Littoral cell angioma of the spleen: a study of 25 cases with confirmation of frequent association with visceral malignancies.

AIMS: Littoral cell angioma (LCA) is a rare primary splenic tumour that is frequently associated with internal malignancies. Immunohistochemistry can demonstrate a distinct hybrid endothelial-histiocytic phenotype of littoral cells, and is a helpful adjunct for making the correct diagnosis. The aims of this study were to present a series of 25 LCAs, with an emphasis on the frequent association of the neoplasm with visceral malignancies, and to provide a detailed immunohistochemical analysis by employing new markers. METHODS AND RESULTS: All 25 cases with available tissue blocks were immunohistochemically stained for endothelial and histiocytic markers. Clinical and follow-up data were retrieved from the respective institutions. The tumours were obtained from 16 males and nine females, whose age ranged from 32 to 86 years (mean 56.2 years). Clinical information was available for 24 of 25 patients, and follow-up for 11 of 25 patients (range 2-19 years; mean 11.6 years). Immunohistochemically, all cases were positive for LYVE-1, factor VIII, FLI-1, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, claudin-5, ERG, LMO2, CD31, CD163, lysozyme, and CD4, but negative for D2-40, CD8, and factor XIIIa. Fifteen of 25 cases were associated with various malignancies, including epithelial, mesenchymal and haematological tumours. CONCLUSIONS: The cohort of 25 patients is the largest series of LCAs published to date. By using antibodies against recently introduced endothelial markers, we have expanded the immunoprofile of LCA. We have further highlighted the clinical significance of LCA, as more than half of the patients in this study also harboured a coexisting visceral malignancy. Therefore, we conclude that the finding of splenic LCA mandates a thorough clinical evaluation for a concomitant malignancy.

Discovery of Novel TULP4/ACTN4/EWSR1/ACTB::MYB and ESRRG::DNM3 Fusions Expands Molecular Landscape of Adenoid Cystic Carcinoma Beyond Fusions Between MYB/MYBL1 and NFIB Genes.

Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs in all major and minor salivary gland and seromucous gland sites. AdCCs of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost consistent presence of fusion genes MYB::NFIB, or less commonly MYBL1::NFIB. We collected a cohort of 95 cases of AdCC, which were largely characterized by canonical fusions MYB::NFIB (49 cases) or MYBL1::NFIB (9 cases). In additional 11 cases of AdCC, rearrangements in MYB or NFIB genes were detected by FISH. In addition, NGS revealed novel noncanonical fusion transcripts EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, MYB::TULP4, and ACTN4::MYB, each of them in 1 case. The tumors that showed noncanonical fusions had features of metatypical AdCC with a diverse architecture, lobulated multinodular growth pattern, and hypercellular peripheral palisading of nuclei (2 cases), tubular hypereosinophilia (2 cases), and pale eosinophilic to vacuolated (bubbly) cytoplasm (3 cases). Our study documented 3 cases of AdCC of salivary glands harboring novel gene fusions TULP4::MYB, ACTN4::MYB, and ACTB::MYB, in 1 case each, which have not been described before. A rare EWSR1::MYB fusion was detected in 1 case. Moreover, 1 case of sinonasal metatypical AdCC showed EWSR1 rearrangement detected by FISH. Also, 1 case with an ESRRG::DNM3 fusion of unknown significance is described in this study. These discoveries illustrate how broad molecular profiling will expand understanding of changes in known entities.

Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking.

UNLABELLED: The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1-positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator-activated receptor (PPAR) α and ß as well as steroid regulatory element-binding protein (SREBP)-1c was decreased in HCV-infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels. CONCLUSION: Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury.

Adenocarcinoma arising in an ectopic mediastinal pancreas.

Pancreatic ectopia in the mediastinum is rare, and there are no reports that it has ever given rise to malignancy. Here we report a case of adenocarcinoma arising in ectopic pancreatic tissue in the mediastinum of a 66-year-old woman. The tumor arose in a partially cystic and partially solid ectopic pancreas containing both exocrine and endocrine components. Thorough clinical examination and clinical follow-up did not reveal other primary sites. The tumor was partially resected but metastasized to the anterior sternum 6 months later and was re-excised. No other similar cases of primary mediastinal pancreatic adenocarcinoma are on record in medical literature.

Biphasic alveolosquamoid renal carcinoma: a histomorphological, immunohistochemical, molecular genetic, and ultrastructural study of a distinctive morphologic variant of renal cell carcinoma.

