Non-Hodgkin's lymphomas in leukaemic phase: incidence, prognosis and therapeutic implications

248 patients with non-Hodgkin lymphomas (NHL) were retrospectively analysed in an attempt to elucidate the risk factors, the prognostic importance and the therapeutic implications of blood involvement. Bone marrow involvement and large spleen were significantly correlated to leukaemic manifestations (P less than 0.0001 and P less than 0.0005, respectively); conversely no correlations were seen with bulky disease and symptoms. Among low-grade malignant lymphomas (LGML) centroblastic-centrocytic follicular and diffuse or diffuse and "CLL" subtypes were mostly associated with blood involvement (31% and 55%, respectively). Among high-grade malignant lymphomas (HGML) lymphoblastic type is more frequently associated with blood involvement (42%) than the other subtypes. Blood involvement was not clearly correlated with the prognosis either in LGML (median survival 39 and 36 months for leukaemic and non-leukaemic patients, respectively) or HGML (median survival 12 and 18 months, respectively), although a shorter survival of leukaemic than non-leukaemic lymphoblastic lymphoma was observed (median survival 8 months versus 14 months, respectively). The poorer response rate to therapy of leukaemic patients (median duration of CR22 and 5 months in LGML and HGML, respectively) as opposed to non-leukaemic patients (median duration of CR 29 and 23 months, respectively) led us to consider an alternative treatment in such patients.     

The prognostic impact of bone marrow involvement in patients with diffuse large cell lymphoma varies according to the degree of infiltration and presence of discordant marrow involvement

BACKGROUND: The prognostic significance of marrow involvement in diffuse large cell lymphoma (DLCL) is controversial. Factors that that have been reported to influence prognosis include the pattern and extent of marrow infiltration and histological discordance between the primary site and the bone marrow. METHODS: Bone marrow biopsies from 172 patients with newly diagnosed DLCL entered in two consecutive trials of the Australasian Leukaemia and Lymphoma Group were analyzed. Progression-free (PFS) and overall survival (OS) were calculated according to the absence or presence of bone marrow involvement (BMI), the extent of lymphomatous infiltration and the presence of histological discordance between the primary site and the bone marrow. RESULTS: Of 172 patients with DLCL accrued between 1982 and 1990, who were treated with CHOP or CHOP-like regimens, 47 (27%) demonstrated marrow involvement on examination of multiple levels. Seventy two percent (34/47) of patients had discordant marrow involvement (<50% large cells) and 28 had minimal (<10%) involvement; these latter patients with minimal marrow involvement (<10%) had similar PFS & OS to the 113 patients without involvement. Within the group of 47 patients with marrow involvement, an increasing percentage of BM involvement was significantly associated with an increasing percentage of concordant histology and a decreasing PFS & OS. CONCLUSIONS: Minimal BMI, seen in the majority of patients with DLCL with marrow infiltration, appears not to influence the PFS & OS. However, an increasing degree of marrow involvement is associated with an increasing component of large cells and a poorer prognosis in DLCL patients, independent of other risk factors.     

Lymphocyte populations and T cell subpopulations in blood of patients with non-Hodgkin lymphomas

Lymphocytic populations and T cell subsets were studied in the blood of patients with nonleukemic non-Hodgkin lymphoma. A statistically significant decrease of both the T lymphocytes and the OKT4-, OKT8-binding cells was detected in low-grade malignant lymphomas (LGML). A significant decrease of the T cell population and of the OKT4-binding cells was also found in high-grade malignant lymphomas (HGML); in these, the OKT8-binding cells were not lowered. The amount of the circulating B lymphocytes was not found to be altered both in HGML and in LGML.     

