Utility of myeloperoxidase stain in the differential diagnosis of leukemia cutis vs. hystiocitoid Sweet syndrome.

Leukemia cutis is defined as a skin infiltration by leukemic cells. The diagnosis of myeloid leukemia cutis (MLC) can represent a challenge, especially in those cases without symptoms of systemic disease. The clinical appearance, histopathological analysis and immunohistochemical profile can be indistinguishable from those observed in cases of hystiocitoid Sweet syndrome (HSS). We present a case of MLC in which the cutaneous affectation was the first sign of the systemic leukemia. In this setting, the myeloperoxidase stain was the clue to rule out the possibility of HSS. We discuss the role and the utility of the myeloperoxidase stain in the differentiation of these two entities.

Central nervous system involvement of previously undiagnosed chronic lymphocytic leukemia in a patient with neuroborreliosis.

Leukemic involvement of the central nervous system (CNS) in previously undiagnosed chronic lymphocytic leukemia (CLL) is very rare. We report the case of a 62-year-old man with neuroborreliosis in which cytologic, immunocytochemical, and flow cytometry analyses revealed the presence of clonal B-lymphocytes in the cerebrospinal fluid (CSF). After the patient received antimicrobial therapy, his meningeal symptoms cleared up, and the number of cells in the CSF decreased. Monoclonal lymphocytes were still detectable at the same percentage, however, despite systemic chlorambucil therapy. The application of intrathecal dexamethasone therapy led to the disappearance of B-cell CLL (B-CLL) cells in the CSF. We presumed that the neuroborreliosis enabled the transmigration of leukocytes, including B-CLL cells, across the blood-brain barrier via activation of matrix metalloproteinase 9, an enzyme known to open the blood-brain barrier.

Infiltrative capacity of T leukemia cell lines: a distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1).

Infiltrative capacity was found to distinguish separate T leukemia cell lines. Of seven T-cell lines four exhibited capacity to infiltrate Matrigel. Analysis of infiltration was performed at the single-cell level throughout the Matrigel using a depth meter. Further, we examined differences in migration capacity and metalloproteinase production between infiltrating and non-infiltrating T-cell lines. The capacity to infiltrate was not directly correlated to the capacity to adhere to the Matrigel or to migrate on/to extracellular matrix components. It is concluded that infiltration capacity does not simply reflect capacity to migrate but represents a distinct functional property. The production of metalloproteinases and their inhibitors by the separate T-cell lines was analyzed using rt PCR, biosynthetic labelling, zymography, immunoprecipitation and ELISA. All T-cell lines with capacity to infiltrate produced matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) while non-infiltrating cell lines did not express MMP-9. Expression of MMP-1, 2, 3, 10, 14 and 17 showed no correlation to capacity to infiltrate. Analysis of infiltration in the presence of a metalloprotease inhibitor showed an increased number of cells within the gel. This enhancement of infiltration suggests that the function of MMPs and/or their inhibitors in lymphocyte infiltration is more complex than previously thought.

Increased risk of neurological relapse in acute lymphoblastic leukemias with high levels of cerebrospinal fluid thymidine kinase at diagnosis.

Cerebrospinal fluid thymidine kinase (CSF-TK) was measured at diagnosis in 62 patients with acute lymphoblastic leukemia (ALL) without initial neurological manifestations, who achieved a complete remission after chemotherapy. During the follow-up period, 10 patients developed central nervous system (CNS) involvement. At the onset of the disease mean CSF-TK levels in these subjects were found to be significantly higher than those observed in patients without subsequent CNS complications. In particular, 7/10 (70%) of these patients who presented CSF-TK levels above the upper limit of normal (1.4 U/microliters) had evidence of a neurological relapse, while 49/52 (94.2%) of subjects with presenting CSF-TK levels of up to 1.4 U/microliters did not develop a neurological leukemic disease (p < 0.00001). The white blood cell count at diagnosis was significantly increased, but not directly correlated to CSF-TK levels, in the group with CNS involvement, while age, serum thymidine kinase levels and lactic dehydrogenase, FAB classification or immunophenotype were not different in patients with or without neurological relapse. In conclusion, increased levels of CSF-TK at presentation correlate with a high risk of subsequent CNS involvement in patients with responsive ALL.

