A Western Case of Intravascular Large B-Cell Lymphoma as Unusual Cause of Persistent Fever.

Fever of unknown origin (FUO) is a common and challenging clinical condition that can be referred, among others, to infections, drug's effects, various inflammatory disorders, and cancers. Among the latter, lymphomas can indeed cause fever, which is therefore accounted as a lymphoma-related sign in patients' staging. Intravascular large B-cell lymphoma (IVLBCL) is a very rare tumor, characterized by lymphoma cell accumulation within sinusoids and, despite a very aggressive course, the evidence of this disease is scarce. Two variants are currently recognized, respectively, occurring in either Western (mainly characterized by neurological symptoms and skin involvement) or Eastern countries (with hemophagocytic syndrome, bone marrow, spleen, and liver involvement). We describe an atypical and unprecedented IVLBCL patient, presenting with pronounced features of Eastern cases as well as skin involvement. Due to the scant amount of neoplastic cells, the diagnosis was very challenging, with FUO being the first and for a certain time unique clinical sign. Although lymphoma was suspected, the lack of evidence for neoplastic cells delayed the final diagnosis. Eventually, only autopsy revealed the extensive involvement of different organs and tissues.

Early gene expression changes by Epstein-Barr virus infection of B-cells indicate CDKs and survivin as therapeutic targets for post-transplant lymphoproliferative diseases.

Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered.

Primary bone marrow lymphoma: an uncommon extranodal presentation of aggressive non-hodgkin lymphomas.

Bone marrow involvement by lymphoma is considered a systemic dissemination of the disease arising elsewhere, although some tumors may arise primarily in the bone marrow microenvironment. Primary bone marrow lymphoma (PBML) is a rare entity whose real boundaries and clinicobiological significance are not well defined. Criteria to diagnose PBML encompass isolated bone marrow infiltration, with no evidence of nodal or extranodal involvement, including the bone, and the exclusion of leukemia/lymphomas that are considered to primarily involve the bone marrow. Twenty-one out of 40 lymphomas retrospectively reviewed by the International Extranodal Lymphoma Study Group from 12 institutions in 7 different countries over a 25-year period fulfilled the inclusion criteria. These cases comprised 4 follicular lymphomas (FLs), 15 diffuse large B-cell lymphomas (DLBCLs), and 2 peripheral T-cell lymphomas, not otherwise specified. The FL cases showed paratrabecular infiltration, BCL2 protein and CD10 expression, and BCL2 gene rearrangement. DLBCL showed nodular infiltration in 6 cases and was diffuse in 9 cases; it also showed positivity for BCL2 protein (9/10) and IRF4 (6/8). Median age was 65 years with male predominance. All but 3 FL patients were symptomatic. Most cases presented with cytopenias and high lactate dehydrogenase. Four patients (3 FL cases and 1 DLBCL case) had leukemic involvement. Most DLBCL patients received CHOP-like or R-CHOP-like regimens. The outcome was unfavorable, with a median overall survival of 1.8 years. In conclusion, PBML is a very uncommon lymphoma with particular clinical features and heterogenous histology. Its recognition is important to establish accurate diagnosis and adequate therapy.

Immunohistochemical and other prognostic factors in B cell non Hodgkin lymphoma patients, Kampala, Uganda.

BACKGROUND: Non Hodgkin lymphomas are the most common lymphomas in Uganda. Recent studies from developed countries have shown differences in survival for the different immunophenotypes. Such studies are lacking in Africa where diagnosis is largely dependent on morphology alone. We report immunohistochemical and other prognostic factors in B cell non Hodgkin lymphoma patients in Kampala, Uganda. METHODS: Non Hodgkin lymphoma tissue blocks from the archives of the Department of Pathology, Makerere University College of Health Sciences, Kampala, Uganda, from 1991-2000, were sub typed using haematoxylin and eosin, Giemsa as well as immunohistochemistry. Using tissue micro array, 119 biopsies were subjected to: CD3, CD5, CD10, CD20, CD23, CD30, CD38, CD79a, CD138, Bcl-6, Bcl-2, IRTA-1, MUM1/IRF4, Bcl-1/cyclin D1, TdT, ALKc, and Ki-67/Mib1. Case notes were retrieved for: disease stage, chemotherapy courses received and retrospective follow up was done for survival. RESULTS: Non Hodgkin B cell lymphomas comprised of Burkitt lymphoma [BL] (95/119) diffuse large B cell lymphoma (19/119), mantle cell lymphoma (4/119) and precursor B lymphoblastic lymphoma (1/119). For Burkitt lymphoma, good prognosis was associated with receiving chemotherapy, female gender and CD30 positivity. Only receiving chemotherapy remained significant after Cox regression analysis. Diffuse large B cell lymphomas with activated germinal centre B cell (GCB) pattern (CD10+/-, BCL-6+/-, MUM+/-, CD138+/-) had better survival (98.4 months; 95% CI 89.5 -107.3) than the others (57.3 months; 95% CI 35.5 - 79.0) p = 0.027 (log rank test). CONCLUSIONS: Activated GCB diffuse large B cell lymphoma had a better prognosis than the others. For Burkitt lymphoma, not receiving chemotherapy carried a poor prognosis. Availability of chemotherapy in this resource limited setting is critical for survival of lymphoma patients.

