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PubMed2003

Acute myeloid leukemia mimicking primary testicular neoplasm. Presentation of a case with review of literature.

We describe a new unique case of acute myeloid leukemia (AML) in a 21-yr-old male presenting with abdominal pain, bilateral testicular masses and gynecomastia. Further work-up with computed tomography of the chest, abdomen and pelvis revealed massive retroperitoneal, peripancreatic and mediastinal lymphadenopathy, suggesting primary testicular neoplasm. The patient was subjected to right orchiectomy that showed infiltration of testicular tissue with malignant cells, originally misinterpreted as undifferentiated carcinoma. Immunohistochemistry studies, however, showed these cells to be strongly positive for myeloperoxidase and CD45, indicating a myeloid cell origin. Bone marrow (BM) aspirate and biopsy demonstrated replacement of marrow with immature myeloid cells. Both the morphology and immunophenotype of the blast cells were consistent with AML type M4 (acute myelo-monocytic leukemia), using French-American-British (FAB) classification. The patient received standard induction chemotherapy with cytosine arabinoside (ARA-C) and daunorubicin followed with two cycles of consolidation therapy with high dose ARA-C, which resulted in remission of BM disease and resolution of lymphadenopathy and left testicular masses. After the second cycle of consolidation therapy, the patient developed sepsis that was complicated by refractory disseminated intravascular coagulopathy. He expired with a clinical picture of multiple organ failure. The unique features of this case are presented and the related literature is reviewed.

Abdominal Pain↗
PubMed1998

Tumor-infiltrating macrophages influence the glycosphingolipid composition of murine brain tumors.

A procedure was developed to analyze glycosphingolipids (GSLs) in tumor-infiltrating macrophages (TIMs). The procedure entailed dissociating tumors into single cell suspensions with a concurrent metabolic labeling of GSLs using [14C]galactose. TIMs were then separated from tumor cells and other host cells by magnetic activated cell sorting and CD11b (Mac-1) microbeads. Gangliosides and neutral glycosphingolipids were analyzed in the TIM-enriched and TIM-depleted fractions in two different murine brain tumors (EPEN and CT-2A). The TIM gangliosides consisted of over 30 structures as assessed by two-dimensional high performance thin-layer chromatography. GSLs enriched in TIMs, relative to the tumors, included Gg4Cer (asialo GM1), GM1b, and GD1alpha. TIM GSLs were similar in EPEN and CT-2A despite their differences in growth and morphology. TIM GSLs were similar whether TIMs were isolated from tumors grown intracranially or subcutaneously. TIM GSLs were also similar to activated peritoneal macrophage GSLs, although differences in the ceramide structure were observed. Knowledge of TIM GSLs will be important in determining the function of these molecules in macrophage-tumor interactions. In addition, these methods will be helpful in determining the cellular origin of human brain tumor GSLs and in identifying tumor-associated GSLs for immunotherapy.

Animals↗
PubMed1998

Relationship between cleaved L-selectin levels and the outcome of acute myeloid leukemia.

High plasma levels of the shed form of L-selectin (sL-selectin) are frequently detectable in acute myeloid leukemia (AML). sL-selectin can inhibit blast cell adhesion to vascular endothelium and may thereby influence the phenotype of AML. In this study, we have investigated the relationship between sL-selectin levels and clinical presentation or disease outcome in 100 patients with AML. Fifty-eight patients were found to have sL-selectin levels >/=3.12 microgram/mL (>/=3 SD above the mean of healthy controls: "increased"). Patients with extramedullary disease such as lymphadenopathies, splenomegaly, hepatomegaly, and/or muco-cutaneous infiltration had significantly increased sL-selectin levels (P < .001). sL-selectin levels were significantly heterogeneous in the French-American-British subtypes (P = .0003). Patients with "normal" sL-selectin levels had higher probability of achieving complete remission (CR) than with "increased" levels: 81% versus 64%, respectively (P = .06). When adjusting for clinically relevant covariates predictive for CR (sex, age, Auer rods), "normal" sL-selectin levels were significantly associated with CR (odds ratio, 3.08; 95% confidence interval [CI], 1.10 to 8.58; P = .03). Moreover, patients with "increased" sL-selectin levels (>/=3.12 microgram/mL) had shorter event-free survival (EFS) (median 7.3 v 12 months, P = .008) and overall survival (median 1 v 2.05 years, P = .03) than patients with sL-selectin <3.12 microgram/mL. Multivariate statistical analysis (adjusted for age and presence of Auer rods) indicated that sL-selectin was an independent prognostic factor for EFS (hazard ratio [HR], 1.96; 95% CI, 1.21 to 3.17, P = .006) and overall survival (HR, 1.80; 95% CI, 1.09 to 2.98; P = .02). Thus, plasma sL-selectin may be a useful prognostic marker in the evaluation of AML at diagnosis.

