STAT6 and phosphorylated STAT6 are differentially expressed in lymphomas.

BACKGROUND: The STAT6 pathway is implicated in the pathogenesis of various lymphomas; however, its immunohistochemical expression has not been fully investigated. Thus, the aim of this study was to investigate the immunohistochemical expression of the two forms of STAT6, phosphorylated or not, in a series of systemic lymphomas. MATERIALS AND METHODS: Immunohistochemical expression of two antibodies, STAT6 (clone YE361) and pSTAT6 (clone Y641), which recognise the phosphorylated form of the molecule was studied in 60 lymphomas. RESULTS: STAT6YE361 expression was cytoplasmic, with 23.3% of the cases showing high expression. pSTAT6Y641 expression was mostly nuclear and found in 45% of the cases. pSTAT6Y641 nuclear expression was associated with the lymphoma type (p < 0.0001), as it was seen mostly in follicular, Hodgkin and angioimmunoblastic T cell lymphomas. STAT6YE361 cytoplasmic expression was also associated with lymphoma type (p = 0.001), as it was mostly found in diffuse large B cell and marginal B cell lymphomas. No association with PD-L1 expression, other clinicopathological data or prognosis was found. CONCLUSION: The two STAT6 clones are differentially expressed between lymphoma types.

Orbital soft tissue composite lymphoma presenting as recurrence of a nodal lymphoma with mantle and follicular cell components: A case report, literature review and guideline for the treatment of patients.

Composite lymphoma with mantle and follicular cell components is a challenging diagnosis. Flow cytometry, immunohistochemistry and molecular genetics are required to distinguish the two components, as often the more aggressive one is predominant and masks the other. A 58-year-old man with history of nodal composite lymphoma presented with right exophthalmos and diplopia. A head CT scan showed an orbital tumor. A biopsy of the tumor revealed a mantle cell lymphoma predominating over a follicular lymphoma. Immunoglobulin heavy chain and light chain rearrangements analysis by PCR proved that both components of the orbital tumor were recurrences of the same nodal composite lymphoma diagnosed two years earlier. The nodal lymphoma was composed of a follicular lymphoma and an in situ mantle cell neoplasia. Consensus view is that dominant lymphoma should be treated when needed but taking into account if the mantle cell lymphoma is an in situ neoplasia and if it expresses CD5 and SOX11.

As the world turns, evolving lymphoma classifications-past, present and future.

The last century and a half has seen first the recognition of lymphomas, and then the publication of one lymphoma classification after another often together with highly critical comments about preceding classifications or a welcome that was less than warm. The introduction of HUMAN PATHOLOGY in 1970 came just before one of the very acrimonious periods in lymphoma classification, as we were learning more about the normal immune system and with the proposed functional lymphoma classifications of Lukes/Collins and Kiel in 1974 relating the lymphomas to their normal B-cell or T-cell 'counterparts'. Those difficult times were followed by the regressive strictly morphologic NCI Working Formulation in 1982, with the REAL classification in 1994 putting us back on a rational path, once again grouping the lymphoid neoplasms first into those of B-cell and T- and putative NK-cell origin, and then using multiple parameters to define specific entities. Planning for the first modern WHO lymphoma classification began soon afterward, with concordance and collegiality leading to the 2001 WHO classification, which then evolved with publication of the 2008 and 2016 WHO classifications. While this review looks at these important past developments which have gotten us to where we are today, it also concentrates on where we are now, what has been learned since the most recent WHO classification and 'Blue Book' were published and on some of the unanswered questions that remain as we look to the future.

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

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

Hematolymphoid lesions of the breast.

Hematolymphoid malignancies of the breast are most commonly neoplasms of mature B-lymphocytes, and may arise as a primary disease or by secondary involvement of a systemic disease. Primary breast lymphomas (PBL) account for 0.04-0.5% of breast malignancies, less than 1% of all non-Hodgkin's lymphomas (NHL), and less than 5% of extranodal lymphomas (Lakhani et al., 2012; Swerdlow et al., 2008; Joks et al., 2011; Barista et al., 2000; Giardini et al., 1992; Brogi and Harris, 1999; Topalovski et al., 1999).1-7 Secondary breast lymphomas (SBL) are also rare, with an estimated annual incidence of 0.07% (Domchek et al., 2002; Talwalkar et al., 2008).8,9 Recognition of breast lesions as hematolymphoid is critical to distinguish them from other entities that can occur in the breast.

Membrane cholesterol is essential for triterpenoid saponin augmentation of a saporin-based immunotoxin directed against CD19 on human lymphoma cells.