Myeloid sarcoma: extramedullary manifestation of myeloid disorders.

Myeloid sarcoma (MS), also termed extramedullary acute myeloid leukemia, extramedullary myeloid tumor, and granulocytic sarcoma or chloroma, is a rare manifestation that is characterized by the occurrence of 1 or more tumor myeloid masses occurring at an extramedullary site. The wide spectrum of this disorder and the conditions that it overlaps diagnostically were well reflected in the 25 cases submitted to the Society for Hematopathology/European Association for Haematopathology Workshop held in Indianapolis, IN, in November 2007. This review, on the one hand, focuses on the definition and most recent achievements on the pathobiology of MS, and on the other, also in the light of the revised World Health Organization classification, summarizes the main features of a representative series of this condition aiming to provide readers a useful document for daily practice.

Clinical, phenotypic and genetic similarities and disparities between post-transplant and classical Hodgkin lymphomas with respect to therapeutic targets.

OBJECTIVE: Post-transplant Hodgkin lymphoma (ptHL) is a rare but serious complication. We explored the clinical, phenotypic and genetic similarities and disparities between ptHL and classical Hodgkin lymphoma (cHL) in immunocompetent patients and sought proteins/pathways in ptHL that might have potential as therapeutic targets. RESEARCH DESIGN AND METHODS: Eight ptHL cases in solid organ recipients (mean patient age 36 years; mean duration between organ transplant and onset of ptHL 80 months) were phenotypically and genotypically analyzed and the results were compared with known phenotypic and molecular characteristics of cHL. RESULTS: All ptHL expressed CD15, CD30 and LMP-1 of EBV; the B-cell markers BOB-1, Oct2, CD79a and CD20 were more commonly expressed in ptHL versus cHL (100%, 86%, 50% and 38% in ptHL compared to 6%, 14%, 10% and 33% in cHL, respectively); all ptHL expressed phosphoinositide 3-kinase (PI3K) versus 81% of cHL; 2/6 (33%) ptHL displayed gains at 9p24 that were similar to cHL (32%). The JAK2 downstream pSTAT3 slightly predominated in ptHL versus cHL (60% versus 50%). Clonal immunoglobulin gene rearrangements were found in 2/4 cases. CONCLUSIONS: ptHL and cHL are closely related, but not identical, neoplasms, with the primary differences being the strict association with EBV infection, persistent phenotypic B-cell signature and high expression of PI3K as well as the slightly CD4-depleted but TIA-1/Granzyme B-enriched cellular background composition in ptHL.

Histopathological and molecular features of persistent polyclonal B-cell lymphocytosis (PPBL) with progressive splenomegaly.

Five cases of persistent polyclonal B-cell lymphocytosis (PPBL) with progressive splenomegaly are reported; three were splenectomized. BCL2/IGH rearrangements were found in three cases; HLA-DRB1*07 in all. Bone marrow (BM) trephines showed a moderate lymphoid infiltrate with intrasinusoidal distribution resembling a splenic marginal-zone lymphoma. Splenic white pulp revealed an enlargement of the marginal-zone area; red pulp was infiltrated by the same lymphocytes engulfing the sinuses. Splenic and BM B-lymphocytes were CD79a(+)/CD20(+)/IgM(+)/IgD(+)/bcl-2(+)/CD27(+)/DBA.44(-)/CD31(-) and polyclonal by immunophenotype/polymerase chain reaction. PPBL features an expansion of splenic marginal-zone B-lymphocytes, which infiltrate BM sinusoids and circulate in the blood with no evidence of clonality, even in cases with progressive splenomegaly.