Acute Disease↗
PubMed2001

Clinical tumor cell distribution pattern is a prognostically relevant parameter in patients with B-cell chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: B-cell chronic lymphocytic leukemia (B-CLL) cells are variably distributed among the major lymphoid compartments contributing to the heterogeneous clinical presentation and course of this disease. In order to evaluate this variable distribution we propose a model for its clinical assessment. DESIGN AND METHODS: We introduce the model for tumor distribution (TD) assessment based on TTM scoring system, where TD value represents percentage of total tumor mass infiltrating peripheral blood and bone marrow (TD=TM(1)/TTM). TD in B-CLL can be categorized into 3 subgroups: pure leukemia if TD=100%, predominantly leukemia if TD=50-99% and predominantly lymphoma TD<50%. RESULTS: Among 341 B-CLL patients there were 22.6%, 55.1%, 22.3%, pure leukemia, predominantly leukemia and predominantly lymphoma cases, respectively. TD parameter was strongly associated in univariate analysis with TTM size, Rai and Binet stages, spleen size and beta(2) microglobulin. TD was associated with response to therapy and survival, with higher TD values translated into higher response rates and longer survival. However, in univariate and multivariate Cox analysis TD displayed much stronger relationship with prognosis in female patients, where it is the strongest independent predictor of survival along with age and Binet stage. INTERPRETATION AND CONCLUSIONS: TD, a quantitative and simple clinical parameter, easily assessed in all patients, offers a reliable tool for evaluation of tumor cell distribution in B-CLL. It has independent and strong prognostic power in females, as opposed to males, possibly unmasking important, yet unrecognized, biological difference in B-CLL patients.

Adult↗
PubMed1993

Long-term follow-up of patients with hairy cell leukaemia treated with pentostatin: lymphocyte subpopulations and residual bone marrow infiltration.

Peripheral blood lymphocyte (PBL) subsets and bone marrow biopsies were analysed in six patients with hairy cell leukaemia (HCL) treated with 2'-deoxycoformycin (pentostatin, DCF) according to a phase II trial of the EORTC Leukemia Cooperative Group. All patients responded to DCF with four complete and two partial remissions according to conventional criteria. Within the PBL subsets, major changes concerned the CD4+ T cells, which during DCF therapy were distinctly suppressed to nadir values of 0.038-0.18 (median 0.126) x 10(9)/l. In five patients these cells returned to normal 3.0-49.5 (median 14.5) months after the last DCF injection. CD8+ cells were decreased to a lesser extent, and NK cell numbers improved during treatment. Bone marrow immunohistology applying the MoAb B-ly7 demonstrated residual hairy cells (HCs) in all of the six patients following DCF treatment with nadir HC numbers of 0.2-3.0% of bone marrow cells. Immunoglobulin gene rearrangement analysis of DNA obtained from these biopsies showed only germline bands, whereas rearranged bands had been present on the pretreatment specimens. Within the observation period of 15.5-54.0 (median 47.0) months after discontinuation of DCF therapy, immunohistology demonstrated a continuous increase in HC numbers in five of the six patients with clonal rearrangement detectable in bone marrow specimens from three of these patients at last follow-up date. Although established on the basis of a small number of patients, these data suggest that DCF treatment as currently employed in HCL is unable to eradicate the malignant B cell clone.

Adult↗
PubMed2001

Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: a multiparameter flow cytometry study.