Only a few cases of sarcomatoid renal cell carcinomas (RCCs) with squamous differentiation have been published. We present 2 RCCs exhibiting a hitherto not reported biphasic neoplastic cell population exhibiting a predominantly alveolar architecture where squamoid differentiation was identified in one of the neoplastic cell populations. None of the tumors showed chromophobe features or any evidence of sarcomatoid transformation. The tumors arose in 2 adult patients and were characterized by routine histology, immunohistochemistry, ultrastructure, array comparative genomic hybridization, confirmatory fluorescent in situ hybridization, and loss of heterozygosity analysis. Tumors measured 3 and 4 cm and were located within the renal parenchyma and had no pelvicalyceal connection. Both tumors were composed of a distinctly dual-cell population. The larger tumor cells displayed squamoid features and formed round well-demarcated solid alveolated islands that, in large parts, were surrounded by a smaller neoplastic cell component. The squamoid cells were immunoreactive for cytokeratins (CKs) (AE1-AE3, Cam 5.2, CK5/6, CK7, and CK20), epithelial membrane antigen, racemase/AMACR, and carboanhydrase IX (in 1 case focally). The small cell population was positive for CK7, epithelial membrane antigen, and racemase/AMACR, whereas CK20, AE1-3, and carboanhydrase IX were negative. CD10 was focally positive in the large squamoid cells in 1 case. Cathepsin K, E-cadherin, and CD117 displayed focal positivity in 1 case. Vimentin, RCC marker, parvalbumin, S100 protein, S100 A1, p63, p53, CDX2, uroplakin III, HMB45, TFE3, WT1, synaptophysin, chromogranin A, thyroglobulin, and TTF1 were negative. The proliferative activity (Ki-67) was low (1%) in the small cell component in both cases, whereas the large neoplastic tumor cells displayed a significantly higher proliferation (20%-35%). Ultrastructurally, desmosomes and tonofilaments were identified in the large tumor cells, confirming squamoid differentiation in a subset of tumor cells. Array comparative genomic hybridization of 1 analyzable case (confirmed with fluorescent in situ hybridization and loss of heterozygosity analysis) revealed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22, (including biallelic loss of CDKN2A locus) and partial gains of chromosomes 1, 5, 11, 12 and 13. Follow-up at 6 years showed no recurrence or metastasis in 1 patient. The other (male) patients had a subcutaneous metastasis at presentation, but during a 1-year follow-up no evidence of recurrence or further metastatic events have been documented. Our data indicate that biphasic alveolosquamoid renal carcinoma is a unique and distinctive tumor. The large squamoid and small tumor cells have overlapping but still distinctive immunohistochemical patterns of protein expression. Multiple chromosomal aberrations were identified, some of them located in regions with known tumor suppressor genes and oncogenes.

Rosai-Dorfman disease presenting as a breast mass and enlarged axillary lymph node mimicking malignancy: a case report and review of the literature.

Rosai-Dorfman disease (also called sinus histiocytosis with massive lymphadenopathy) involves lymph nodes or lymph nodes with extranodal sites. We present a unique case of a patient presenting with a breast mass and axillary lymphadenopathy, mimicking malignancy clinically and radiographically. Core needle biopsies of the breast and axillary lymph node showed histologic features concerning the lymphoma. However, excisional biopsy specimen demonstrated characteristic features of Rosai-Dorfman disease. The disease recurred locally 6 months later in the same breast, 1 month later in the contralateral breast, and 11 month later in the subcutaneous tissue of left flank. A review of the literature of Rosai-Dorfman disease involving the breast is also presented.

Testicular Germ Cell Tumors: Serological and Immunohistochemical Diagnosis.

This review deals with serologic and immunohistochemical tumor markers used in clinical laboratories for the diagnosis of testicular germ cell tumors. Time tested serologic markers such as alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are routinely used in the work-up of patients with testicular tumors. Professional organizations regulating the practice of medicine in most countries worldwide require that the laboratory values for these serologic reactants be included in the pathology reports on testicular tumors as part of the tumor staging process. Immunohistochemical markers of testicular germ have been identified and widely tested during the first two decades of the XXI century. We have selected the most useful immunohistochemical markers from a few of these markers and discussed them in this review. CONCLUSION: Published data show that testicular tumor markers are widely used in routine practice. The study of tumor markers has improved the pathologic and clinical diagnosis of testicular germ cell tumors and has thus contributed to their treatment.

The protective role of pregnane X receptor in lipopolysaccharide/D-galactosamine-induced acute liver injury.