B-cell non-Hodgkin lymphomas in Uganda: an immunohistochemical appraisal on tissue microarray.

The most common non-Hodgkin lymphomas in Uganda are neoplasms of B-cell derivation. The field of B-cell lymphoma immunophenotype has rapidly progressed because of the increasing availability of markers applicable to routine sections. Although the latter have allowed the identification of distinctive lymphoma entities in the developed countries, such approach has not yet been used in Uganda. One hundred twenty-nine formalin-fixed, paraffin-embedded tissue samples from the Department of Pathology of Makerere University were used for tissue micro-array (TMA) construction. Four-micrometer-thick sections were cut from TMAs and stained with hematoxylin and eosin and Giemsa. They were also used for immunohistochemistry and in situ hybridization. According to morphology and immunohistochemistry, lymphoid neoplasms were classified as Burkitt's lymphoma (BL) (95 cases), diffuse large B-cell lymphoma (19 cases), mantle cell lymphoma (4 cases), and B-cell lymphoblastic lymphoma (1 case). In BL, a homogeneous phenotype (CD10(+), Bcl-6(+), Bcl-2(-), MUM1/IRF4-, and Ki-67 approximately 100%) and a stable Epstein-Barr virus integration were found. A distinctive and unusual feature was the frequent plasma cellular differentiation, along with the positivity for CD30 and CD138 (recorded in 35 and 43 cases, respectively). According to our findings, most non-Hodgkin B-cell tumors in Uganda are endemic BLs followed by diffuse large B-cell lymphomas. The rest consist of rare but clinically important entities such as mantle cell lymphoma and B-cell lymphoblastic lymphoma. The availability of TMAs and immunohistochemistry has enabled us to precisely categorize tumors that have so far been diagnosed in Uganda as "high-grade/aggressive" lymphomas on the basis of cell morphology alone.

Autoimmune pancreatitis associated with high levels of chromogranin a, serotonin and 5-hydroxyindoleacetic Acid.

We report a case of a male patient with autoimmune pancreatitis in whom biochemical examination revealed high plasma chromogranin A concentrations, histological demonstration of a small lymphocytic infiltrate and rapid decrease in size of the pancreatic mass following short-lasting therapy with methylprednisolone. To our knowledge, this is the first patient with autoimmune pancreatitis who had a simultaneous increase of serum chromogranin A levels, circulating and urinary serotonin concentrations and urine 5-hydroxyindoleacetic acid concentrations. This is one of the few cases of mass forming pancreatitis with small lymphocytic infiltrate found in a Caucasian patient and rapid decrease in size of the pancreatic mass following short-lasting therapy with methylprednisolone.

Efficacy of hormonal manipulation in lymphangioleiomyomatosis. A 20-year-experience in 36 patients.

RATIONALE: Lymphangioleiomyomatosis (LAM) is a rare disease of unknown aetiology which mainly affects women of reproductive age. A growing body of evidence suggests a relation between the disease and estrogenic hormones. In particular, pregnancy and use of estrogens favour the progression of the disease, which is in turn slowed down by menopause. These observations suggested already in the past a treatment strategy based on hormonal manipulation: discontinuation of estrogens containing medications, avoiding pregnancy, inhibition of estrogens activity and induction of menopause. OBJECTIVES: In the present study, conducted on a relatively large population for a rare disease, we sought to show the hormonal manipulation's positive effects for the survival rate. METHODS: 36 women suffering from LAM were evaluated between January 1985 and March 2005. All our patients were treated with hormonal therapy, following different schemes. The response to the treatment was evaluated in all patients with arterial blood sampling, lung function tests (total body plethysmography, DLCO), measurement of the hormones in the blood, chest and abdomen CT scan. MEASUREMENTS AND MAIN RESULTS: The survival rate since the clinical onset was 97% at the 5 year timepoint, 90% at 10 years, and 71% at 25 years. Previous studies, conducted before the introduction of the hormonal treatment showed a survival rate of 20% at 10 years. CONCLUSIONS: Our results highlight the role of the hormonal manipulation as a mainstay in the treatment of LAM, with the capability of reducing mortality and improving the quality of life as well.

