 days. At autopsy, a huge main tumor, histologically kaposiform hemangioendothelioma, was discovered in the mediastinum between the right chest cavity and pericardium. Furthermore, kaposiform hemangioendothelioma with the same histology involved the lungs, heart, liver, subserosa of cardial part of the stomach, retroperitoneum around the right adrenal gland, broad ligament of the uterus, and muscular tissue around the thyroid. To date, a few previously reported cases of multifocal kaposiform hemangioendothelioma have demonstrated locally aggressive distributions mainly in bone and soft tissues. The present case with extensive distribution including visceral organs implies that kaposiform hemangioendothelioma may have higher potential to spread than considered before.
The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5(+) crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5(+) stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of ?-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of ?-catenin in Lgr5(+) stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/?-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer.
Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12-0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.
Evidence suggests that CD204-positive (CD204(+)) tumor-infiltrating macrophages are associated with aggressive behavior of various cancers; however, the clinical, pathological, and prognostic associations of tumor-infiltrating CD204(+) macrophages in urothelial cancer have not been reported.
Esophageal adenocarcinomas usually develop in Barrett's esophagus, typically through the metaplasia-dysplasia-carcinoma sequence, but adenocarcinomas can occur from heterotopic gastric mucosa in cervical esophagus (inlet patch). This report describes the first case of synchronous presentation of adenocarcinoma arising from cervical inlet patch and Barrett's esophagus-related dysplasia in a 76-year-old man. Surveillance CT detected a 3-cm polypoid mass in the cervical esophagus. Endoscopic biopsies confirmed a diagnosis of adenocarcinoma of the cervical esophagus. Barrett's esophagus was present also in the lower esophagus. Histologic examination of the surgically resected specimen revealed the polypoid mass as composed of tubular adenocarcinoma, and was associated with non-neoplastic columnar mucosa representing pre-existing inlet patch. Another isolated cervical inlet patch with intestinal metaplasia was also recognized. In the lower esophagus, high-grade dysplasia was noted within the Barrett's esophagus. Immunohistochemically, the adenocarcinoma associated with inlet patch had intestinal immunophenotype (CDX2-, CD10- and MUC2-positive), whereas the Barrett's esophagus-related high-grade dysplasia showed mixed immunophenotype (MUC5AC- and MUC6-positive, with scattered MUC2-positive goblet cells). Previous studies and our findings suggest that intestinal metaplasia might predispose to the development of adenocarcinoma in the inlet patch. Therefore, endoscopists and pathologists should be aware of rare malignant transformation of inlet patches, especially those with intestinal metaplasia.
The lymphatic system plays important roles not only in the physiological processes, such as maintenance of tissue fluid homeostasis, but also in pathological processes including the lymph node metastasis of tumor cells. Therefore, understanding of the molecular mechanisms underlying lymphatic vessel formation is crucial. Previous studies have shown that proliferation and migration of lymphatic endothelial cells (LECs) are activated by multiple types of signals mediated by tyrosine kinase receptors such as vascular endothelial growth factor receptor (VEGFR) 3. Although signals mediated by platelet-derived growth factor receptor ? (PDGFR?) have been implicated in lymphangiogenesis, the mechanisms explaining how PDGFR? expression is maintained in LECs remain to be fully elucidated. In the present study, we show that PDGFR? expression in LECs is maintained by Prox1 transcription factor. Knockdown of Prox1 expression in human dermal LECs decreased the expression of PDGFR?, leading to the lowered migration of human dermal LECs towards PDGF-BB. Furthermore, we found that PDGF signals play important roles in inflammatory lymphangiogenesis in a chronic aseptic peritonitis model. Intraperitoneal administration of imatinib, a potent inhibitor of PDGFR?, and transduction of PDGFR?/Fc chimeric protein by an adenoviral system both reduced inflammatory lymphangiogenesis induced by thioglycollate in mice. We also found that the expression of PDGFR?/Fc reduced tumor lymphangiogenesis in a BxPC3 human pancreatic cancer xenograft model. These findings suggest that PDGFR? is one of the key mediators of lymphatic vessel formation acting downstream of Prox1.
Radical prostatectomy is used to treat patients with clinically localized prostate cancer, but there have been few reports of its use in locally advanced disease. We evaluated the long-term results of radical prostatectomy and immediate adjuvant androgen deprivation therapy in Japanese patients with pT3N0M0 prostate cancer.