Central nervous system involvement in patients with mantle cell lymphoma

 In small cell lymphomas, central nervous system (CNS) involvement has been considered to be very rare. Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin's lymphomas consisting of small or intermediate lymphatic B-cells. It has a poorer prognosis than the other small cell lymphomas. Only a few MCL patients with CNS involvement have been reported in the literature to date. We analyzed retrospectively the incidence, clinical characteristics, and outcome of CNS involvement in 94 patients with confirmed MCL treated at one center from 1980 to 1997. Four of the 94 patients (4%) developed CNS lymphoma during the median follow-up of 51 months. The diagnosis was based on clinical, cytological and radiological findings. CNS involvement appeared at 4.6, 56, 66, or 86 months from the diagnosis of MCL. All patients had neurological symptoms and a leukemic disease; two cases were seen with a blastoid morphology. Malignant lymphatic cells were detected in spinal fluid in all cases and parenchymal infiltrations in brain in two. All patients were treated with intrathecal chemotherapy, without response. Survival time after diagnosis of CNS lymphoma ranged from 18 to 55 days. At diagnosis, no adverse prognostic factors predictive of CNS lymphoma were found. CNS involvement was associated with a progressive leukemic disease as a late event or a blastoid transformation. The prognosis of MCL patients with CNS involvement is poor. Received: July 30, 1998 / Accepted: November 12, 1998     

Intravascular B-cell lymphoma with leukemic presentation: case report and literature review

Intravascular lymphoma is an extremely rare, disseminated, and aggressive extranodal CD20⁺ non-Hodgkin's lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels. We report a 72-year-old woman with a diagnosis of intravascular lymphoma presented with splenomegaly and leukemic appearance in the peripheral blood smear. Her clinical course was rapidly deteriorated before the initiation of specific chemotherapy and finally died due to multiorgan insufficiency. Bone marrow biopsy revealed a characteristic infiltration of CD5, CD10 B-cell lymphoma. To our knowledge, this is the first reported case of a CD5, CD10 intravascular B-cell lymphoma with leukemic presentation in peripheral blood with multiple cytogenetic aberrations.     

Risk factors for poor treatment outcome and central nervous system relapse in diffuse large B-cell lymphoma with bone marrow involvement

Although several studies have described the prognostic implication of bone marrow (BM) involvement (BMI) in lymphoma, studies focused on BM-involved diffuse large B-cell lymphoma (DLBCL) are very rare and small-sized. This study was performed to examine the prognostic impact of morphologic findings of BMI by lymphoma and risk factors for central nervous system (CNS) relapse in BM-involved DLBCL. Between 1993 and 2005, 675 patients were diagnosed with DLBCL, and 88 patients who had BMI at initial diagnosis were eligible for this study. The median overall survival (OS) and failure-free survival (FFS) of 88 patients were 36.6 and 20.1 months, respectively. When three variables from BM morphologic findings (the pattern of BM infiltration, extent of BMI by lymphoma, and percentage of large cells in the infiltrate) were simultaneously included into multivariate model, the increased extent of BMI by lymphoma (≥10%) in BM area was the only negative prognostic factor, independent of the International Prognostic Index (IPI). Patients with both lower IPI scores and less extent of BMI showed an excellent prognosis with chemotherapy alone (5-year OS and FFS rates, 80% and 69%). However, morphologic BM features were not independent predictive factors for CNS recurrences. An increased lactate dehydrogenase (LDH) level at initial diagnosis was the only independent predictive factor for CNS relapse. Further efforts should be directed toward finding optimal treatment modalities based on the IPI and the extent of BMI by lymphoma. CNS prophylaxis may be considered only in patients with initial elevated LDH levels. K.-W. Lee and J. Yi equally contributed to this study.     

DAP-kinase hypermethylation in the bone marrow of patients with follicular lymphoma

We studied whether DAP-kinase hypermethylation plays a role as a prognostic marker in patients with follicular lymphoma (FL). We found that DAP-kinase was frequently hypermethylated in bone marrow (BM) samples of 52 FL patients at diagnosis (71%) and identified patients with worse progression-free survival (p=0.06). In particular, patients with histologically proven BM infiltration and DAP-kinase hypermethylation had a poorer outcome (p=0.037). In a total of 170 BM samples obtained at diagnosis or during follow-up, DAP-kinase hypermethylation and the bcl2/IgH rearrangement gave concordant results in 67% of samples (48% both positive, 19% both negative). Both mrakers were independent predictors of the disease status (p<0.001).     

