Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.

The landscape of additional chromosomal alterations (ACAs) and their impact in chronic myeloid leukemia, blast phase (CML-BP) treated with tyrosine kinase inhibitors (TKIs) have not been well studied. Here, we investigated a cohort of 354 CML-BP patients treated with TKIs. We identified +8, an extra Philadelphia chromosome (Ph), 3q26.2 rearrangement, -7 and isochromosome 17q (i(17q)) as the major-route changes with a frequency of over 10%. In addition, +21 and +19 had a frequency of over 5%. These ACAs demonstrated lineage specificity: +8, 3q26.2 rearrangement, i(17q) and +19 were significantly more common in myeloid BP, and -7 more common in lymphoid BP; +Ph and +21 were equally distributed between two groups. Pearson correlation analysis revealed clustering of common ACAs into two groups: 3q26.2 rearrangement, -7 and i(17q) formed one group, and other ACAs formed another group. The grouping correlated with risk stratification of ACAs in CML, chronic phase. Despite the overall negative prognostic impact of ACAs, stratification of ACAs into major vs minor-route changes provided no prognostic relevance in CML-BP. The emergence of 3q26.2 rearrangement as a major-route change in the TKI era correlated with a high frequency of ABL1 mutations, supporting a role for TKI resistance in the changing cytogenetic landscape in CML-BP.

Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines.

Pharmacological inhibitors of the anabolic enzyme, fatty acid synthase (FAS), including the natural product cerulenin and the novel compound c75, are selectively cytotoxic to cancer cells via induction of apoptosis, apparently related to the tumor cell phenotype of abnormally elevated fatty acid synthetic metabolism. As part of a larger effort to understand the immediate downstream effect of FAS inhibition that leads to apoptosis, the effects of these inhibitors on cell cycle progression were examined. Both FAS inhibitors produce rapid, profound inhibition of DNA replication and S phase progression in human cancer cells. The dose responses for fatty acid synthesis inhibition and DNA synthesis inhibition are similar. The kinetics of both effects are rapid, with fatty acid synthesis inhibition occurring within 30 min and DNA synthesis inhibition occurring within 90 min of drug exposure. Meanwhile, apoptotic changes are not detected until 6 h or later after inhibitor exposure. Fatty acid synthetic pathway activity and the magnitude of DNA synthesis inhibition by FAS inhibitors are increased in parallel by withdrawal of lipid-containing serum from the cultures. The mechanism of DNA synthesis inhibition by cerulenin is indirect, because expression of certain viral oncogenes rescues DNA synthesis/S phase progression in cerulenin-exposed cells. The data suggest a direct linkage at a regulatory level, between fatty acid synthesis and DNA synthesis in proliferating tumor cells.

Prolonged N-myc protein half-life in a neuroblastoma cell line lacking N-myc amplification.

Genomic amplification of the oncogene N-myc is associated with rapid tumor progression and poor prognosis in patients with neuroblastoma (NB). However, 40% of NBs which lack N-myc amplification are also clinically aggressive. Factors other than N-myc copy number must therefore play a role in determining tumor progression in these NBs. We have established an unusual human NB cell line (NBL-S) from the primary tumor of a patient with rapidly progressive disease which lacks N-myc amplification. The doubling time in vitro (48 h) and the time from injection of 2 x 10(7) cells to detectable tumors in nude mice (46 days) in similar to NB cell lines with amplified N-myc. However, karyotype analysis reveals no evidence of double minutes (DMs), homogeneously staining regions (HSRs), or chromosome 1p deletions, features commonly seen in NB cell lines. The cells have the cell surface phenotype typical of N-myc amplified NB (HLA-A,B,C negative and HSAN 1.2 positive), and similar to other NB cell lines, N-myc RNA and protein are expressed. Interestingly, the half-life of the N-myc protein in NBL-S is prolonged (approximately 100 min) compared to the short N-myc protein half-life previously described in N-myc amplified NB cell lines (approximately 30 min). Because N-myc protein is thought to have a regulatory role, prolongation of the half-life of this protein may be an important factor in the regulation of growth in NBs which lack N-myc amplification and rapidly progress.

Intravascular lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherapy.