Triterpenoid saponins from Saponinum Album (SA) exert potent lytic effects on eukaryotic cell plasma membranes and, when used at sub-lytic concentrations, significantly augment the cytotoxicity of saporin-based immunotoxins (IT). To help elucidate the mechanism(s) behind these two phenomena we investigated the role of cholesterol to both. Human Daudi lymphoma cells were lipid deprived using a combination of three different approaches. Following treatment, the total cellular lipid content was analyzed by electrospray ionization mass spectrometry (ESI-MS) and plasma membrane (PM) cholesterol content measured using the lipophilic fluorescent probe NR12S. Maximal lipid deprivation of cells resulted in a complete loss of sensitivity to lysis by SA. Similarly augmentation of the anti-CD19 immunotoxin (IT) BU12-SAPORIN by SA was lost but without a concomitant loss of intrinsic IT cytotoxicity. The lytic activity of SA was restored following incubation of lipid deprived Daudi cells with Synthecol or LDL. The augmentative effect of SA on IT cytotoxicity for Daudi cells was restored following repletion of PM cholesterol levels with LDL. NR12S fluorescence and ESI-MS analysis of cellular lipids demonstrated that restoration of SA lytic activity by Synthecol was entirely due to increased PM cholesterol levels. Restoration of cellular and PM cholesterol levels by LDL also restored the augmentative effect of SA for IT, an effect associated with repletion of PM cholesterol with minor changes in some phospholipid species. These results indicate that the lytic and IT augmentative properties of SA are cholesterol-dependent in contrast to intrinsic IT cytotoxicity that is at least partially cholesterol independent.

Utility of CEA and CA 15-3 measurements in non-purulent pleural exudates in the diagnosis of malignancy: A single-center experience. / Utilidad de la medición de CEA y CA 15-3 en los exudados pleurales no purulentos para diagnosticar malignidad: experiencia de un único centro.

OBJECTIVE: To establish the diagnostic accuracy of pleural fluid (PF) CEA and CA 15-3 in identifying malignancy, and to determine the additional value of these markers in patients with malignant pleural effusions (MPEs) with false negative results from cytological fluid examination. METHODS: PF concentrations of CEA and/or CA 15-3 were determined in 1,575 patients with non-purulent exudates, 549 of whom had confirmed MPEs, 284 probable MPEs, and 742 benign effusions. Tumor marker cut-off points were set to ensure 100% specificity for malignant effusion. RESULTS: The 41, 40 and 60% of MPE patients had high PF levels of CEA (>45ng/mL), CA 15-3 (>77 UI/l) or both, respectively. These percentages were 30, 19 and 41% in MPEs with positive pleural biopsy and negative PF cytology; and 24, 13 and 35% in clinical MPEs without histocytological confirmation. Tumor markers were of no value in lymphomas and mesotheliomas. The area-under-the-curve for CEA was 0.819 (95% CI: 0,793-0,845) and for CA 15-3, it was 0.822 (95% CI: 0,796-0,847). The use of tumor markers compared to cytology alone, increased the diagnosis of malignancy by 14%. CONCLUSIONS: Measurements of PF CEA and CA 15-3 may complement pleural cytology in the identification of MPEs.

Antibacterial and Cytotoxic Phenolic Metabolites from the Fruits of Amorpha fruticosa.

Fourteen new natural products, namely, 2-[(Z)-styryl]-5-geranylresorcin-1-carboxylic acid (1), amorfrutin D (2), 4-O-demethylamorfrutin D (3), 8-geranyl-3,5,7-trihydroxyflavanone (4), 8-geranyl-5,7,3'-trihydroxy-4'-methoxyisoflavone (5), 6-geranyl-5,7,3'-trihydroxy-4'-methoxyisoflavone (6), 8-geranyl-7,3'-dihydroxy-4'-methoxyisoflavone (7), 3-O-demethyldalbinol (8), 6a,12a-dehydro-3-O-demethylamorphigenin (9), (6aR,12aR,5'R)-amorphigenin (10), amorphispironones B and C (11 and 12), resokaempferol 3-O-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranoside-7-O-α-l-rhamnopyranoside (13), and daidzein 7-O-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranoside (14), together with 40 known compounds, were isolated from the fruits of Amorpha fruticosa. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopic analysis as well as from the mass spectrometry data. ECD calculations were performed to determine the absolute configurations of 11 and 15. Compounds 1, 4-6, and 16-23 showed potent to moderate antibacterial activities against several Gram-positive bacteria with MIC values ranging from 3.1 to 100 µM. In addition, compounds 11 and 24-33 were significantly cytotoxic against the L5178Y mouse lymphoma cell line and exhibited IC50 values from 0.2 to 10.2 µM.

Primary lymphoma of bone in the pediatric and young adult population.