The pregnane X receptor (PXR) is a nuclear receptor transcription factor regulating drug-metabolizing enzymes and transporters that facilitate xenobiotic and endobiotic detoxification. Recent studies show that PXR is important in abrogating intestinal tissue damage. This study examines the role of PXR in lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver injury using wild-type and PXR-null mice. LPS/GalN-treated PXR-null mice had greater increases of alanine transaminase (ALT), hepatocyte apoptosis, necrosis, and hemorrhagic liver injury than wild-type mice. LPS/GalN-mediated phosphorylation of JNK1/2 and ERK1/2 was differentially regulated in wild-type and PXR-null mice. Importantly, LPS/GalN-induced hepatic Stat3 survival signaling was impaired and early activation of Jak2 was delayed in PXR-null mice. Expression levels of pro-survival proteins Bcl-xL and heme oxygenase-1 (HO-1), which are downstream of Stat3, were substantially lower in PXR-null than wild-type mouse livers after LPS/GalN treatment. Autophagy is also involved in LPS/GalN-induced liver injury. Lack of PXR resulted in a significant reduction of LC3B-I, -II as well as Beclin-1 protein levels after LPS/GalN treatment. In addition, PXR is implicated in hepatocytes homeostasis. Taken together, PXR is a critical hepatoprotective factor. Increases of LPS/GalN-induced hepatocyte apoptosis and liver injury in PXR-null mice are due to deregulated mitogen-activated protein (MAP) kinase activation as well as delayed Jak2/Stat3 activation, which lead to a compromise in defense mechanisms that involve Bcl-xL-, HO-1, and autophagy-mediated pathways.

Characterization of human embryonic stem cell lines by the International Stem Cell Initiative.

The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue-nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.

Hepatocyte retinoid X receptor alpha-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury.

Hepatocyte retinoid X receptor alpha (RXRalpha)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXRalpha-mediated pathways are implicated in lipid homeostasis and the inflammatory response, we hypothesized that a compromise in lipid metabolism and associated production of proinflammatory mediators are responsible for the hepatotoxicity observed in ethanol-treated hepatocyte RXRalpha-deficient mice. Wild-type and hepatocyte RXRalpha-deficient mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks. After ethanol treatment, serum ALT levels increased significantly (4-fold) in hepatocyte RXRalpha-deficient mice, but not in the wild-type mice. Hepatic liver fatty acid binding protein (L-FABP) mRNA and protein levels were reduced due to RXRalpha deficiency. Ethanol induced L-FABP mRNA and protein in wild-type mice and provided protection against nonesterified fatty acid toxicity; however, this effect was absent in the mutant mice. Accordingly, hepatic nonesterified fatty acid level was increased in ethanol-fed mutant mice. Ethanol increased nuclear factor (NF)-kappaB binding activity in hepatocyte RXRalpha-deficient mice, but not in wild-type mice. In agreement, hepatic mRNA levels of proinflammatory cytokines and chemokines were increased to a greater extent in the mutant than in wild-type mice. Furthermore, signal transducer and activator of transcription factor (STAT) 3 and associated Bcl-xL induction was observed in ethanol-fed wild-type mice but not in ethanol-fed hepatocyte RXRalpha-deficient mice. Taken together, after ethanol treatment, hepatocyte RXRalpha deficiency results in lack of L-FABP induction, increased hepatic free fatty acids, NF-kappaB activation, and proinflammatory cytokines production and a lack of STAT3 activation, which in part may contribute to alcohol-induced liver damage.

Right Ventricular Heart Failure from a Cardiac Yolk Sac Tumor.

BACKGROUND Cardiac involvement by a malignant tumor is rare. However, this is a case of right heart failure due to cardiac metastasis from a yolk sac tumor. Although a few case reports of cardiac metastasis from yolk sac tumors have been published, to our knowledge this is the first instance of multiple metastases to the right ventricular of yolk sac tumor in an adult male. CASE REPORT The patient is a 46-year-old male with a history of testicular cancer that presented with dyspnea on exertion. He was found to have two large right sided intracardiac masses on echocardiography. Cardiac magnetic resonance imaging (MRI) was obtained to further investigate these masses. Right ventricular function was decreased and concern for right ventricular outflow tract (RVOT) obstruction was present. The patient was taken to the operating room (OR) for resection of the cardiac masses. Pathology revealed the masses to be yolk sac tumors. Despite urgent resection of the tumors, the patient deteriorated clinically, ultimately succumbing to heart failure. CONCLUSIONS This unique presentation of a yolk sac tumor emphasizes the need to keep a broad differential and complete a thorough workup for any cardiac mass. Early diagnosis and treatment of intra-cardiac masses is imperative due to their high rates of mortality. Albeit an uncommon etiology for heart failure, germ cell tumors can potentially metastasize to the heart and present with such a clinical picture.

High-grade renal cell carcinoma with emperipolesis: Clinicopathological, immunohistochemical and molecular-genetic analysis of 14 cases.