Genomic imbalances associated with secondary acute leukemias in Hodgkin lymphoma.

Secondary tumors and leukemias are major complications in Hodgkin lymphoma (HL). They likely arise from clonal selection of cells that have accumulated genomic lesions induced by chemo- and radiotherapy and may be further promoted by the loss of DNA repair and/or other pathways ensuring the fidelity of replicated DNA. To distinguish genomic imbalances associated with the development of acute myeloid leukemia (AML) in HL we used an array-based comparative genomic hybridization (aCGH) strategy on whole lymph node biopsies of HL patient. Genomic imbalances (amplifications and deletions) associated with AML outcome in 3 classic HL patients, at clinical diagnosis they exhibited a discrete individual variability. Three amplifications and 5 deletions were shared by all 3 patients. They involved AFM137XA11, a 9p11.2 pericentric region; FGFR1, the FGF receptor most frequently translocated in AML; PPARBP, a co-activator of nuclear receptors RARalpha, RXR and TRbeta1; AFM217YD10, a 17q25 telomeric region; FGR, an SRC2 kinase involved in cytokine production by NK and CD4+ NKT cells; GATA3, a Th2-specific transcription factor; TOP1, involved in DNA recombination and repair; WT1, a transcription factor involved in CD8+ T cell response against leukaemic blasts. Immunohistochemistry confirmed aCGH results and distinguished the distribution of either amplified or deleted gene products in neoplastic Reed Sternberg (RS) cells and non-neoplastic lymph node components.

Simultaneous occurrence of peripheral T-cell lymphoma unspecified and B-cell small lymphocytic lymphoma. Report of 2 cases.

We report on 2 composite lymphomas occurring in elderly patients, morphologically characterized by the combination of peripheral T-cell lymphoma (PTCL) unspecified and B-cell small lymphocytic lymphoma. Immunohistochemistry provided objective confirmation of the coexistence of the 2 malignancies, as did molecular biology by revealing clonal T-cell receptor gamma and immunoglobulin heavy chain gene rearrangements. One of the patients had no history of indolent lymphoma either at the personal and family level, whereas the other showed a strong familial predisposition, his mother and sister having suffered from B-cell chronic lymphocytic leukemia. Epstein-Barr virus was detected in the PTCL component of 1 case, but was negative in the other. To the best of our knowledge, the simultaneous occurrence of PTCL unspecified and B-cell small lymphocytic lymphoma is an exceptional event; the possible pathogenetic correlations between the 2 neoplasms are discussed.

B cell chronic lymphocytic leukaemia/small lymphocytic lymphoma: role of ZAP70 determination on bone marrow biopsy specimens.

BACKGROUND: The course of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) partly depends on the mutational status of the variable region of immunoglobulin heavy chain genes (IgV(H)), which defines two subgroups of tumours: mutated and unmutated. The expression of zeta-associated protein 70 (ZAP70) is significantly associated with the more aggressive unmutated forms. AIMS: To assess the feasibility of the ZAP70 immunohistochemical test on bone-marrow biopsy (BMB) specimens and to compare the results with those of western blotting (WB) and IgV(H) mutational status assessed on neoplastic cells from peripheral blood. METHODS: 26 patients with CLL/SLL detected on BMB and with known IgV(H) mutational status were selected. ZAP70 was determined by immunohistochemistry (IHC) comparing three antibodies from different sources (Upstate, Cell Signaling, Santa Cruz, California, USA) and two different methods (APAAP and EnVision(+)). In 23 cases, ZAP70 WB results were also available. RESULTS: ZAP70 determination on BMB specimens turned out to be easily feasible with routine procedures with reagents from Upstate and Cell Signaling. The results were concordant with those obtained with WB and mutational status analysis in >80% of the cases with both reagents. Three of four discordant cases were mutated/ZAP70 positive, with two staining weakly for ZAP70 on both WB and IHC. CONCLUSIONS: The study confirms the role of ZAP70 as a possible surrogate of mutational status and emphasises its application in routine diagnostics; it discloses a small subset of discordant cases (mutated/ZAP70 weakly positive) that clinically cluster with the more favourable forms.