Commercial LightCycler-based quantitative real-time PCR compared to nested PCR for monitoring of Bcl-2/IgH rearrangement in patients with follicular lymphoma

Translocation of chromosomes 14 and 18 [t(14;18)] for detection of minimal residual disease in follicular lymphoma patients can be analyzed by nested polymerase chain reaction (PCR) or by quantitative PCR like LightCycler-based assays. We have compared both methods in blood and bone marrow samples of 28 patients enrolled in a clinical study on immunochemotherapy. In 42% of samples, the bcl2-IgH rearrangement was detectable by nested PCR, but not by LightCycler PCR. Nested PCR was able to reveal a significant drop in positive bone marrow or peripheral blood samples after therapy. In contrast, with LightCycler PCR, the detected drop in t(14;18)-positive cells did not reach statistical significance. The majority of patients showed positive results with nested PCR of peripheral blood or bone marrow without any associations to presence or absence of histological bone marrow (BM) infiltration by lymphoma cells. With LightCycler PCR, the numbers of positive cells were higher in samples from patients with BM infiltration of lymphoma cells (1.9 x 10(-2)) compared to samples from patients without involvement (4.08 x 10(-5)). A similar trend was seen in samples derived from the peripheral blood. Positivity for t(14;18) after therapy in two patients correlated with clinical relapse 6 months later. The data shown here demonstrate a lower sensitivity of LightCycler vs. nested PCR for detection of t(14;18). The usefulness of nested PCR for t(14;18) for risk stratification after primary therapy has to be validated in larger trials.     

Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature

Anaplastic large cell lymphoma (ALCL) is an aggressive neoplasm of T- or null cell phenotype and is recognized as a distinct clinicopathologic subtype of non-Hodgkin lymphoma (NHL) in the revised World Health Organization (WHO) classification of hematopoietic neoplasms. It is rarely associated with leukemic phase. Most cases with leukemic involvement are the small cell variant of ALCL. These cases often lack the pleomorphism seen in the common variant of ALCL and may be misdiagnosed. We report a series of three patients who presented with leukemic phase ALCL. The patients included an 11-year-old boy, a 29-year-old man, and a 59-year-old woman. The clinical and pathologic features of these cases are reviewed. The patients in our case series with leukemic phase ALCL exhibited rare clinical features. The patients presented with massive extranodal disease involving cerebrospinal fluid (CSF), liver, spleen, lungs, and bone marrow. CSF involvement was documented morphologically as well as by flow cytometry in two patients. Two of the patients had small cell variant and the third patient had common type ALCL. The neoplastic cells in all three patients were ALK positive; however these patients died within months of diagnosis. Leukemic phase ALCL is rare, and behaves in an aggressive manner. Some, but not all, cases in the literature presenting with peripheral blood involvement had small cell variant ALCL, as seen in two of our cases. The leukemic phase of ALCL should be considered when a T-cell leukemia with unusual morphologic features is encountered.     

Stage I/II follicular lymphoma: spread of bcl-2/IgH+ cells in blood and bone marrow from primary site of disease and possibility of clearance after involved field radiotherapy

Stage I/IIA follicular lymphoma (FL) is considered a localised disease that can be adequately treated with radiotherapy alone. Bone marrow (BM) and peripheral blood (PB) involvement in FL was investigated by polymerase chain reaction (PCR) in a series of 24 consecutive patients with histologically revised diagnosis and treated with involved field radiotherapy. Despite the limited stage, Bcl-2/IgH+ cells were found at diagnosis in PB and/or BM of 16 patients (66.6%). After treatment, in 9/15 Bcl-2/IgH positive evaluable patients, a disappearance of Bcl-2/IgH+ cells was observed, which persisted after a median follow-up of 43.5 months (range 11-70) in all but one patient. Quantitative PCR demonstrated the feasibility of clearing PB and BM Bcl-2+ cells after local irradiation of the primary site of the disease only when the basal number of lymphoma cells was <1:100 000. Patients with Bcl-2/IgH+ cells at diagnosis or after treatment had a higher likelihood of relapse. Thus, despite a negative BM biopsy, the majority of localised FL Bcl-2/IgH+ cells were found in the PB and BM. Lymphoma cells can reversibly spread from the affected lymph node to PB and BM and, in a proportion of cases, durably disappear after irradiation. The possibility of a persistent lymphoma cell clearance is proportional to the amount of cells detected at presentation by quantitative PCR.     