PURPOSE: We report a clinicopathologic study of 10 cases of intravascular lymphomatosis (IVL) seen at a single institution, and assess the response to chemotherapy in these patients, as well as those collected from a literature review. PATIENTS AND METHODS: The clinical, pathologic, and immunophenotypic features of 10 cases of IVL diagnosed at the Johns Hopkins Hospital since 1977 were studied. Follow-up information was obtained in each case by consultation with the treating physician. In addition, cases of IVL reported previously in which patients were treated with chemotherapy and for which follow-up data were available at the time of publication were reviewed. RESULTS: In the present series of 10 cases, the most common clinical features were fever of unknown origin (FUO), mental status changes, and rash. Diagnostic specimens were obtained from a variety of sources, including brain, skin, prostate, liver, kidney, and gallbladder. All of the four patients treated with combination chemotherapy are alive and two have achieved long-term survival (48 and 45 months, respectively); the remaining two are alive and in complete remission (CR) after short follow-up duration of 6 months. Among 35 patients reported in the literature who received chemotherapy (including four from this series), 43% attained a CR and were free of disease at the time of publication. None of the three patients in our series who received localized therapy (surgery with or without radiation therapy) is alive (mean survival duration, 9 months). For the three patients diagnosed at postmortem examination, the mean interval between onset of symptoms and death was 3 months, and disease was widespread. CONCLUSION: These findings suggest that IVL represents a high-grade non-Hodgkin's lymphoma (NHL) with a propensity for systemic dissemination, and that CR and long-term survival may result in patients treated with aggressive combination chemotherapy.

Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis.

The aromatic fatty acid phenylbutyrate (PB) induces cytostasis, differentiation, and apoptosis in primary myeloid leukemic cells at clinically achievable concentrations. In the present study, we have investigated the structural and cellular basis for PB-induced cytostasis, using the ML-1 human myeloid leukemia cell line as a model system. PB induced a dose-dependent increase in cells in G1 with a corresponding decrease in cells in S-phase of the cell cycle. At comparable doses, PB induced expression of CD11b, indicating myeloid differentiation. At higher doses, the drug induced apoptosis. The antitumor activity was independent of the aromatic ring, as butyric acid (BA) was of equal or greater potency at producing these biological changes. In contrast, shortening of the fatty acid carbon chain length, as demonstrated with phenylacetate (PA), significantly diminished drug potency. Consistent with their effects on cell cycle, PB and BA, but not PA, induced the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1), and led to the appearance of hypophosphorylated Rb, suggesting a role for p21(WAF1/CIP1) in PB-induced cytostasis. Therefore, it appears that the fatty acid moiety of PB, rather than its aromatic ring, is critical for its activity in myeloid leukemic cells. These data provide a potential mechanistic basis for the increased potency of PB over PA previously demonstrated in primary leukemic samples, and support the further clinical development of PB in the treatment of hematologic malignancies.

Clinical utility of flow cytometry in the chronic lymphoid leukemias.

The chronic lymphoid leukemias comprise a number of biologically distinct neoplasms of mature lymphocytes. The availability of specific therapies for certain of these tumors makes accurate diagnosis imperative. In most cases, detailed immunophenotypic analysis of the chronic lymphoid leukemias permits specific classification and initiation of the most appropriate therapy. For example, the characteristic immunophenotype of B-cell chronic lymphocytic leukemia (CLL): CD5+, CD23+, FMC7-, CD20 dim+, clonal surface immunoglobulin (sIg) dim+, distinguishes it from another CD5+ B-cell lymphoproliferative disorder, mantle cell lymphoma, which typically displays the composite phenotype: CD5+, CD23-, FMC7+, CD20 bright+, clonal sIg bright+. Likewise, hairy cell leukemia has a characteristic immunophenotype: CD5-, CD11c bright+, CD25+, CD103+, which distinguishes it from other CD5- B-cell lymphoproliferative disorders, including the morphologically similar splenic lymphoma with circulating villous lymphocytes. Immunophenotypic analysis by flow cytometry may also identify clinically relevant subsets of patients within a diagnostic category of leukemia. Thus, in patients with CLL, deviation from the typical immunophenotype is associated with trisomy 12 and mixed-cell morphology. In summary, careful immunophenotyping by flow cytometry facilitates accurate diagnosis in the chronic lymphoid leukemias, and in some settings, may also offer additional therapeutically relevant information.