Activation of nuclear factor κB in cerebral arteriovenous malformations.

BACKGROUND: Cerebral arteriovenous malformations (AVMs) do not seem to be static congenital vascular malformations, but rather are dynamically changing pathologies. It is well-known from clinical situations that these AVMs can enlarge or shrink. Nuclear factor κB (NF-κB) is a nuclear transcription factor that regulates a number of physiological processes, such as inflammation, apoptosis, and cellular growth. OBJECTIVE: To analyze phosphorylation of NF-κB and related molecules in cerebral AVM specimens. METHODS: We examined 19 specimens of cerebral AVMs from 18 patients. Immunohistochemical analysis was performed using an NF-κB p65 (C22B4) rabbit monoclonal antibody, the phosphorylated form of NF-κB (PNF-κB) p65 (Ser276) rabbit antibody, and an IκBα mouse monoclonal antibody. RESULTS: Expression of NF-κB was mainly confined to the endothelial lining and the infiltrating inflammatory cells in the perivascular regions. PNF-κB showed the highest level of expression in both endothelial cells and perivascular infiltrating cells. PNF-κB was intensely expressed in the endothelium and perivascular infiltrating cells of 15 specimens (78.9%). NF-κB and IκB were also expressed in endothelial cells and perivascular infiltrating inflammatory cells, but at lower levels than PNF-κB. Immunohistochemical studies revealed that PNF-κB was mainly concentrated in the nuclei of endothelial and infiltrating inflammatory cells. On the contrary, expression of both NF-κB and IκB was mainly concentrated in the cytoplasm of endothelial and inflammatory cells. CONCLUSION: We detected activation of NF-κB in the endothelium and perivascular infiltrating inflammatory cells within the cerebral AVM nidus, suggesting a role in the pathophysiology of cerebral AVM.

Expression of activation-induced cytidine deaminase in malignant lymphomas infiltrating the bone marrow.

Somatic hypermutation of immunoglobulin genes and class switch recombination are pivotal processes in the germinal center (GC) reaction and have been implicated in the development of malignant B-cell lymphoma. Both processes require the enzyme activation-induced cytidine deaminase (AID). Expression of AID is largely restricted to GC B cells and B cells that undergo class switch recombination outside the GC. AID is also expressed in many B-cell lymphomas. This study investigates the expression of AID of malignant lymphomas infiltrating the bone marrow. Bone marrow trephines (n=130) with infiltration of Hodgkin lymphoma and non-Hodgkin lymphoma of B cell and T-cell type and trephines with reactive lymphoid follicles (n=16) were analyzed immunohistochemically for AID protein. AID is expressed in bone marrow infiltrates of malignant lymphomas. AID was generally detected in lymphomas of GC origin. Tumor cells of hairy cell leukemia are mostly AID. There is apparently no different expression of AID found in bone marrow infiltrates of malignant lymphomas compared with a control group with nodal malignant lymphoma infiltrates (n=105). These results suggest that the expression pattern of AID in lymphoma infiltrates in the bone marrow reflects that of extramedullary lymphoma infiltrates.

Changes in lactate dehydrogenase isoenzymes associated with relapse of childhood acute lymphocytic leukemia.

Twenty-eight children with high-risk acute lymphocytic leukemia underwent monthly serum lactate dehydrogenase (LDH) and LDH isoenzyme fraction determinations to examine whether LDH isoenzyme fractions change with an increase in the body burden of tumor cells. The 9 patients who relapsed and 5 patients who presented with leukemia during the study period had a slightly lower mean LDH-1 isoenzyme fraction. When the period from 3 months before to 3 months after relapse was examined, significant increases in the LDH-3 isoenzyme fraction and decreases in the LDH-1 and LDH-2 isoenzyme fractions were seen at the time of relapse. These results were highly significant when patients with non-T-cell and T-cell leukemia were combined and when bone marrow and central nervous system relapse was included. The changes at relapse appeared to revert with intensification of chemotherapy. The changes at relapse were not different in magnitude from random variation occurring in patients who remained in remission throughout the study. Although changes in LDH isoenzymes appeared to occur at the time of relapse compared with the periods immediately before and after relapse, these changes were not specific for relapse. LDH isoenzymes do not appear to be useful in predicting relapse in children with leukemia.