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ABSTRACT: Natural killer (NK)-like T cells are major histocompatibility complex-unrestricted cytotoxic T cells that are surface CD3-positive, express NK-cell antigens, and rearrange their T-cell receptor. Most neoplasms arising from this T-cell subpopulation have been a chronic lymphoproliferative disease referred to as T-large granular lymphocyte (LGL) leukemia. Only 10 NK-like T-cell lymphomas have been described in detail previously; this study presents the clinicopathologic features of six others and distinguishes these lymphomas from T-LGL leukemia. All patients presented with B-symptoms and often had marked hepatosplenomegaly without significant peripheral lymphadenopathy. Four of the six patients were immunosuppressed. All had CD3, CD8, CD56-positive tumors, presumably of hepatosplenic (n = 3), intestinal (n = 1), pulmonary (n = 1), or nodal (n = 1) origin. Three patients had lymphomatous bone marrow infiltrates, and four had peripheral blood involvement by neoplastic large lymphocytes, some of which had a blastic appearance or resembled virocytes. Azurophilic granules, ultrastructurally corresponding to cytoplasmic dense core and/or double density granules, were seen in all cases. T-cell clonality was shown in five tumors by Southern blot analysis, and three had abnormal karyotypes. Two untreated patients died 20 days after presentation, and three patients who received combination chemotherapy died within 5 months of presentation. One patient remains in complete remission 22 months after treatment. These findings suggest NK-like T-cell lymphomas are aggressive, are clinicopathologically distinct from T-LGL leukemia, and should be in the differential diagnosis of extranodal T-cell lymphoproliferations, including those in immunosuppressed patients. Furthermore, the LGL morphology, phenotype, and tissue distribution of some NK-like T-cell lymphomas suggest they arise from thymic-independent T cells of the hepatic sinusoids and intestinal mucosa.
Blood 03/1996; 87(4):1474-83. · 9.90 Impact Factor
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ABSTRACT: Dyserythropoiesis after bone marrow transplantation is common, but the presence of ringed sideroblasts (RS) has not been evaluated fully. To examine for RS, a combined silver and Perls' Prussian blue stain, shown previously to be more sensitive for detecting RS than Perls' Prussian blue stain alone, was used on post-transplant marrow aspirate sections from 39 patients who received marrow transplants (allogeneic, 28; autologous, 11) for a variety of disorders. Marrow aspirate sections were available for comparison from 11 of these patients before any treatment as well as from five patients with normal marrows and normal peripheral blood cell counts. Aspirates were not performed on donor marrows. By the modified silver stain, RS were present in 34 (87%) patients whose marrows were sampled 0.5 to 39 (median, 1.5) months post-transplant including 10 of 11 patients with autologous transplants (no graft versus host disease prophylaxis). In contrast, seven of 36 (19%) of these marrows contained RS when stained with Perls' reaction alone. Only one of 11 pretransplant marrows and none of five normal marrows contained RS when stained by either method. These results demonstrate that RS are present in most post-transplant marrows even beyond the usual period of reconstitution (28 days), and this finding can be included among the features of dyserythropoiesis seen after transplantation. RS apparently are not related to pretransplant pathology or post-transplant therapy. This study also confirms previous observations that modified silver stains are more sensitive for detecting RS than Perls' Prussian blue stain.
Modern Pathology 10/1995; 8(7):782-5. · 4.79 Impact Factor
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American Journal of Surgical Pathology 08/1995; 19(7):850-1. · 4.35 Impact Factor
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ABSTRACT: Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy.
Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study.
The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation.
TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.
Journal of Clinical Oncology 08/1995; 13(7):1742-50. · 18.37 Impact Factor
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ABSTRACT: Peripheral T-cell lymphomas (PTCLs) are regarded as diffuse proliferations. We describe an unusual paracortical nodular growth pattern in four nodal PTCLs that were initially interpreted as atypical lymphoid hyperplasia in three patients and small B-cell lymphoma with plasmacytic differentiation in a fourth. The nodules were vague to easily discernible and produced minimal to partial architectural distortion. Sinuses were often open, and scattered cortical lymphoid follicles with atretic to hyperplastic germinal centers were present. Clusters of tumor cells abutted some follicles in all cases, and in one case they exhibited focal T-zone expansion. Hypervascularity was not prominent, but a few nodules surrounded epithelioid venules, imparting an angiofollicular appearance. The nodules were composed primarily of small lymphocytes with irregular nuclei admixed with scattered large transformed cells, both cell types having clear cytoplasm. Paraffin immunoperoxidase showed that the nodules were composed of T cells. Dendritic cell networks were present only in follicular centers. Southern blot analysis found T-cell receptor gene rearrangements and a germline immunoglobulin gene configuration in all four nodes. These paracortical clear cell nodules of clonal T cells may be a special type of PTCL. Alternatively, they may represent early foci of lymphoma or they may be a subgroup of T-zone lymphoma. Paracortical nodular PTCL must be differentiated from atypical hyperplastic lesions and some B-cell lymphomas.