Although protein arginine methyltransferase 5 (PRMT5) has been implicated in various cancers, its expression pattern in lung adenocarcinoma cell lines and tissues has not been elucidated enough. In this study, microarray analysis of 40 non-small-cell lung carcinoma cell lines showed that PRMT5 was a candidate histone methyltransferase gene that correlated with epithelial-mesenchymal transition. Immunocytochemical analysis of these cell lines indicated that the expression of PRMT5 was localized to the cytoplasm of E-cadherin-low and vimentin-high cell lines, whereas it was predominant in the nucleus and faint in the cytoplasm of E-cadherin-high and vimentin-low cell lines. Immunohistochemical analysis of lung adenocarcinoma cases (n = 130) revealed that the expression of PRMT5 was high in the cytoplasm of 47 cases (36%) and the nuclei of 34 cases (26%). The marked cytoplasmic expression of PRMT5 was frequently observed in high-grade subtypes (1 of 17 low grade, 21 of 81 intermediate grade, and 25 of 32 high grade; P < .0001) such as solid adenocarcinoma with the low expression of thyroid transcription factor 1 (the master regulator of lung) and low expression of cytokeratin 7 and E-cadherin (2 markers for bronchial epithelial differentiation), whereas the high nuclear expression of PRMT5 was frequently noted in adenocarcinoma in situ, a low-grade subtype (6 of 17 low grade, 25 of 81 intermediate grade, and 3 of 32 high grade; P = .0444). The cytoplasmic expression of PRMT5 correlated with a poor prognosis (P = .0089). We herein highlighted the importance of PRMT5 expression, especially its cytoplasmic expression, in the process of epithelial-mesenchymal transition and loss of the bronchial epithelial phenotype of lung adenocarcinoma.
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic masses is an established procedure for obtaining a pathological specimen. However, application of suction during EUS-FNA is still controversial and the efficacy of the slow-pull technique was recently reported for new core biopsy needles.
The QuantiFERON-TB Gold In-Tube(®) test has excellent specificity for Mycobacterium tuberculosis. However, diagnosis of miliary tuberculosis remains challenging, and the interpretation of QuantiFERON(®) results in immunocompromised individuals has not been fully established. Here, we present a patient with military tuberculosis who showed an indeterminate QuantiFERON(®) result. A 76-year-old male presented with fever and pancytopenia. Radiological tests did not show the classical miliary pattern. Acid-fast staining and polymerase chain reaction of several specimens were negative for M. tuberculosis. The QuantiFERON(®) responses were indeterminate on two separate tests, as interferon-? (IFN-?) concentration was high in the negative control. The patient did not respond to anti-microbiological therapy, and developed sepsis and disseminated intravascular coagulation, leading to lethal intracranial hemorrhage. An autopsy showed miliary tuberculosis and aplastic anemia. A literature review suggests a tendency towards indeterminate or false-negative QuantiFERON(®) results in immunocompromised individuals or patients with miliary tuberculosis due to low production of IFN-?. Our patient, however, showed substantial amounts of IFN-? despite lymphocytopenia, which has not been reported in the literature. The present case suggests that indeterminate results of QuantiFERON(®) should be interpreted with caution, as IFN-? production in patients with miliary tuberculosis can vary significantly, even with sustained lymphocytopenia.
Overexpression of periostin (POSTN), an extracellular matrix protein, has been observed in several cancers. We investigated the importance of POSTN in gastric cancer. Genome-wide gene expression analysis using publicly available microarray data sets revealed significantly high POSTN expression in cancer tissues from stage II-IV gastric cancer, compared with background normal tissues. The POSTN/vimentin mRNA expression ratio was highly associated with gene groups that regulate the cell cycle and cell proliferation. IHC showed that periglandular POSTN deposition, comprising linear deposition abutting the glandular epithelial cells in normal mucosa, disappeared during intestinal gastric cancer progression. Stromal POSTN deposition was also detected at the invasive front of intestinal-type and diffuse-type cancers. In situ hybridization confirmed POSTN mRNA in cancer-associated fibroblasts, but not in tumor cells themselves. POSTN enhanced the in vitro growth of OCUM-2MLN and OCUM-12 diffuse-type gastric cancer cell lines, accompanied by the activation of ERK. Furthermore, coinoculation of gastric cancer cells with POSTN-expressing NIH3T3 mouse fibroblast cells facilitated tumor formation. The OCUM-2MLN orthotopic inoculation model demonstrated that tumors of the gastric wall in Postn(-/-) mice were significantly smaller than those in wild-type mice. Ki-67 and p-ERK positive rates were both lower in Postn(-/-) mice. These findings suggest that POSTN produced by cancer-associated fibroblasts constitutes a growth-supportive microenvironment for gastric cancer.
Gastric cancer is a leading cause of cancer death worldwide, and significant effort has been focused on clarifying the pathology of gastric cancer. In particular, the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer; for example, aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis. The etiological viewpoint is also essential for the study of gastric cancers, and two distinct pathogens, Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), are known to participate in gastric carcinogenesis. Chronic inflammation of the gastric epithelium due to H. pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer. In addition, EBV infection is known to cause extensive methylation, and EBV-positive gastric cancers display a high methylation epigenotype, in which aberrant methylation extends to not only Polycomb repressive complex (PRC)-target genes in embryonic stem cells but also non-PRC-target genes. Here, we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H. pylori and EBV.