Primary lymphoma of bone (PLB) accounts for 3% to 7% of primary neoplasms of bone and must be distinguished from more common bone tumors in the pediatric population such as osteosarcoma, Ewing sarcoma, and other small round blue cell tumors. In this study, pathology databases from 4 institutions were queried for PLB in individuals 1 to 21 years old. A total of 54 cases of PLB were identified, including 41 diffuse large B-cell lymphomas (DLBCL, 76%), 8 B-lymphoblastic lymphomas (BLL, 15%), 3 anaplastic large cell lymphomas (ALCL, 6%), and 2 low-grade follicular lymphomas (4%). The male/female ratio was 1.8:1 and median age was 16 years (range, 2-21). Patients with DLBCL were significantly older (P<.001), and patients with ALCL and BLL were significantly younger (P=.050 and P=.008, respectively) when compared with the other patients. Due to necrosis, crush artifact, and/or insufficient material, 30% of cases required multiple biopsies for diagnosis. The femur, tibia, pelvic bones, humerus, and vertebrae were most commonly involved. DLBCL patients had significantly more solitary bone involvement (P=.001), whereas BLL had significantly more polyostotic involvement (P<.001). Of the 37 patients with outcome data, all had no evidence of disease on last follow-up. This largest pediatric series of PLB identifies DLBCL as the most frequent subtype and documents rarer occurrences of BLL, ALCL, and follicular lymphomas. The differential diagnosis of bone neoplasms in pediatric patients, including those with necrosis, should include PLB.

Assessment of bone marrow involvement in patients with lymphoma: report on a consensus meeting of the Korean Society of Hematology Lymphoma Working Party.

In September 2011, the Korean Society of Hematology Lymphoma Working Party held a nationwide conference to establish a consensus for assessing bone marrow (BM) involvement in patients with lymphoma. At this conference, many clinicians, hematopathologists, and diagnostic hematologists discussed various topics for a uniform consensus in the evaluation process to determine whether the BM is involved. Now that the discussion has matured sufficiently to be published, we herein describe the consensus reached and limitations in current methods for assessing BM involvement in patients with lymphoma.

Hematolymphoid lesions of the sinonasal tract.

Various hematolymphoid lesions involve the sinonasal tract, including aggressive B, T, and NK-cell neoplasms; myeloid sarcoma; low-grade lymphomas; indolent T-lymphoblastic proliferations; and Rosai-Dorfman disease. Differentiating aggressive lymphomas from non-hematopoietic neoplasms such as poorly differentiated squamous cell carcinoma, olfactory neuroblastoma, or sinonasal undifferentiated carcinoma may pose diagnostic challenges. In addition, the necrosis, vascular damage, and inflammatory infiltrates that are associated with some hematolymphoid disorders can result in misdiagnosis as infectious, autoimmune, or inflammatory conditions. Here, we review hematolymphoid disorders involving the sinonasal tract including their key clinical and histopathologic features.

Coronary Embolization from a Left Atrial Myxoma Containing Malignant Lymphoma Cells.

Systemic embolization from a primary cardiac tumor is a relatively frequent presentation. However, an acute myocardial infarction due to coronary embolization is rarely seen. We offer an unusual case of a 50-year-old man who presented with severe angina and was diagnosed with an inferolateral ST-segment-elevation myocardial infarction. Aside from otherwise healthy coronary arteries, his coronary angiogram revealed an acute occlusion of the first obtuse marginal branch, which was treated with balloon angioplasty. Because no residual plaque or dissection was found after the angioplasty, an embolic source was suspected. An echocardiogram then revealed a large mobile left atrial myxoma prolapsing into the left ventricle, so the patient underwent minimally invasive resection. Detailed pathologic examination of the myxoma revealed a concomitant high-grade B-cell lymphoma.

Primary CNS lymphoma.

PURPOSE OF REVIEW: Despite recent progress, the diagnosis of primary CNS lymphoma (PCNSL) remains a challenge and is often delayed by several months. Treatment options are still debated and the prognosis of PCNSL lymphoma is poor for most patients. This review will describe recent progress and future orientations for diagnosis of PCNSL and report on the recent trends regarding therapeutic options. RECENT FINDINGS: PCNSL must be suspected in cases of chronic posterior uveitis, especially in patients over 50 years old. Diagnosis is based on cytology and molecular analysis of clonality of vitreous samples. Intraocular interleukin (IL)-10 level has proved to be a valuable tool for screening purposes in cases where there is a suspicion of primary vitreoretinal lymphoma. Intraocular cytokine dosage could also be a useful marker to follow the therapeutic response of patients with PCNSL. Treatment of PCNSL remains under debate. SUMMARY: Diagnosis of PCNSL is challenging. Suspicion relies on clinical history and on IL-10 and IL-6 levels in ocular fluid samples. Definite diagnosis is based on cytology and molecular analysis of clonality. New diagnostic and prognostic markers are currently evaluated. Whether isolated vitreoretinal lymphoma should be treated locally or with systemic treatment remains highly controversial.

Involvement of bone marrow in lymphoma: pathological investigation in a single-center from northern China.