American Journal of Surgical Pathology 04/1995; 19(3):297-303. · 4.35 Impact Factor
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ABSTRACT: Marrow mast cells, frequently elevated in chronic B-lymphoproliferative disorders, were counted per high magnification field (HMF) on toluidine blue stained marrow biopsies from 34 patients diagnosed with hairy cell leukemia (HCL); similar counts were performed on splenic sections from nine of these patients. Biopsies from 28 normal marrow transplant donors and 10 normal spleens served as controls. Mast cells were distributed irregularly throughout normal and HCL marrows, but tended to be more concentrated about the hairy cells in cases focally involved by HCL. HCL marrows averaged 12.7 mast cells/HMF compared to 1.1 for controls. Although most normal marrows (86%) averaged < 2 mast cells/HMF, 88% of HCL cases averaged > or = 2 mast cells/HMF. Splenic mast cells averaged < 1/HMF for both HCL and control cases. By electron microscopy, marrow mast cells in HCL demonstrated normal substructure with numerous granules. The cell surfaces of mast cells showed filopodia that often came in contact with those of hairy cells. These results indicate most HCL marrows, but not spleens, are associated with varying degrees of mast cell hyperplasia. Furthermore, this study suggests a biologic interaction between mast cells and hairy cells. The significance of marrow mast cell hyperplasia in HCL is unknown, but these mast cells may contribute to the increased reticulin fiber network observed in HCL marrows.
Modern Pathology 11/1993; 6(6):695-8. · 4.79 Impact Factor
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ABSTRACT: A 35-year-old homosexual man developed a composite nodal Kaposi's sarcoma and peripheral T-cell lymphoma that were associated with a peripheral blood CD4-positive lymphocyte count of only 43/mm3. The patient subsequently developed Pneumocystis carinii pneumonitis and eventually died due to disseminated Cryptococcus neoformans. Numerous premortem tests for the presence of human immunodeficiency virus (HIV) types 1 and 2 were negative by the enzyme-linked immunosorbent assay, Western blot, viral isolation, and polymerase chain reaction techniques. Postmortem evaluations for HIV-1, HIV-2, human T-cell lymphotropic virus (HTLV)-I, and HTLV-II also were negative by polymerase chain reaction, immunofluorescence assays, and viral isolation. A systemic infection by Mycoplasma fermentans, however, was documented by immunohistochemistry and polymerase chain reaction in premortem and postmortem tissues. This recently recognized human pathogen has produced systemic infections in patients with the acquired immunodeficiency syndrome (AIDS) and in previously healthy non-AIDS patients who characteristically have a fulminant flu-like illness. Additionally, M fermentans has enhanced the cytopathic effect of HIV in in vitro studies and has produced fatal wasting illnesses with terminal lymphopenia in inoculated adult silvered leaf monkeys. This report is the first description of an association between M fermentans infection and an AIDS-like illness in an HIV-negative individual. The etiology of the severe immunosuppression in this patient and the associated role of M fermentans remain to be determined by further investigations.
Human Pathlogy 06/1993; 24(5):554-8. · 2.88 Impact Factor
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ABSTRACT: T-cell-rich B-cell lymphomas (TCRBCLs) are diffuse lymphomas that contain a minority of large neoplastic B cells amidst a majority of non-neoplastic T cells and numerous histiocytes, an unusually pronounced reactive component not seen in most diffuse large B-cell lymphomas (DLBCLs). This reaction may be influenced by various cytokines secreted by lymphoma or reactive cells; therefore, expression of interleukin (IL)-1 beta, IL-2, IL-4, IL-6, and IL-9 was evaluated immunohistochemically on paraffin-embedded sections of 18 TCRBCLs and was compared with that of 15 DLBCLs containing a minority of reactive T cells and to that of seven reactive lymph nodes. Moderate to intense expression of IL-4 was detected in variable numbers of tumor cells and in numerous histiocytes in 16 TCRBCLs. In contrast, intense IL-4 expression in numerous histiocytes was observed in only one of 15 DLBCLs with few T cells. In four other DLBCLs and three reactive nodes, moderate to intense staining for IL-4 was noted only in rare large transformed cells or in occasional histiocytes. Except for one IL-1 beta positive and another IL-9 positive TCRBCL, there was no marking or weak staining only with other cytokine antibodies in the neoplastic and reactive cases studied. The expression of IL-4 in most TCRBCLs, but not in other DLBCLs or in reactive nodes, suggests that this cytokine is one factor involved in the pathobiology of the abundant T-cell reaction and, perhaps, contributes to the paucity of neoplastic B cells in TCRBCLs.