Tumour-infiltrating T lymphocytes (TIL-T) have been implicated in playing a role in controlling tumour growth. We evaluated TIL-T in 55 cases of de novo diffuse large B-cell lymphoma (DLBCL) using three- or four-colour flow cytometric immunophenotyping (FCI). The percentage of TIL-T varied from 3% to 72% of total viable cellular events (mean 32 +/- 20%). The CD4:CD8 ratio varied from 0.17 to 13 (mean 2.3 +/- 2.2). Cases with >/= 20% T cells and those with CD4:CD8 ratios > or = 2.0 showed a significantly better overall survival (P = 0.017 and P = 0.034 respectively). These findings were independent of clinical stage at diagnosis. The T-cell percentage and CD4:CD8 ratio were moderately correlated (Spearman correlation coefficient = 0.47, P = 0.001) and multivariate analysis revealed that the association of the two factors with prognosis was mutually dependent. The T cells in 23 cases were studied for CD45RO. The mean percentage of total T cells expressing CD45RO was 86 +/- 10%. There was a trend towards better survival for those patients with a higher percentage of CD45RO+ T cells (P = 0.06). These results suggest that TIL-T, particularly CD4+ T cells, may play a role in the control of DLBCL, and measurement of T-cell percentage and T-cell subsets using FCI may be useful in predicting the clinical behaviour of DLBCL.

Adolescent↗
PubMed2006

Early immunization induces persistent tumor-infiltrating CD8+ T cells against an immunodominant epitope and promotes lifelong control of pancreatic tumor progression in SV40 tumor antigen transgenic mice.

The ability to recruit the host's CD8+ T lymphocytes (T(CD8)) against cancer is often limited by the development of peripheral tolerance toward the dominant tumor-associated Ags. Because multiple epitopes derived from a given tumor Ag (T Ag) can be targeted by T(CD8), vaccine approaches should be directed toward those T(CD8) that are more likely to survive under conditions of persistent Ag expression. In this study, we investigated the effect of peripheral tolerance on the endogenous T(CD8) response toward two epitopes, designated epitopes I and IV, from the SV40 large T Ag. Using rat insulin promoter (RIP) 1-Tag4 transgenic mice that express T Ag from the RIP and develop pancreatic insulinomas, we demonstrate that epitope IV- but not epitope I-specific T(CD8) are maintained long term in tumor-bearing RIP1-Tag4 mice. Even large numbers of TCR-transgenic T cells specific for epitope I were rapidly eliminated from RIP1-Tag4 mice after adoptive transfer and recognition of the endogenous T Ag. Importantly, immunization of RIP1-Tag4 mice at 5 wk of age against epitope IV resulted in complete protection from tumor progression over a 2-year period despite continued expression of T Ag in the pancreas. This extensive control of tumor progression was associated with the persistence of functional epitope IV-specific T(CD8) within the pancreas for the lifetime of the mice without the development of diabetes. This study indicates that an equilibrium is reached in which immune surveillance for spontaneous cancer can be achieved for the lifespan of the host while maintaining normal organ function.

Animals↗
PubMed2001

Transformation of T-cell large granular lymphocyte leukaemia into a high-grade large T-cell lymphoma.

We describe a case of T-cell large granular lymphocyte (LGL) leukaemia that transformed into a large-cell T-cell lymphoma 11 years from diagnosis. A 29-year-old asymptomatic female presented in 1989 with lymphocytosis, neutropenia and mild bone marrow infiltration. The circulating cells were LGL with a CD2+, CD3+, CD8+, CD4-, CD16+, CD56+, CD57- phenotype. In August 2000, she developed fever, a large submandibular mass and hepatosplenomegaly. Biochemistry showed abnormal liver function tests and raised lactate dehydrogenase (LDH) levels. A serological screen for Epstein-Barr virus, cytomegalovirus, human T-lymphotropic virus-I, human herpes virus (HHV)-6 and HHV-7 was negative. Histology of the mass was consistent with the diagnosis of peripheral T-cell lymphoma composed of large cells, and immunohistochemistry showed that the lymphoma cells had a phenotype identical to the mature LGL. Molecular analysis with the polymerase chain reaction (PCR) demonstrated rearrangement of the T-cell receptor (TCR) gamma-chain gene with a band of identical size in both bone marrow mature LGL and lymph node cells. The patient was treated with CHOP (cyclophosphamide, vincristine, doxorubicin and prednisolone), resulting in the disappearance of the mass and improvement of the hepatosplenomegaly, LDH and liver abnormalities. She underwent splenectomy, and spleen histology showed involvement by T-cell LGL leukaemia with no evidence of transformation. This case illustrates that transformation or Richter syndrome may occur in a minority of patients with T-cell LGL leukaemia, a disease that has a benign clinical course in most cases. This is the first case documented by molecular methods of the transformation of the pre-existing clone.