Emperipolesis has recently been described as a constant feature of "biphasic squamoid" papillary renal cell carcinoma (BPRCC). We also noticed this in some high-grade (HG) RCC, which promoted the present study to estimate the incidence of emperipolesis in RCCs and to describe them in further detail. 14 cases of HGRCC showing emperipolesis were retrieved from our registry. Microscopic examination of filed slides was supplemented with immunohistochemical and molecular-genetic analyses using paraffin embedded tissue. 12 of 14 patients were males with a mean age of 58.6 years (range 41-72 years). Tumor size ranged from 6-16.5 cm (mean of 8.8 cm). Follow up data were available for 8/14 patients (range 0.5-10 years). Metastases were documented in 6 cases. All tumors showed solid-alveolar growth patterns with focal pseudopapillary features, and were composed of large cells with bizarre nuclei and eosinophilic rhabdoid-like cytoplasm. Emperipolesis was a constant and prominent feature in large bizarre cells. All cases were positive for OSCAR, CANH 9, vimentin, cyclin D1, INI-1, and myoD1, while negative for melanocytic markers, CK 7, myoglobin, cathepsin K, and TFE3. VHL gene abnormalities were found in 6/9 analyzable cases, of which 2 demonstrated polysomy of chromosomes 7, 17. Emperipolesis is a rare histomorphologic feature which can be seen not only in BPRCCs but also in highgrade CCRCCs. All RCC cases with prominent emperipolesis fulfilled both morphologic and immunohistochemical diagnostic criteria of high-grade CCRCC. The majority of patients with available follow up information developed metastases.

Grading invasive ductal carcinoma of the breast: advantages of using automated proliferation index instead of mitotic count.

Breast carcinomas are graded according to the "Nottingham modification of the Bloom-Richardson system" (SBR). The system is hindered, however, by lack of precision in assessing all three parameters including nuclear grade, mitosis, and tubular formation, leading to an element of subjectivity. Our objective was to evaluate a new grading system [the nuclear grade plus proliferation (N+P) system] for subjectivity, ease, and better representation of tumor biology. Its components are nuclear grade and automated proliferation index. Invasive ductal carcinomas, consisting of 137 SBR grade I, 247 grade II, and 266 grade III, were re-evaluated by the N+P system. The two systems were compared with each other and correlated with patients' overall survival, tumor size, angiolymphatic invasion, lymph node status, and biomarker status including estrogen receptor, progesterone receptor, p53, epidermal growth factor receptor, BCL-2, and Her-2. Although there was an agreement between the two systems with histologic and prognostic parameters studied, there was 37% disagreement when grading individual tumors. Fifty-three percent of SBR grade II tumors were "down-graded" to N+P grade I, and 7% were "up-graded" to N+P grade III. Distinction among the different histologic grades for overall survival curves was better indicated by the N+P than the SBR system.

ITGCN of the testis, contralateral testicular biopsy and bilateral testicular cancer.

Over 30 years ago Skakkebaek was the first to characterize a noninvasive precursor lesion (intratubular germ cell neoplasia or carcinoma in situ) that would progress to invasive testicular tumors. In this article we discuss the molecular changes thought to cause this malignant transformation, various conditions that predispose to the development of testicular germ cell tumors, diagnostic strategies, and treatment options. Additionally we discuss the current patterns of contralateral testicular biopsy to identify intratubular germ cell neoplasia, as well as the incidence and management of bilateral testicular tumors.

Myxoid leiomyosarcoma of the liver.

This is the first report of a myxoid leiomyosarcoma arising in a cirrhotic liver. The tumor was resected from a 64-year-old man. On gross examination, it was soft and hemorrhagic. The tumor was composed of deceptively benign-looking smooth muscle cells with clear cytoplasm suspended in a myxoid stroma with foci of hemorrhage. Immunohistochemistry and electron microscopy confirmed that this was a smooth muscle cell neoplasm. The abundance of glycogen and ultrastructural signs of smooth muscle differentiation were considered consistent with an immature smooth muscle cell phenotype consistent with the diagnosis of myxoid leiomyosarcoma. Since myxoid leiomyosarcomas are aggressive tumors, it is important to recognize them histologically and also bear in mind that these tumors can occur even in unusual extrauterine locations such as a cirrhotic liver.

Extranodal NK/T Cell Lymphoma Causing Cardiorespiratory Failure.

Extranodal NK/T cell lymphoma is an uncommon malignancy usually involving the sinonasal area. We report an unusual case of extranodal NK/T cell lymphoma diagnosed in a 62-year-old Caucasian male who died of progressive cardiorespiratory failure but had no clinically detectable upper respiratory system lesions. The initial diagnosis was made cytologically on a sample of pericardial fluid that contained neoplastic lymphoid cells. These cells were positive for CD2, cytoplasmic CD3, and Epstein-Barr virus and negative for CD56. The diagnosis was confirmed at the autopsy, which disclosed lymphoma infiltrates in the myocardium, lungs, stomach, and pancreas. The death was caused by heart and lung failure due to uncontrollable arrhythmia and respiratory insufficiency due to the lymphoma infiltrates. To the best of our knowledge, this is the first case of extranodal NK/T cell lymphoma presenting with cardiopulmonary failure.