Evidence suggests that overexpression of enhancer of zeste homologue 2 (EZH2) is associated with aggressive behavior in various cancers. However, the clinical, pathological, and prognostic associations of EZH2 expression in the upper urinary tract carcinoma have not been reported. This study aimed to investigate the significance of EZH2 expression in the upper urinary tract carcinoma by immunohistochemical analysis using a tissue microarray. High EZH2 expression was observed in 94 of 171 (55 %) cases and was significantly associated with several adverse prognostic factors, including sessile architecture, high histological grade, presence of lymphovascular invasion, concomitant carcinoma in situ, higher tumor stage, and higher Ki-67 expression (all P?0.01). EZH2 expression status in primary and metastatic lesions was concordant in all 13 cases examined. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional hazards regression models. High EZH2 expression was significantly associated with a shorter metastasis-free survival (log-rank P?=?0.005; multivariate hazard ratio, 1.85; 95 % confidence interval, 0.93-3.71) and cancer-specific survival (log-rank P?=?0.006; multivariate hazard ratio, 3.08; 95 % confidence interval, 1.30-7.32) after nephroureterectomy. Our results suggest that EZH2 may serve as a novel prognostic biomarker and a potential therapeutic target in upper urinary tract carcinoma.
Carcinoma of unknown primary site (CUP) is said to account for approximately 3 to 5% of all carcinomas. However, an isolated lesion in the abdominal cavity is rare, and there are no reports describing associated abscess formation.
Mucosa-associated lymphoid tissue (MALT) lymphoma usually arises from chronic inflammation. We herein report a case of small intestinal MALT lymphoma with protein-losing enteropathy (PLE). A 73-year-old woman presented with lower leg edema and severe hypoalbuminemia. She had a medical history of pylorus-preserving pancreaticoduodenectomy with Billroth II reconstruction. Oral and anal route double-balloon enteroscopies revealed irregular nodular mucosal lesions with erosion extending from the jejunum to terminal ileum. Histopathological evaluation of the biopsied mucosa showed proliferation of small-to-medium-sized lambda light chain-restricted B cells. Plasmacytic differentiation and lymphoepithelial lesions were present, leading to the diagnosis of MALT lymphoma. Tc-99m albumin scintigraphy indicated tracer exudation in the small bowel, suggesting the presence of PLE. Combination immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen improved both MALT lymphoma and PLE, whereas rituximab monotherapy was not successful. This case is considered to be common type of MALT lymphoma at an uncommon site and is distinct from immunoproliferative small intestinal disease (IPSID). To our knowledge, this is the first case of non-IPSID-type small intestinal MALT lymphoma complicated by PLE. Gastrointestinal reconstruction may be responsible for underlying chronic inflammation via small intestinal bacterial overgrowth.
Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n?=?10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed to improve the visibility of photoacoustic signals emitted from deeply-located lesions.
Autoimmune neutropenia (AIN), resulting from granulocyte-specific autoantibodies, is much less frequent than other autoimmune hematologic disorders including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). These autoimmune disorders may precede, synchronize, or follow collagen disorders, viral infections, and lymphoid neoplasms. Herein we present the first case of AIN in association with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma with nodal dissemination. In our case, AIN, accompanied by ITP, occurred prior to the clinical manifestation of lymphoma. AIN and ITP were well managed afterwards, but they relapsed in accordance with the recurrence of lymphoma. The administration of prednisolone at 0.5 mg/kg daily alleviated the cytopenias within a week. In general, combination chemotherapy is performed for the treatment of lymphoma-associated autoimmune hematologic disorders and indeed seems to be effective. Our case indicates that corticosteroid monotherapy may be effective for lymphoma-associated AIN especially when AIN precedes the onset of lymphoma.
Mucormycosis is an increasingly important cause of morbidity and mortality for patients with hematological malignancies. The diagnosis of mucormycosis usually requires mycological evidence through tissue biopsy or autopsy because the signs and symptoms are nonspecific and there are currently no biomarkers to identify the disease. We herein present two autopsied cases of acute myeloid leukemia with prolonged neutropenia who developed invasive mucormycosis accompanied by pulmonary artery embolism. Our cases were featured by unexplained fever and rapidly progressive dyspnea. Computed tomography scan detected nodular lesions or nonspecific consolidations in the lungs. Cultures, cytological study, and serum fungal markers consistently gave negative results. Autopsy revealed embolism of the pulmonary artery which consisted of fibrin clots by filamentous fungi. Genomic DNA was extracted from the paraffin-embedded clots and was applied to polymerase chain reaction amplification, leading to the diagnosis of infection by Rhizopus microsporus. We should carefully search for life-threatening pulmonary embolism when patients with hematological malignancies develop pulmonary mucormycosis.
ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models.