Adult↗
PubMed2003

The utility of the in situ detection of T-cell receptor Beta rearrangements in cutaneous T-cell-dominant infiltrates.

The diagnostic assessment of cutaneous T-cell infiltrates is problematic for dermatopathologists. A variety of conditions, including lymphomatoid hypersensitivity reactions and lymphomatoid lupus erythematosus, can demonstrate lymphoid atypia and phenotypic changes that can mimic cutaneous T-cell lymphoma (CTCL). A similar issue revolves around lymphoid dyscrasias, which includes parapsoriasis, atypical pigmentary purpura, pityriasis lichenoides chronica, indeterminate lymphocytic lobular panniculitis, and lymphomatoid papulosis, which can progress to CTCL. A reverse transcription (RT) in situ PCR assay for T-cell receptor beta rearrangements (TCRbeta) was used to assess T-cell clonality in formalin-fixed, paraffin-embedded tissues. In 7 of 8 cases of classic CTCL, the RT in situ PCR assay for TCRbeta rearrangement showed monoclonality; the other was biclonal. Further, in cases with multiple lesions over time, the same T-cell clone could be detected including in those patients whose biopsies showed large-cell transformation. Monoclonality was also demonstrated in each of 2 cases of cutaneous lymphomatoid papulosis. Demonstration of oligoclonality (and one case of biclonality) by RT in situ PCR was confined to those cases that either represented prelymphomatous conditions such as large plaque parapsoriasis or pityriasis lichenoides or lesions of drug-induced lymphomatoid hypersensitivity that all demonstrated clinical regression. In conclusion, RT in situ PCR for TCRbeta, which can be done on formalin-fixed biopsies and allows direct correlation of the molecular data with the histology, is a useful adjunctive test in the differentiation of CTCL from its mimics.

Adult↗
PubMed1996

Improved outcome in adult B-cell acute lymphoblastic leukemia.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

Adolescent↗
PubMed1996

Central nervous system granulocytic sarcoma in a patient with essential thrombocythemia.

We report a rare case of central nervous system granulocytic sarcoma (GS) in a patient with essential thrombocythemia (ET). The diagnosis of GS was established by morphological and cytochemical findings (peroxidase and naphthol-AS-D-chloroacetate esterase positivity) of neoplastic cells. GS was detected as an intracranial frontal mass 7 months before the transformation of ET in acute myeloid leukemia and relapsed as two extradural spinal masses during the course of leukemic evolution.

Acute Disease↗
PubMed1996

Mitoxantrone-containing regimen for treatment of childhood acute leukemia (AML) and analysis of prognostic factors: results of the EORTC Children Leukemia Cooperative Study 58872.

The objective of this study was to evaluate the feasibility, the toxicity and the efficiency of a BFM-like treatment protocol for acute nonlymphoblastic leukemia (ANLL) of children in which mitoxantrone was substituted for conventional anthracycline. The chemotherapy called for induction (mitoxantrone, cytosine arabinoside, etoposide), consolidation (mitoxantrone, cytosine arabinoside, 6 thioguanine), followed by two intensification courses with cytosine arabinoside plus, respectively, mitoxantrone during the first and etoposide during the second courses. Maintenance therapy consisted of daily 6 thioguanine, four-weekly courses of cytosine arabinoside (s.c. daily during 4 days) and eight-weekly courses of mitoxantrone. The latter drug was pursued up to a total cumulative dose of 150 mg/sqm. Maintenance therapy was stopped at 2 years of diagnosis. Out of 108 patients, 84 (77%) achieved a complete remission, 10 died during induction of hemorrhage, sepsis or pulmonary infiltration by leukemic cells. A total of 32 relapses occurred. The median follow-up was 3.5 years. Actuarial event-free survival, disease-free survival and overall survival at 3 years as 41%, 52%, 56%, respectively. These results compare favorably with most reported data, and cytogenetic findings appear to be the most important prognostic factor.

Adolescent↗
PubMed1997

Lymphoblast morphology in predicting leukemic meningeal relapse with low chamber count and lymphoblasts.