Hepatosplenic and subcutaneous panniculitis-like gamma/delta T cell lymphomas are derived from different Vdelta subsets of gamma/delta T lymphocytes.

Gamma/delta T cell lymphomas (gamma/delta TCL) represent rare, often aggressive types of T cell malignancy that are clinically and pathologically diverse. Most gamma/delta TCL occur as a hepatosplenic or subcutaneous type. To date, analysis of the T cell receptor delta (TCRS) gene repertoire of hepatosplenic gamma/delta TCL (gamma/delta HSTCL) and subcutaneous panniculitis-like gamma/delta TCL (gamma/delta SPTCL) has been reported only in a limited number of cases. In this study we analyzed 11 gamma/delta HSTCL and 4 gamma/delta SPTCL by polymerase chain reaction and immunostaining to determine their usage of the Vdelta subtypes (Vdelta1-6). It is noteworthy that 10 of 11 gamma/delta HSTCL expressed the Vdelta1 gene. The remaining case also expressed T cell receptor delta (TCRS) as determined by flow cytometry and TCRdelta rearrangement in Southern blot. However, the Vdelta gene expressed by this lymphoma could not be determined, which suggests usage of an as yet unidentified Vdelta gene. In striking contrast to the gamma/delta HSTCL, all 4 gamma/delta SPTCL expressed the Vdelta2 gene. Our data demonstrate that gamma/delta HSTCL are preferentially derived from the Vdelta1 subset of gamma/delta T lymphocytes, whereas gamma/delta SPTCL are preferentially derived from the Vdelta2 subset. The pattern of Vdelta gene expression in HSTCL and SPTCL corresponds to the respective, predominant gamma/delta T cell subsets normally found in the spleen and skin. This finding suggests that gamma/delta TCL are derived from normal gamma/delta T lymphocytes which reside in the affected tissues. Furthermore, the selective, lymphoma type-specific Vdelta gene segment usage may provide a molecular tool to distinguish better among various types of gamma/delta TCL lymphoma particularly in the clinically advanced, widely disseminated cases.

Increasing incidence of minimal residual cancer in radical prostatectomy specimens.

Residual cancer in radical prostatectomy specimens from men with biopsy-proven adenocarcinoma occasionally may be difficult, or even impossible, to identify. Although this finding was recently described as "minimal residual cancer" or the "vanishing cancer phenomenon," there are no data on the incidence of this phenomenon in surgical pathology practice. We evaluated 3,038 consecutive radical prostatectomies performed at the Johns Hopkins Hospital between 1988 and 1995, excluding cases with a history of transurethral resection, prior therapy with a luteinizing hormone-releasing hormone agonist, focal Gleason grade 4 or 5, capsular penetration, or a positive surgical margin. Of this group, 84 cases with minimal or no residual cancer were identified. In 60 of these cases, residual cancer was "difficult to find" (mean total volume, 0.03 cc; range, 0.01-0.08 cc); in 20 cases, residual cancers were classified as "minute" (mean total volume, 0.07 cc; range, 0.03-0.13 cc). In four cases, no residual cancer could be identified, including two cases in which the diagnosis of cancer on needle biopsy was confirmed, one case in which review of the diagnostic needle biopsy revealed only high-grade prostatic intraepithelial neoplasia, and one case in which molecular analysis demonstrated mislabeling of the needle biopsy specimen. The annual incidence of minimal residual cancer increased from 0.5% in 1988 to 4% in 1993 and has begun to plateau at 3 to 4% since 1993 (p = 0.0016 for increasing trend). These data confirm the general impression that with more vigilant screening of men for prostate cancer, there has been an associated increase in cancer with little or no residual cancer at radical prostatectomy.

Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study.