Abdominal ultrasound findings mimicking hematological malignancies in a study of 218 gaucher patients

Gaucher disease, the most prevalent sphingolipidosis, generally presents with splenomegaly, anemia, and thrombocytopenia. Hence, hematologists are often the specialists involved in diagnosis and management of these patients. We present ultrasonographic characteristics in a cohort of 218 consecutive Gaucher patients evaluated in our clinic during the past 5 years. Our data emphasize the high prevalence of lesions mimicking hematological malignancies in Gaucher disease. One fifth of 184 non-splenectomized patients had intra-splenic lesions, 6% of all patients had similar lesions in the liver, and 32% of 34 splenectomized patients (but none of the other patients) had marked retroperitoneal or peri-portal lymphadenopathy. The presence of splenic lesions correlated with age and splenic size, but not with extent of bone involvement or genotype. Interestingly, they were not affected by reduction in splenomegaly following enzyme replacement therapy. The importance of these findings is to include Gaucher disease in the differential diagnosis of splenic or hepatic lesions, especially in Ashkenazi Jews. Conversely, they are relevant for follow-up of all Gaucher patients, including asymptomatic individuals, because of the reported increased incidence of hematological malignancies in Gaucher disease. Am. J. Hematol. 55:28-34, 1997. © 1997 Wiley-Liss, Inc.     

Bulky lymphadenopathy in acute myeloid leukemia

 Two cases of acute myeloid leukemia (AML) presenting with bulky adenopathy are reported. Both patients were febrile at admission and showed massive and diffuse lymph node involvement, hepatomegaly, and splenomegaly. Erythematopapular leukemic skin lesions were present in one case at the onset and developed in the other at the time of relapse. Anemia, thrombocytopenia, and moderate leukocytosis were present in both. The presence of immature cells in peripheral blood and bone marrow allowed a rapid diagnosis of AML, FAB M1, in one patient. In the other case, owing to the paucity of immature cells in peripheral blood and bone marrow, lymph node biopsy with histology, imprint cytology, and immunocytochemistry were essential for the diagnosis (AML, FAB M2, with trilineage dysplasia and basophilic involvement). Both patients achieved complete remission (CR), followed by an early relapse 3 months later. They underwent allogeneic bone marrow transplantation (BMT) from HLA identical siblings. One patient is actually alive and in CR at 6 months after BMT; the other patient showed a leukemic regrowth after transplantation and died 4 months later. Received: December 8, 1997 / Accepted: April 29, 1998     

Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis

Myeloproliferative disorders (MPD) are reported in 25-65% of patients with splanchnic vein thrombosis (SVT). Diagnostic criteria for MPD have not been fully established in this context. Using clusters of abnormal megakaryocytes in bone marrow (BM) biopsy as a reference standard for Philadelphia negative MPD, we assessed the relevance of other criteria currently recommended for the diagnosis of MPD in SVT (128 consecutive SVT patients). First, usual criteria were compared with BM results: endogenous erythroid colony formation (EEC) was strongly correlated with BM results; splenomegaly, blood cell count, total red cell volume, erythropoietin level and cytogenetic were much less accurate. Then, patients were assigned to three groups according to the combination of BM and EEC findings (group I: both present; group II: both absent; group III: other patients); clinical presentation and outcome were compared in each group. At a mean follow-up of 6.09 +/- 6.6 years, progression to a severe form of MPD occurred in 7 of 31 group I patients (23%), in 1 of 34 group III patients (3%) and 0 of 63 group II patients. The combination of marked splenomegaly and platelet count >200 x 10(9)/l was restricted to groups I and III. In conclusion, in patients with SVT, BM findings and EEC allowed the diagnosis of MPD at risk of aggravation. Marked splenomegaly in association with platelet counts >200 x 10(9)/l constitute a simple index with high specificity but low sensitivity.     