We report an extremely rare case of urothelial carcinoma (UC) of the urinary bladder with diverse histological differentiation into squamous, glandular, and plasmacytoid components. A 65-year-old man presented with gross hematuria. Cystoscopy showed a papillary-growing tumor with a wide-based stalk on the left wall of the urinary bladder. Based on the clinical diagnosis of locally invasive bladder cancer, the patient underwent radical cystectomy. Histological examination of the cystectomy specimen revealed UC with histological differentiation into multiple tumor subtypes. The tumor was composed of squamous cell carcinoma with marked keratinization, adenocarcinoma characterized by tall columnar cells with scattered goblet cells, conventional high-grade invasive UC and UC in situ, and plasmacytoid UC composed of discohesive cancer cells with eccentric nuclei and eosinophilic cytoplasm that diffusely infiltrated the bladder wall through the serosal surface. Immunohistochemically, the loss of membranous E-cadherin expression was noted only in the plasmacytoid UC component. The patient developed local recurrences 2 months postoperatively and died of the disease 6 months postoperatively. It is critical to correctly diagnose the histological variants of UC to predict a patient's prognosis and to determine the optimal treatment.
Esophageal complications occur after hematopoietic stem cell transplantation (HSCT). There are, however, only limited reports on the etiology or management of esophageal complications. Here, we report the occurrence of intramucosal hematoma presenting continuous esophageal hemorrhage in a 34 year-old man following the second peripheral blood stem cell transplantation for acute myeloid leukemia. His hematemesis started 2 months after HSCT and was repeated in supportive care. On day 156, he underwent total esophagectomy as a result of uncontrollable massive hematemesis. Histopathological testings of the resected esophagus confirmed intramucosal hematoma as a cause of hematemesis. This case highlights intramucosal hematoma as one of the important etiologies of esophageal complications following HSCT.
In Lewy body disease, Lewy pathology (LP: the accumulation of ?-synuclein in neuronal perikarya and processes as Lewy bodies and Lewy neurites and dots, respectively) is observed in the central and peripheral nervous systems. Previous autopsy or biopsy studies of individuals with Lewy body diseases (LBDs) indicated that LP could be observed in the peripheral nerves of the gastrointestinal (GI) systems. The aim of this study is to clarify whether examination of GI and biliary surgical specimens would be useful for diagnosing LBD. We analyzed eight patients diagnosed clinically with LBD and with medical histories of GI or biliary surgery at our hospital. LP was identified by using ?-synuclein immunohistochemistry in GI and biliary surgical specimens obtained before, at or after the clinical onset of LBD. LP was frequently observed in Auerbach's plexus, Meissner's plexus and the subserosal nerve fascicles within the GI and biliary surgical specimens. LP was observed in the specimens obtained 7 years before the onset of LBD. Our approach does not require any invasive procedures for patients. The immunohistochemical analysis of anti- ?-synuclein antibody to archival GI or biliary surgical specimens from patients with clinically suspected LBD may contribute to clinical diagnosis of LBD.
Analysis of acetylation and tri-methylation of the same residue of histone molecules might identify a subset of hepatocellular carcinoma (HCC) with aggressive behavior. In the present study, we examined acetylation and tri-methylation of lysine 27 on histone H3 (H3K27ac and H3K27me3, respectively) because these two modifications are known to exhibit opposite effects (enhancing and silencing) on gene expression. Neoplastic and non-neoplastic tissues from 198 HCC cases were immunostained with specific monoclonal antibodies against H3K27ac and H3K27me3. The stained tissues were evaluated by an image analyzing program to generate histological scores (H-scores, range 0-300), which were determined by multiplying the percentage of positive-stained cells with the classified immunohistochemical marker intensity (0-3). HCC tissues showed significantly higher H3K27ac (156.7±86.8) and H3K27me3 H-scores (151.8±78.1) compared with the background liver (40.3±33.0 and 64.7±45.6, respectively) (both P<0.001). The cases with H-scores of high-H3K27ac/high-H3K27me3 (n?=?54) showed significant correlation with poor differentiation of morphology (P<0.01) and p53-positive staining (P<0.05), and poor prognosis (P<0.01). Confocal microscopy revealed segregated intranuclear localization of both modifications in the individual cancer cells: H3K27ac localization in central euchromatin regions and H3K27me3 in peripheral heterochromatin regions. Concurrent acetylation and methylation at H3K27 occurs in HCC cells in association with p53 abnormalities. These findings demonstrate that image analyzer-assisted H-scores of H3K27ac and H3K27me3 identified an aggressive subgroup of HCC, and could serve as a prognostic marker for HCC.
Upper urinary tract urothelial carcinomas (UUTUC) are infrequent and show an occurrence of about 5-10% of all urothelial carcinomas. In this study, we investigated the HER2 status of 171 UUTUC patients with nephroureterectomy. The number of patients is the largest of any HER2 study. All 171 cases were analyzed for both HER2 overexpression using immunohistochemistry and HER2 gene amplification using dual-color in situ hybridization. The scoring system proposed by the ASCO/CAP and ToGA trials was used. Out of 171 patients, 140 patients had a HER2 score-0 or score-1 (81.9%), 17 a score-2 (9.9%), and 14 a score-3 (8.2%) with immunohistochemistry. HER2 gene amplification was observed in 31 out of 171 cases (18.1%). A good correlation was observed between protein overexpression and gene amplification (p<0.0001). Twenty-three UUTUC (13.5%) were determined as HER2-positive cancer according to ASCO/CAP and ToGA criteria. HER2 positivity in patients over 70 years old was higher than that of patients under 70 years old (p=0.0132). HER2 expression correlated to a high histological grade (p=0.0003) and the coexistence of a high grade carcinoma in situ (p=0.0089). No HER2-positive cancer was observed in patients with renal pelvic UUTUC (0 out of 76, p<0.0001). HER2-positive UUTUC showed a shorter recurrence time in the residual urinary bladder after nephroureterectomy with Kaplan-Meier analysis (p=0.0284) and multivariate analysis (p=0.0034). The results suggest that HER2 positivity in UUTUC is an independent predictive marker for early recurrence of urothelial carcinoma in the residual urinary bladder after surgery.
Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a rare mesenchymal tumor of the stomach. We report herein a case with CT findings, which illustrate the characteristic growth pattern of PAMT. A 27-year-old female patient visited our hospital because of epigastric pain and anemia. The CT scan showed a heterogeneous tumor in the gastric antrum, which was drastically enhanced with contrast medium, and consisted of a number of highly stained small nodules around the tumor rim. The resected tumor, 4.6 cm in size, was c-kit negative and SMA-positive by immunohistochemistry, and composed of bland spindle cells which were separated by abundant myxomatous stroma. The tumor showed plexiform growth in the entire stomach wall, with multiple nodules protruding outward within the serosa. The CT findings in this case reflect the characteristic PAMT growth pattern, and are distinct enough to differentiate it from gastrointestinal stromal tumor (GIST).
We herein report two cases of relapsed follicular lymphoma (FL) with transformation in the retroperitoneal muscles. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT) showed high uptakes in the retroperitoneal muscles. We considered excisional biopsy at first, since it is definitely the most reliable means to obtain histological diagnosis. However, excisional biopsy of the retroperitoneal muscles is challenging for anatomical reasons. Moreover, our patients were kept under poor performance status. Thus, CT-guided percutaneous needle biopsy of FDG-avid retroperitoneal muscles was performed. Histopathological examination of the biopsied specimens demonstrated proliferation of transformed large B cells in both cases. Sheets of large B cells were also recorded in one case. CT-guided needle biopsy is less prioritized than excisional biopsy because of limited information on tissue architecture and increasingly complicated WHO classification. Our series indicate that image-guided needle biopsy of FDG-avid lesions is sufficient for the diagnosis of transformation. Higher priority should be given to this method in the setting of transformed aggressive lymphoma.
Lung cancer is one of the most frequent causes of cancer-related death worldwide. However, molecular markers for lung cancer have not been well established. To identify novel genes related to lung cancer development, we surveyed publicly available DNA microarray data on lung cancer tissues. We identified lipase member H (LIPH, also known as mPA-PLA1) as one of the significantly upregulated genes in lung adenocarcinoma. LIPH was expressed in several adenocarcinoma cell lines when they were analyzed by quantitative real-time polymerase chain reaction (qPCR), western blotting, and sandwich enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis detected LIPH expression in most of the adenocarcinomas and bronchioloalveolar carcinomas tissue sections obtained from lung cancer patients. LIPH expression was also observed less frequently in the squamous lung cancer tissue samples. Furthermore, LIPH protein was upregulated in the serum of early- and late-phase lung cancer patients when they were analyzed by ELISA. Interestingly, high serum level of LIPH was correlated with better survival in early phase lung cancer patients after surgery. Thus, LIPH may be a novel molecular biomarker for lung cancer, especially for adenocarcinoma and bronchioloalveolar carcinoma.
Although cisplatin (CDDP) is a key drug in the treatment of esophageal squamous cell carcinoma (ESCC), acquired chemoresistance remains a major problem. Combination therapy may represent one strategy to overcome this resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effects of combining CDDP with the HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) on two CDDP-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. The results obtained demonstrated the synergistic inhibitory effects of CDDP and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with CDDP and 17-AAG than by the treatment with either CDDP or 17-AAG alone. Western blotting revealed that the combined action of CDDP and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, which demonstrated that the reduction in both cell growth and cell number was mediated by apoptosis. Time-course experiments showed that reduction in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. The results of the present study demonstrate that 17-AAG synergizes with CDDP and induces apoptosis in CDDP-resistant ESCC cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. Combination therapy with CDDP and an HSP90 inhibitor may represent a promising strategy to overcome CDDP resistance in ESCC.