The classification of natural killer (NK)-cell and NK-like T-cell malignancies has undergone significant evolution in recent years. Although examples of NK-cell tumors resembling acute leukemia have been described anecdotally as blastic, blastoid, or monomorphic NK-cell leukemia/lymphoma (NKL/L), the clinical and pathologic features of these tumors have not been systematically defined. We report four patients with blastic NKL/L and describe the clinical, pathologic, and immunophenotypic findings in these cases. All patients were elderly (58-82 years) and presented with cutaneous plaques. Two patients also had adenopathy, and three patients had marrow involvement at presentation. Biopsy of cutaneous lesions showed atypical superficial and deep dermal lymphoid infiltrates. Involved lymph nodes were architecturally effaced by an interfollicular infiltrate with blastic cytologic features. In Wright-Giemsa-stained blood or marrow smears, tumor cells had finely distributed nuclear chromatin, many with nucleoli, and variable amounts of cytoplasm. In contrast to many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent or inconspicuous. The tumor cells were immunophenotypically distinctive. They expressed intermediate density CD45, as is characteristic of blasts; in addition, the cells were positive for HLA-DR, CD2, CD4, and the NK-associated antigen CD56. Surface CD3, cytoplasmic CD3, and CD5 were negative in all cases tested, whereas CD7 was expressed in two cases. In formalin-fixed tissue, tumor cells marked with antibodies to CD43, but not with other T- or B-lineage-related antibodies. All three cases studied for Epstein-Barr viral RNA by in situ hybridization were negative. Although treatments varied, all three patients with clinical follow-up died within months of the diagnosis. The clinical course in two patients culminated in an overtly leukemic phase. These findings suggest that blastic NKL/L represents a distinct clinicopathologic entity, characterized by cutaneous, nodal, and marrow involvement by blastic cells with immunophenotypic characteristics of true NK cells. The disease afflicts elderly patients, pursues an aggressive course, and may culminate in overt leukemia.

Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms.

Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/neu expression was absent in all but one case. By contrast, HER-2/neu was expressed in 82% (P = .008 vs normal ) of ducts with flat mucinous hyperplasia, 86% (P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% (P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/neu expression was observed in 69% (P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.

Multiparameter flow-cytometric analysis of bcl-2 and Fas expression in normal and neoplastic hematopoiesis.

Apoptosis (programmed cell death) is an important regulatory mechanism in hematopoiesis, and is thought to be a principal mechanism of action of cytotoxic chemotherapy. Proteins that modulate apoptosis include bcl-2, which inhibits apoptosis, and Fas (CD95, also known as APO-1), which induces apoptosis in susceptible cells bound by Fas ligand (FasL). To characterize precisely the expression of these apoptosis-regulatory proteins in normal and neoplastic hematopoiesis, the authors have performed multiparameter flow cytometric (FCM) analysis in a series of normal and abnormal marrow specimens. Among normal hematopoietic elements, bcl-2 expression was highest in myeloblasts (29 [+/- 9] x 10(3) molecules of equivalent soluble fluorochrome [MESF]), and lymphocytes (28[+/- 7] x 10(3) MESF). bcl-2 was essentially undetectable in granulocytes and nucleated red blood cells, whereas monocytes and B-cell precursors expressed intermediate levels of bcl-2 (11[+/- 4] x 10(3) and 7[+/- 1] x 10(3) MESF, respectively). Fas expression increased with granulocytic and monocytic differentiation; myeloblasts expressed 8(+/- 2) x 10(3) MESF, whereas granulocytes (15 [+/- 2] x 10(3) MESF) and monocytes (28[+/- 5] x 10(3) MESF) displayed relatively greater intensity of staining for Fas. Among lymphoid cells, Fas expression was heterogeneous. B cells expressed lower intensity Fas staining than both CD4+ and CD8+ T cells. Myeloblasts in 30 cases of myeloid leukemia and myelodysplasia studied for bcl-2 and/or Fas expression manifested variable levels of these molecules (range 9-105 x 10(3) MESF for bcl-2 and 3-33 x 10(3) MESF for Fas). In addition, intraclonal heterogeneity of bcl-2 and Fas expression was seen in certain cases of AML, which correlated with extent of differentiation. Among 28 cases of B-precursor ALL studied for bcl-2 and/or Fas expression, bcl-2 ranged from 22 to 60 x 10(3) MESF (P < .001 versus normal marrow B-cell precursors), and Fas varied between essentially undetectable levels and 6 x 10(3) MESF. In summary, normal marrow subsets display characteristic levels of the apoptosis-regulatory molecules, bcl-2 and Fas. In hematopoietic neoplasms, expression of bcl-2 and Fas varies among cases, and in some instances, within leukemic blast populations. Further study is required to understand the potential significance of this heterogeneous expression of bcl-2 and Fas in hematologic neoplasia.