American Journal Of Pathology 12/1992; 141(5):1031-6. · 4.89 Impact Factor
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ABSTRACT: T-cell-rich B-cell lymphomas (TCRBCLs) are recently described, unusual non-Hodgkin's lymphomas that have a diffuse morphology, a predominance of reactive T-cells, and a minority of neoplastic B-cells. The clinical and pathological features of 19 TCRBCLs, all of which demonstrated B-cell clonality, are presented. These lymphomas generally affected older patients by widespread disease and usually were nodal in origin. Treatment varied, but continuous complete remissions (eight patients) were achieved only in those receiving chemotherapy directed at intermediate-grade lymphomas. Although morphologically heterogeneous, all cases resembled peripheral T-cell lymphomas (PTCLs); several TCRBCLs also contained Reed-Sternberg-like cells. Flow cytometry or frozen-section immunoperoxidase failed to detect monotypic immunoglobulin (Ig) in eight of eight cases tested. In contrast, paraffin immunoperoxidase was very useful diagnostically, showing large L26 (CD20-associated) positive cells scattered singly or in small clusters among numerous small T-cells (UCHL1[CD45RO] positive) in all cases. Monotypic cytoplasmic Ig was present in 16 of 19 cases, one of which exhibited plasmacytic differentiation. Southern blot analysis demonstrated relatively faint Ig JH and/or JK bands, indicating a small monoclonal B-cell population in nine of 11 cases, one of which also showed a bcl-2 rearrangement. No T-cell receptor gene rearrangements were observed. These results showed that TCRBCLs may be easily confused with PTCLs or occasionally confused with Hodgkin's disease. TCRBCLs are probably heterogeneous biologically; some cases are of follicular center cell origin. These lymphomas respond to chemotherapy directed at intermediate-grade lymphomas, apparently have a better prognosis than PTCLs, and seem to represent morphological variants of different types of large B-cell lymphomas.
American Journal of Surgical Pathology 05/1992; 16(4):351-63. · 4.35 Impact Factor
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ABSTRACT: A lymphoblastic malignancy presented as the lymphoid component of a recurrent invasive lymphocyte-rich thymoma that had been previously resected and treated with chemotherapy. This high grade lymphoid neoplasm concurrently involved mediastinal nodes and subsequently disseminated to pleural fluid and peripheral blood. Lymphocytes with convoluted nuclei demonstrated a T-lymphoblastic phenotype (UCHL1+, Leu-22+, TdT+) by immunohistochemical studies. T-cell lymphoblastic leukemia/lymphomas in this clinical setting have not been reported, and this case suggests that neoplastic transformation of lymphocytes may occur in longstanding refractory thymomas.
Modern Pathology 08/1991; 4(4):524-8. · 4.79 Impact Factor
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ABSTRACT: Paraffin-embedded sections of 77 peripheral T-cell lymphomas (PTCLs) were stained with several monoclonal antibodies, including the preferential T-cell markers Leu-22 (L60[CD43]) and UCHL1 (CD45RO). The staining characteristics of L60 and UCHL1 were compared to determine the value of each in the immunophenotypic analysis of PTCLs. Lineage specificity was evaluated among 39 B-cell lymphomas and 33 cases of Hodgkin's disease (HD). L60 and/or UCHL1 stained 95% of PTCLs, whereas L60 and UCHL1 alone stained 90% and 69% of cases, respectively. L60 demonstrated significantly greater numbers of immunopositive tumor cells than UCHL1 in 37% of the PTCL cases, principally because of enhanced marking of large, neoplastic cells. UCHL1 was a better marker in only 10% of the PTCL cases. L60 stained 33% of B-cell lymphomas, usually small lymphocytic or lymphoplasmacytic types. UCHL1 stained only 8% of B-cell lymphomas, all large-cell types. L60 and UCHL1 stained Reed-Sternberg cells and variants in three cases of nodular sclerosing HD. These results suggest that both L60 and UCHL1 are useful markers of PTCLs in routinely processed tissue. L60 is a more sensitive marker of large neoplastic T-cells than UCHL1 but is less lineage-specific. These antibodies are most effective when used as part of a panel of monoclonal antibodies.