We report an extremely rare case of Langerhans cell histiocytosis (LCH) of the urinary bladder. A 68-year-old man presented with gross hematuria. Cystoscopy showed multiple papillary tumors in the urinary bladder, and transurethral resection was performed. Pathological diagnosis was high-grade papillary urothelial carcinoma with lamina propria invasion. The patient received six treatments with intravesical Bacillus Calmette-Guérin (BCG) therapy. Seven months after surgery, follow-up cystoscopy showed three elevated lesions in the urinary bladder, two of which were identified histologically as recurrent urothelial carcinoma. Microscopic examination of the lesion at the anterior wall revealed diffuse infiltration of medium to large histiocytoid cells in the lamina propria, many of which had distorted nuclei and nuclear grooves. Dense eosinophilic infiltration was also observed. Immunohistochemically, the histiocytoid cells were diffusely positive for S-100 and CD1a, but negative for cytokeratin AE1/AE3 and melanosome-associated antigen recognized by HMB-45. Based on the histological and immunohistochemical features, we diagnosed the lesion as LCH of the urinary bladder. There was no evidence of recurrence of either bladder cancer or LCH after an 18-month follow-up. To avoid misdiagnosis, urologists and pathologists should be aware that LCH may develop in the urinary bladder after intravesical BCG therapy for bladder cancer.
Object Meningiomas treated by subtotal or partial resection are associated with significantly shorter recurrence-free survival than those treated by gross-total resection. The Simpson grading system classifies incomplete resections into a single category, namely Simpson Grade IV, with wide variations in the volume and location of residual tumors, making it complicated to evaluate the achievement of surgical goals and predict the prognosis of these tumors. Authors of the present study investigated the factors related to necessity of retreatment and tried to identify any surgical nuances achievable with the aid of modern neurosurgical techniques for meningiomas treated using Simpson Grade IV resection. Methods This retrospective analysis included patients with WHO Grade I meningiomas treated using Simpson Grade IV resection as the initial therapy at the University of Tokyo Hospital between January 1995 and April 2010. Retreatment was defined as reresection or stereotactic radiosurgery due to postoperative tumor growth. Results A total of 38 patients were included in this study. Regrowth of residual tumor was observed in 22 patients with a mean follow-up period of 6.1 years. Retreatment was performed for 20 of these 22 tumors with regrowth. Risk factors related to significantly shorter retreatment-free survival were age younger than 50 years (p = 0.006), postresection tumor volume of 4 cm(3) or more (p = 0.016), no dural detachment (p = 0.001), and skull base location (p = 0.016). Multivariate analysis revealed that no dural detachment (hazard ratio [HR] 6.42, 95% CI 1.41-45.0; p = 0.02) and skull base location (HR 11.6, 95% CI 2.18-218; p = 0.002) were independent risk factors for the necessity of early retreatment, whereas postresection tumor volume of 4 cm(3) or more was not a statistically significant risk factor. Conclusions Compared with Simpson Grade I, II, and III resections, Simpson Grade IV resection includes highly heterogeneous tumors in terms of resection rate and location of the residual mass. Despite the difficulty in analyzing such diverse data, these results draw attention to the favorable effect of dural detachment (instead of maximizing the resection rate) on long-term tumor control. Surgical strategy with an emphasis on detaching the tumor from the affected dura might be another important option in resection of high-risk meningiomas not amenable to gross-total resection.
Unicentric Castlemans disease is a rare, benign lymphoproliferative disorder that is curable with surgical resection. However, significant bleeding often occurs during surgery because of tumor hypervascularity. We herein present a case of hyaline-vascular-type mediastinal unicentric Castlemans disease, successfully resected using video-assisted thoracoscopic surgery with preoperative embolization. In the present case, tumor hypervascularity and feeding vessels were revealed by computed tomography (CT), which led us to perform preoperative angiography and embolization to the tumor feeding arteries to reduce intraoperative bleeding. Castlemans disease should be considered in the differential diagnosis of hypervascular mediastinal tumors. Tumor vascularity should be assessed prior to surgery, and preoperative embolization should be considered.
Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear.
Previously, we reported that the overexpression of fer tyrosine kinase (FER), a non-receptor tyrosine kinase, is correlated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer (NSCLC). In the present study, we further analyzed FER-overexpressed NSCLC cases and identified various patterns of chimeric mRNAs, composed of paraja ring finger 2 (PJA2) and FER. We detected no genomic rearrangements between PJA2 and FER and attributed these chimeric mRNAs to alterations at the transcriptome level: i.e., trans-splicing. Several chimeric patterns were detected concurrently in each patient, and the pattern sets varied among patients, although the pattern in which PJA2 exon 1 was fused to FER exon 3 (designated as Pe1-Fe3 mRNA) was detected constantly. Therefore, in a wide screening for PJA2-FER mRNAs in NSCLC, we focused on this chimeric pattern as a representative chimera. In analyses of 167 NSCLC samples, Pe1-Fe3 mRNA was identified in about 10% of the patients, and the presence of chimeric mRNA was significantly correlated with a high expression level of parental FER mRNA. Furthermore, we found that the detection of Pe1-Fe3 mRNA was correlated with poor postoperative survival periods in NSCLC, consistent with a previous finding in which FER overexpression was correlated with poor postoperative prognosis in NSCLC. This report is the first to suggest a correlation between chimeric mRNA and the expression level of parental mRNA. Furthermore, our findings may be clinically beneficial, suggesting that PJA2-FER mRNAs might serve as a novel prognostic biomarker in NSCLC.