Laboratory, morphologic, and immunophenotypic correlates of surface immunoglobulin heavy chain isotype expression in B-cell chronic lymphocytic leukemia.

We compared surface immunoglobulin heavy chain isotype expression with a number of laboratory, morphologic, and immunophenotypic features in a series of 76 cases of B-cell chronic lymphocytic leukemia (B-CLL). Fifty-five cases were IgM+/IgD+, a phenotype associated with antigenically naïve B cells; 16 cases expressed IgD without IgM, a phenotype seen in a subset of normal B cells with extensive somatic immunoglobulin variable region (IgV) gene mutations; and 5 cases were IgD-, a phenotype associated with memory B cells. WBC count, atypical morphologic features, atypical immunophenotypic characteristics, and CD38 expression were nonrandomly distributed among the 3 categories of heavy chain isotype expression. Moreover, a WBC count more than 30,000/microL (30 x 10(9)/L), atypical morphologic features, and CD38 expression in more than 30% of neoplastic cells (all adverse prognostic factors in B-CLL) were less common among IgD-only cases than among IgM+/IgD+ and IgD- cases. These data demonstrate that surface immunoglobulin heavy chain isotype expression is associated with several laboratory, morphologic, and immunophenotypic features in B-CLL. The subset of B-CLL with the IgD-only phenotype is associated with several favorable prognostic factors, suggesting the possibility that IgD-only B-CLL may be associated with a favorable prognosis.

Overexpression of p53 protein in adenocarcinoma of the pancreas.

Mutations in the p53 tumor suppressor gene are frequently identified in human neoplasms. These mutations may be associated with stabilization and, therefore, with overexpression of the p53 protein product as determined by immunohistochemical staining. Using a new antigen retrieval method and a polyclonal antibody to p53 (CM-1), the authors examined 48 formalin-fixed paraffin-embedded adenocarcinomas of the pancreas for overexpression of the p53 gene product. These 48 carcinomas were obtained from a series of patients with well-documented clinical histories and extensive follow-up. The carcinomas had been analyzed previously for K-ras gene mutations, tumor ploidy, and tumor proliferating index. Specific diffuse nuclear staining for the p53 protein was identified in 19 of the 48 (40%) infiltrating carcinomas examined. Focal or negative staining was seen in the remaining 29 cases (60%). In addition, 17 of the neoplasms contained synchronous in situ carcinomas; two (12%) of these displayed diffuse nuclear staining for the p53 protein. Overexpression of p53 was associated with aneuploidy (P = .05), which had been a poor prognosticator in this series of adenocarcinomas of the pancreas. Although overexpression of p53 appeared to be associated with poor prognosis (hazard ratio, 1.8; P = .07), this was not statistically significant. Overexpression of p53 was not significantly associated with K-ras oncogene mutations or tumor proliferating index. The authors conclude that overexpression of the p53 protein occurs frequently in invasive adenocarcinomas of the pancreas and in some in situ carcinomas, as well.

Tacrolimus-related posttransplant lymphoproliferative disorder presenting as autoimmune hemolytic anemia.

Tacrolimus (formerly known as FK506) is a macrolide immunosuppressant that has been used to prevent rejection of solid organ allografts. Acute hemolytic anemia is one of the side effects associated with tacrolimus therapy, and two mechanisms have been described to account for acute hemolytic anemia in patients receiving tacrolimus: drug-induced hemolysis and alloimmune hemolysis resulting from donor lymphocytes derived from the allograft (passenger lymphocyte syndrome). We report a case of a liver transplant recipient who developed fatal autoimmune hemolytic anemia while under treatment with tacrolimus for allograft rejection, and in whom postmortem examination revealed a clinically unsuspected posttransplant lymphoproliferative disorder. This case implicates autoimmune hemolytic anemia as a novel mechanism of acute hemolysis in patients treated with tacrolimus and further suggests that acute hemolytic anemia in this group of patients may herald an occult lymphoproliferative disorder.