American Journal of Clinical Pathology 06/1991; 95(5):696-701. · 2.60 Impact Factor
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ABSTRACT: We reviewed the clinical and pathologic features in 186 patients with large-cell lymphomas seen at Vanderbilt University Hospital between 1970 and 1986. Ninety-two cases (49%) were large noncleaved-cell lymphoma (LNCCL), 61 cases (33%) were large-cleaved-cell lymphoma (LCCL), 17 cases (9%) were peripheral T-cell lymphoma (PTCL), and 16 cases (9%) were immunoblastic sarcoma of B cells (IBS-B). These subsets of large-cell lymphoma did not differ with respect to median age, distribution by stage, or incidence of bone marrow involvement. Significant differences between groups were noted with regard to male:female ratio, incidence of symptoms, incidence of extranodal disease, and pattern of adenopathy. However, when LCCL was excluded from the analysis, none of these differences were significant. By univariate analysis, age, stage, marrow involvement, extranodal disease, B symptoms, elevated serum lactic dehydrogenase (LDH), and diffuse pattern were unfavorable prognostic features in large-cell lymphoma. However, when cases were stratified by cell of origin, nodular versus diffuse pattern was of no prognostic significance. Nodularity was favorable only because 71% of nodular and nodular-diffuse cases were LCCL, while the majority of diffuse cases were LNCCL. Although IBS-B is considered a "high-grade" lymphoma, we found no evidence for inferior survival in these patients compared with LNCCL or LCCL. In fact, survival was better in IBS-B than in LNCCL or LCCL, although this difference was not significant. However, survival was significantly inferior in PTCL (median, 11 months) compared with the other subsets of large-cell lymphoma (median, 46 months; P = .038, log-rank test). Since the association of PTCL and an inferior survival has most often been noted in the context of "second-generation" chemotherapy, we believe that this association may be therapy-dependent and may be minimized by the use of more aggressive chemotherapy regimens.
Journal of Clinical Oncology 09/1990; 8(8):1370-9. · 18.37 Impact Factor
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ABSTRACT: A modified silver stain is described for the demonstration of ringed sideroblasts in bone marrow. It is more sensitive than Perls' reaction for that purpose, especially when iron stores of marrow are low or absent. Ringed sideroblasts may still be demonstrable by silver stain in cases of sideroblastic anemia without ringed sideroblasts, for which severe iron deficiency prevents detection of the abnormal sideroblasts by Perls' reaction. As iron has been reported to be present in mitochondria of ringed sideroblasts in the form of ferric phosphate, it is possible that the silver stain demonstrates the phosphate moiety and not the iron, thus explaining its greater sensitivity in iron deficiency as compared to Perls' reaction. Further study is necessary to confirm the staining mechanism, to elucidate the composition of iron deposits, and to explain the pathophysiology of sideroblastic anemia.
American Journal of Clinical Pathology 08/1990; 94(1):73-6. · 2.60 Impact Factor
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ABSTRACT: Eleven cases of atypical carcinoid (AC) of the lung were identified during an eight-year period. Their clinical features and treatment responses were contrasted with our experience at Vanderbilt with small cell lung cancer (SCLC) and a literature review of typical bronchial carcinoids (TC). Clinically, there were no features to distinguish AC from TC except for age at diagnosis (59 vs 49 years). Atypical carcinoid was similar to SCLC with respect to many clinical features, although female sex, absence of smoking history and localized disease at presentation were more common in AC. Pathologically, these tumors were distinguished by cellular atypia, necrosis, architectural disorder, or increased mitotic rate in the presence of a recognizable carcinoid pattern. Immunoperoxidase staining revealed no difference between AC and TC or SCLC. Atypical carcinoid of the lung represents a distinct clinicopathologic disease.
Chest 03/1988; 93(2):370-5. · 5.25 Impact Factor
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ABSTRACT: Self-limited adenoviral infections are very common with the majority of infections resolving rapidly. Fatal complications may occur in severely immunocompromised patients. We describe a case of fulminant hepatic failure due to adenovirus in a 54-year-old man treated with fludarabine and cyclophosphamide for non-Hodgkin's lymphoma. There are no previous reports of this complication in conjunction with purine nucleoside therapy.
Leukemia and Lymphoma 42(5):1145-50. · 2.58 Impact Factor
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J. R. Cerhan,
S. M. Ansell,
Z. S. Fredericksen,
N. E. Kay,
M. Liebow,
T. G. Call,
A. Dogan,
J. M. Cunningham,
A. H. Wang,
W. Liu-Mares, W. R. Macon,
D. Jelinek,
T. E. Witzig,
T. M. Habermann,
S. L. Slager
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ABSTRACT: Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P < or = .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P < or = .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.
Blood. 110(13):4455-63.