Sclerogenic biliary changes in hepatic amyloidosis are seldom observed. Here, we report two recent cases initially suspected as primary sclerosing cholangitis (PSC), which were later diagnosed as hepatic amyloidosis (AL type). Case 1: On the basis of magnetic resonance cholangiopancreatography (MRCP) findings, PSC was suspected in a 41-year-old woman with jaundice. Computed tomography (CT) showed nodular pulmonary lesions and swollen cervical, mediastinal and para-aortic lymph nodes, the cause of which was unknown despite detailed examinations. Because of rapid deterioration in the patients liver function, living donor liver transplantation was performed. She was then diagnosed with hepatic amyloidosis, but died of heart failure due to cardiac amyloidosis 74?days after surgery. Case 2: On the basis of MRCP findings, PSC was suspected in a 49-year-old woman with jaundice. CT showed multiple cystic pulmonary lesions, and hypogammaglobulinemia was also observed (immunoglobulin G, 481?mg/dL). After a biliary plastic stent was placed, liver and lung biopsy confirmed the presence of amyloid deposition. These two cases indicate that it is important to consider hepatic amyloidosis as a differential diagnosis of PSC. The presence of atypical extrahepatic lesions may be useful clues for confirming the diagnosis.
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 ?-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 ?-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.
Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which ?100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C-VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC.
Pulmonary tumor thrombotic microangiopathy is a rare but lethal complication in cancer-bearing patients, particularly those with gastric cancer. It is characterized by cancer cell emboli with marked intimal proliferation. In the present study, we tried to elucidate the pathogenesis of pulmonary tumor thrombotic microangiopathy, notably angiogenic factors specific for cancer cells lodged in pulmonary arteries. An autopsy series of gastric cancer (51 cases) was reviewed for pulmonary tumor thrombotic microangiopathy and pulmonary tumor cell emboli without intimal proliferation. Pathological and immunohistochemical characteristics were compared between two groups. In eight cases in muscular pulmonary arteries, tumor thrombotic microangiopathy was noted, and in three cases pulmonary tumor emboli without intimal proliferation was noted. Histological features of pulmonary tumor thrombotic microangiopathy included small nests or single cancer cells accompanied by intimal proliferation, whereas in pulmonary tumor emboli large cell nests prevailed. By immunohistochemistry, in pulmonary tumor thrombotic microangiopathy, cancer cells expressed platelet-derived growth factor-A (7/8 cases) and vascular endothelial growth factor-C (8/8) more frequently than in pulmonary tumor emboli (0/3 and 1/3; P?=?0.02 and P?=?0.055, respectively). Expression of tissue factor, vascular endothelial growth factor-A and -D, osteopontin, fibroblast growth factor-2, and platelet-derived growth factor-B was similar in both groups. Platelet-derived growth factor-A and vascular endothelial growth factor-C might induce intimal proliferation in pulmonary arteries and contribute to the development of pulmonary tumor thrombotic microangiopathy.
Mucinous borderline tumours of the ovary are subclassified as intestinal-type (IMBT) and endocervical-like (EMBT), which differ in their clinicopathological features. In this study, we attempted to elucidate characteristics of the mucinous epithelium in each subtype.
Epstein-Barr virus (EBV) is a representative human oncogenic virus that causes malignancies of various cell lineages. LMP2A, an EBV-encoded latent membrane protein, is expressed in EBV-associated malignancies of various cell lineages. LMP2A caused visible tumor formation transplanted in nude mice when transferred to immortalized non-transformed fibroblasts, NIH3T3. LMP2A-expressing cells showed higher ability of colony formation in soft agar than empty vector-transfected control cells, although the expression of LMP2A did not cause focus transformation in low serum concentrations. LMP2A expression increased the size of Hoechst 33,342 dye excreting side population (SP), in which cancer-initiating cells or cancer stem-like cells were enriched. SP increase by LMP2A was also responsible for colony formation in soft agar. The LMP2A-mediated SP increase depended on the activations of Stat3, MEK/ERK, and PI3K pathways, and on upregulation of HMGA2. Enrichment of SP, stem-like cells, by LMP2A promoted the transformation capability of LMP2A from non-transformed cells. The enrichment of stem-like cell population by a virus-encoded factor might explain the oncogenic functions of oncogenic viruses.
Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr286 by GSK3? triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however, reports of mutations are extremely rare. We analyzed mutations of the cyclin D1 gene, CCND1, in 88 endometrial cancer tissue specimens and detected mutations in 2 cases (2.3%). Both were unreported mutations with substitution of threonine to isoleucine at codon 286 (T286I). These two tumors harbored coexisting mutations in K-ras, PIK3CA and/or PTEN and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry. Furthermore, we analyzed the functions of mutant cyclin D1 (T286I) by luciferase assays, immunofluorescence, western blotting and clonogenic cell survival assays in HEK-293T cells. We found that exogenous mutant cyclin D1 (T286I) accumulated in the nuclei in HEK-293T cells, and that it inhibited the expression of pRb. Additionally, the number of colonies was increased by introduction of mutant cyclin D1 (T286I) compared to that of wild-type cyclin D1. In conclusion, we identified an unreported CCND1 mutation (T286I) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells.
Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes, embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited near-diploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS.
Very well-differentiated gastric adenocarcinoma of intestinal type is a rare variant of gastric cancer characterized by low-grade nuclear atypia, and for which the diagnostic criteria and clinical behavior are not fully established. This study presents a detailed histologic, immunohistochemical, and clinical analysis of 21 cases. Nuclear atypia was mild in all cases. Characteristic architectural features of this gastric adenocarcinoma variant were pit and glandular anastomosis, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth. At least three of these features were present in all the cases. Retrospective review of preoperative biopsies in 18 patients revealed that half of the biopsies were originally reported as negative or indeterminate for malignancy. On the basis of immunohistochemical stains for intestinal (MUC2, CD10, and CDX-2) and gastric (MUC5AC and MUC6) markers, 11 (52%) cases had an intestinal immunophenotype and 10 (48%) cases had a mixed immunophenotype. Foci of discohesive neoplastic cells, indicating dedifferentiation toward a poorly cohesive carcinoma, were observed exclusively in neoplasms of mixed immunophenotype (n=5). All patients with follow-up but one were alive without disease at a mean of 19 months (range 1-60 months). One individual with a pT4 tumor with associated poorly cohesive carcinoma died of disease. In summary, very well-differentiated gastric adenocarcinomas are diagnostically challenging. Architectural features are critical to making the diagnosis. Cases with pure intestinal immunophenotype have not been associated with transformation into poorly cohesive carcinoma, and appear to behave as biologically low grade. Those with mixed immunophenotype appear more likely to dedifferentiate and behave more aggressively.
Hypoxia plays a crucial role in many pathophysiological conditions, including cancer biology, and hypoxia-inducible factor (HIF) regulates transcriptional responses under hypoxia. To elucidate the cellular responses to hypoxia, we performed chromatin immunoprecipitation with deep sequencing in combination with microarray analysis and identified HIF-1 targets. We focused on one of the novel targets, sperm-associated antigen 4 (SPAG4), whose function was unknown. SPAG4, an HIF-1-specific target, is up-regulated in various cultured cells under hypoxia. Examination of SPAG4 expression using a tissue microarray consisting of 190 human renal cell carcinoma (RCC) samples revealed that SPAG4 is an independent prognostic factor of cancer-specific mortality. Live-cell imaging revealed localization of SPAG4 at the intercellular bridge in telophase. We also studied cells in which SPAG4 was knocked down. Hypoxia enhances tetraploidy, which disturbs cell proliferation, and knockdown of SPAG4 increased tetraploid formation and decreased cell proliferation under both normoxic and hypoxic conditions. Studies using deletion mutants of SPAG4 also suggested the involvement of SPAG4 in cytokinesis. Microarray analysis confirmed dysregulation of cytokinesis-related genes by knockdown of SPAG4. In conclusion, SPAG4 is an independent prognostic factor in RCC and plays a crucial role in cytokinesis to defend against hypoxia-induced tetraploid formation. This defensive mechanism may promote survival of cancer cells under hypoxic conditions, thus leading to poor prognosis.
? Multidrug resistance (MDR) in B-cell lymphomas still constitutes a major obstacle to the effectiveness of chemotherapy even in the anti-CD20 antibody therapy era. The aim of this study was to investigate the expression of MDR-associated molecules in reactive lymphadenopathy (RL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).
Metastatic seminoma can potentially be confused with lymphoma in a lymph node biopsy. Here, we report a case in which the immunohistochemistry of CD10 was a pitfall in the differential diagnosis of a metastatic seminoma, and further present a brief study of CD10 expression in a seminoma series. A 67-year-old man, who had a history of lobectomy of the lung due to squamous cell carcinoma 2 years prior, showed lymphadenopathy of the neck and the paraaorta on follow-up study by fluorodeoxyglucose-positron emission computer tomography scan. The biopsy of the cervical node demonstrated infiltration of large atypical cells. The results of the screening immunohistochemistry were CD20(-), CD3(-), CD10(+), CD30(-), AE1/AE3(-), and placental alkaline phosphatase(-), providing the impression of CD10-positive lymphoma. However, the following studies revealed germ cell characteristics [OCT3/4(+), SALL4(+), and CLDN6(+)], confirming the diagnosis of seminoma. We further evaluated CD10 expression in a series of seminomas (n=16). Strong positivity was observed in 14 cases; partial and weak positivity, in 2 cases. These findings should be considered in the differential diagnosis of seminoma.
Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (?4 ALK copies in ?40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement is therapeutically relevant, this comprehensive analysis may help future studies on the utility of ALK-targeted therapy for patients with rhabdomyosarcoma.
Certain tumor characteristics may pose challenges when endoscopically determining the horizontal extent of early gastric cancers (EGC). In the present study, clinicopathological features related to inaccurate endoscopic evaluation of horizontal extent of intestinal-type EGC were analyzed.
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