Assessment of bone marrow involvement in non‐Hodgkin’s lymphomas: comparison between histology and flow cytometry

Bone marrow (BM) examination is essential in the staging of non‐Hodgkin’s lymphoma (NHL) patients. Few studies have compared BM histologic findings with results of flow cytometric (FC) analysis. We analyzed the incidence and patterns of histologic BM involvement in a series of 753 patients with NHL. For 498 patients, a concurrent FC analysis on BM was available. Histologic involvement was detected at diagnosis in 311/753 (41%) patients. By FC, BM involvement was clearly detected in 150/498 (30%). After excluding 12 cases with equivocal histology, concordance between the two methods was detected in 411 (85%) cases (27% BMB+/FC+; 58% BMB?/FC?), while discordance was present in 75 (15%) (P < 0.001): 58 cases (12%) were BMB+/FC? and 17 (3%) were BMB?/FC+. Discordance was more frequent in FL and in lymphoplasmacytic lymphoma (LPL). These data demonstrate that the two methods are comparable in qualitative assessment of BM involvement in NHL, with the exception of FL and LPL. In FL, diffuse large B‐cell lymphoma (DLBCL) and LPL, FC underestimates the extent of infiltrate with respect to histology.     

Grade of bone marrow fibrosis is associated with relevant hematological findings—a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis

Controversy continues to exist regarding not only the exact definition and grading of myelofibrosis (MF), but also whether, and to what extent, this feature may be correlated with clinical findings. A retrospective study was performed involving 865 bone marrow (BM) biopsies together with the clinical records from patients with chronic idiopathic myelofibrosis (CIMF). Diagnosis was established according to the World Health Organization criteria, and assessment of MF followed a consensus scoring system that included four grades (MF-0 to MF-3). Histopathological and clinical evaluations were carried out in an independent fashion. Prefibrotic and early CIMF (MF-0/-1) were presented by 565 patients showing borderline to mild anemia and no or slight splenomegaly, but frequently, thrombocytosis exceeding 500×10⁹/l was shown. In 300 patients, manifest reticulin and collagen fibrosis (MF-2/-3) were characterized by marked anemia, gross splenomegaly, peripheral blasts, and normal to decreased platelet and leukocyte counts. The latter cohort was consistent with findings generally in keeping with MF with myeloid metaplasia. Regarding the stepwise evolution of disease, sequential BM examinations showed that in 103 patients, prefibrotic and early CIMF transformed into advanced stages accompanied by correspondingly developing clinical and histomorphological features. Survival analysis (univariate calculation) revealed a significantly more favorable prognosis in prefibrotic vs advanced stages of CIMF. On the other hand, higher classes of MF also exerted a higher clinical risk profile (Lille score). In conclusion, the dynamics of the disease process in CIMF are characterized by evolving MF in the BM and closely associated changes of relevant hematological findings.     

T cell acute lymphoblastic leukemia (T-ALL): New insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% and 25% of total childhood and adult ALL cases, respectively. During T-ALL, patients are at risk of organ infiltration by leukemic T-cells. Infiltration is a major consequence of disease relapse and correlates with poor prognosis. Transendothelial migration of leukemic cells is required to exit the blood stream into target organs. While mechanisms of normal T-cell transmigration are well known, the mechanisms of leukemic T-cell extravasation remain elusive; but involvement of chemokines, integrins and Notch signaling play critical roles. Here, we summarize current knowledge about molecular mechanisms of leukemic T-cell infiltration with special emphasis on the newly identified subtype early T-cell-progenitor (ETP)-ALL. Furthermore, we compare the extravasation potential of T-ALL cells with that of other hematologic malignancies such as B-ALL and acute myeloid leukemia (AML).