OBJECTIVES: This study aimed to evaluate key features of bone marrow trephine biopsy (BMT) involvement of lymphoma in Northern China. METHODS: 950 cases were assessed for the occurrence of bone marrow involvement and architectural features including volume percentage, involvement pattern (diffuse, nodular, focal, para trabecular, or interstitial), and presence/absence of background changes (granuloma, stromal fibrosis or necrosis). Correlations with bone marrow aspirate (BMA) and flow cytometry (FCM) findings were made in a subset of paired cases (359 BMA and 364 FCM). RESULTS: 153 (16.1%) cases involved BMT. The most frequent type was mantle cell lymphoma (28/153, 18.3%). Architectural features were similar to previous studies except that diffuse large B-cell lymphoma (DLBCL) preferred focal pattern (16/22 cases, 72.7%) most of all. BMA and BMT agreed in 84.1% of cases (302 of 359: 277 both negative, 25 both positive), while FCM and BMT agreed in 80.8% of cases (294 of 364: 242 both negative, 52 both positive). Both varied widely among different subgroups. CONCLUSIONS: Occurrence of BMT involvement by lymphoma in Northern China is relatively low. The volume percentage, distribution patterns and background changes may be useful pointers towards a particular lymphoma type in Chinese. FCM is more sensitive and reliable than BMA in China.

Pitfalls in the pathological diagnosis of lymphoma.

Since the publication of the 2008 World Health Organization classifications of lymphoma, additional immunohistochemical tests and other ancillary methods such as flow cytometry, cytogenetic and other molecular biology techniques, have been applied in routine clinical work. Due to the utilization of these methodologies, there has been great progress in the pathological diagnosis and classification of lymphomas in the mainland of China. Nonetheless, lymphoma pathology still remains very challenging in the field of diagnostic pathology. Ten percent of pathologist's annual consultation cases are lymphomas, thus reflecting the difficulty of this field. Here, we summarize the common misdiagnoses and pitfalls when dealing with lymphoma cases, the cause of the errors and strategies to avoid inaccurate diagnoses.

Pseudocarcinomatous hyperplasia associated with primary lymphoma in the urinary bladder: a case report.

A case of pseudocarcinomatous hyperplasia of the urothelium associated with primary extranodal marginal-type lymphoma of the urinary bladder in an 81-year-old man is described. To the best of our knowledge, this is the first report in the literature of a primary lymphoma of the bladder associated with pseudocarcinomatous hyperplasia of the urothelium, closely mimicking the nested variant of urothelial carcinoma. The lesion enters in the differential diagnosis with a collision tumor, which has been described rarely in the bladder.

Expression profiles of MYC protein and MYC gene rearrangement in lymphomas.

MYC translocations are a defining feature of Burkitt lymphoma and a group of diffuse large B-cell lymphoma (DLBCL) with inferior outcome. However, the clinical relevance of MYC gene rearrangement and its relationship with MYC protein expression has not been well characterized in lymphomas. Tissue microarrays containing 1214 lymphomas were successfully evaluated by immunohistochemistry using anti-MYC clone Y69 and a dual-color break-apart fluorescence in situ hybridization probe to detect MYC gene rearrangements. Aggressive B-cell lymphomas including Burkitt lymphoma and DLBCL showed the highest level of MYC protein staining defined as staining in >50% of lymphoma cells. A significant proportion of plasmablastic, B-lymphoblastic and T-lymphoblastic, and extranodal NK/T-cell lymphomas also showed staining in >50% of cells, whereas only occasional plasma cell myeloma, mantle cell lymphoma, and classical Hodgkin lymphoma showed a high level of staining. Small B-cell lymphomas, when positive, showed MYC protein in <50% of cells. In aggressive B-cell lymphomas, MYC rearrangement and MYC immunohistochemistry showed a high concordance rate; however, some DLBCL and all T-cell and NK-cell lymphomas with MYC protein expression lacked MYC gene rearrangements. Our results provide a baseline for MYC protein expression in lymphomas and indicate that its expression is not specific to lymphoma subtypes, cell lineage, or expected clinical behavior and is highly variable. In addition, MYC protein expression is not necessarily correlated with MYC gene rearrangements and suggests the need for caution in the interpretation of MYC immunohistochemistry in the differential diagnosis of lymphomas.

Aptamer-functionalized barcode particles for the capture and detection of multiple types of circulating tumor cells.

Aptamer-functionalized barcode particles are employed to capture and detect various types of circulating tumor cells (CTCs). The particles are spherical colloidal crystal clusters, and the reflection properties that arise from their structures are how their codes are evaluated. Aptamer functionalization (with TD05, Sgc8, and Sgd5) make the particles interact with specific CTC types; dendrimers are used to amplify the effect of the aptamers, allowing for increased sensitivity, reliability, and specificity in CTC capture, detection, and subsequent release.