The diagnostic criteria for meningeal relapse (MR) of acute lymphoblastic leukemia (ALL) are a cerebrospinal fluid (CSF) chamber count of more than five leukocytes per microliter and a cytomorphological evaluation revealing lymphoblasts. A dilemma arises when confronted with a patient with a low CSF white blood cell (WBC) chamber count and lymphoblasts. We utilized a scoring system to review lymphoblast morphology in 12 such patients. A cell was defined as a lymphoblast if it could not be easily categorized as a lymphocyte, monocyte. histiocyte, or granulocyte. Each lymphoblast was scored on four parameters: presence of nucleoli, homogeneous distribution of chromatin, nucleocytoplasmic ratio greater than 75%, and nuclear irregularity. Cells were scored without knowledge of the patients' out come. Seven patients eventually developed MR by current criteria and five patients never relapsed. The mean lymphoblast scores for patients that did and did not relapse were 2.35 and 1.53, respectively (P < .001). The percent of cells scored as lymphoblasts was also significantly higher in patients that relapsed, 36.9% vs. 19.4% (P = .01). Our study shows that careful cytomorphologic analysis can predict which patients with low chamber counts and "blasts" on cytocentrifuge examination will progress to meningeal relapse. We recommend reviewing the definition of MR and using a scoring system when confronted with blasts in a low chamber count cerebrospinal fluid specimen.

Adolescent↗
PubMed1996

Extramedullary acute promyelocytic leukemia.

BACKGROUND: Extramedullary acute promyelocytic leukemia (APL) is rare, and said to be more common after treatment with all-trans retinoic acid (ATRA) than after any other treatment. METHODS: The case of a child with extramedullary relapse of APL after initial treatment with ATRA and that of an adult whose initial treatment was chemotherapy are presented, and the literature on extramedullary relapse of APL is reviewed. RESULTS: Twenty-six patients were identified, including the 2 current patients. Ethnicity could be determined in 23 patients, 17 of whom were of other than Northern European extraction. The most common sites of extramedullary disease were the skin (15 patients), central nervous system (5 patients), mediastinum (3 patients), and, curiously, gingiva (3 patients). Extramedullary leukemia developed in 19 patients: after treatment with ATRA (6 patients), cytotoxic chemotherapy (12 patients), or both (1 patient), and developed in 7 others before any treatment for leukemia was given. CONCLUSIONS: These data suggest but do not prove that extramedullary APL may occur more frequently after ATRA than other therapy, since ATRA has been available for a relatively short period of time. However, it is clear from the literature that extramedullary APL may occur after chemotherapy or before any treatment.

Adult↗
PubMed1999

Extramedullary tumors of myeloid blasts in adults as a pattern of relapse following allogeneic bone marrow transplantation.

BACKGROUND: Extramedullary tumors of lymphoid and myeloid blasts outside the well-defined sanctuaries following allogeneic bone marrow transplantation (allo-BMT) are rare. Little is known about the biology, treatment, and outcome of these tumors in this setting. METHODS: In this retrospective analysis, 134 consecutive patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who underwent allo-BMT at a single institution between 1990 and 1998 were reviewed. Five cases of isolated extramedullary myeloid sarcoma that occurred as patterns of recurrence following allo-BMT between 1990 and 1998 are reported. These patients were treated with radiotherapy, systemic chemotherapy, or a second allo-BMT. Clinical outcome is compared with posttransplantation bone marrow relapses observed during the same period at the same institution. The literature on the clinical characteristics, currently available treatment, and outcome of posttransplantation myeloid sarcoma patients was reviewed. RESULTS: Excluding isolated skin and central nervous system recurrences, the frequency of extramedullary myeloid sarcoma encountered as a relapse pattern following allo-BMT was determined to be 3.7% among patients with acute or chronic leukemia of myeloid origin. The survival of patients who were managed with radiotherapy and systemic chemotherapy was less than 4 months. A patient who underwent a second allo-BMT following local radiotherapy is alive and in complete remission more than 33 months after the diagnosis of myeloid sarcoma. The median survival of 17 patients with posttransplantation bone marrow relapse following allo-BMT was 2.2 months. When posttransplantation medullary recurrences are analyzed, patients with CML had a median survival of 12 months, with a significantly better 5-year survival rate than patients with AML (0 vs. 60%, P = 0.015; median survival, 12 months). CONCLUSIONS: The clinical outcomes of patients with recurrent isolated extramedullary myeloid sarcoma following allo-BMT are poor, as in any leukemic relapse, with the exception of patients with CML in this setting.

Adult↗