Cytoprotective effects of hematopoietic growth factors on primary human acute myeloid leukemias are not mediated through changes in BCL-2, bax, or p21WAF1/CIP1.

BACKGROUND: Hematopoietic growth factors (HGF) can suppress chemotherapy-induced programmed cell death (apoptosis) in hematopoietic cells. Although HGF can modulate the expression of apoptosis-regulatory genes, including bcl-2, bax, and p21WAF1/CIP1 in cell lines, few data address whether HGF regulate the expression of these proteins in primary acute myeloid leukemia (AML). MATERIALS AND METHODS: We evaluated the expression of bcl-2, bax, and p21WAF1/CIP1 in primary samples from patients with AML in the presence and absence of HGF. The potential association of HGF-induced changes in the levels of these proteins with inhibition of chemotherapy-induced apoptosis was further investigated. RESULTS: While a combination of steel factor (SF) and PIXY321 inhibited etoposide-induced apoptosis in 8/11 primary AML samples studied, Bcl-2 and bax protein levels were unaffected by exposure to HGF and/or etoposide. In contrast, HGF enhanced basal and etoposide-induced p21WAF1/CIP1 protein levels in 9/11 and 7/11 of the cases, respectively. In several cases, inhibition of apoptosis by HGF was seen without up-regulation of p21WAF1/CIP1 levels, suggesting that modulation of p21WAF1/CIP1 is not required for HGF-mediated inhibition of apoptosis. CONCLUSIONS: These data indicate that HGF-mediated inhibition of chemotherapy-induced apoptosis in primary AML samples is not mediated through changes in Bcl-2, bax, and p21WAF1/CIP1 protein levels.

Primary hepatic lymphoma: report of two cases diagnosed by fine-needle aspiration.

Primary hepatic lymphoma (PHL) is a rare disease which tends to progress slowly in the absence of other disorders and remains confined to the liver until late in its course. We report two patients with PHL diagnosed by fine-needle aspiration (FNA). Histopathologically, PHL can be misdiagnosed as poorly differentiated carcinoma or hepatocellular carcinoma. On FNA, cellular smears with artifactual grouping of malignant cells may result in similar errors. Since PHL has an excellent prognosis and is not usually the working diagnosis in patients who present with a solitary liver mass, a high index of suspicion is necessary to make the diagnosis. We report two cases of PHL in which the diagnosis of lymphoma was rendered on FNA. In one patient, who carried a clinical diagnosis of cavernous hemangioma for 18 mo, FNA showed large-cell lymphoma, B-cell type. Subsequent extensive workup did not reveal extrahepatic disease. The other patient, followed for sclerosing cholangitis, was clinically thought to have developed cholangiocarcinoma. FNA revealed high grade lymphoma, B-cell type. We present the clinical, radiologic, and pathologic findings and differential diagnoses of PHL as well as the various clinical settings in which PHL has been described.

Concurrent factor V Leiden and prothrombin G20210A gene mutations in a patient with a history of recurrent thrombosis.

We report a case of a 35-year-old male with a history of recurrent thromboembolic events, who presented to the emergency room with right sided weakness and difficulty with speech. The patient's past medical history included two myocardial infarctions, two deep vein thromboses, and a pulmonary embolism. Subsequent laboratory evaluation indicated that the patient was heterozygous for both the factor V Leiden and prothrombin G20210A mutations. This case report emphasizes the importance of evaluating patients with suspected hereditary thrombophilia for both of these mutations.

Primary lymphoma of CNS, mycophenolate mofetil and lupus.

Lymphoproliferative disorders are known to complicate immunosuppressive therapy and two cases of primary lymphoma of CNS (PCNSL) have previously been described in association with mycophenolate mofetil (MMF) treatment. We report the third case of PCNSL in a patient with lupus nephropathy while on MMF treatment. PCNSL may be seen more frequently considering the increased use of MMF in immunosuppressant responsive conditions.