Mantle cell lymphoma: diagnostic criteria, clinical aspects and therapeutic problems.

In 1992, after a history of more than two decades a subgroup within the diffuse low-grade B cell lymphomas designated centrocytic lymphoma, lymphocytic lymphoma of intermediate differentiation or mantle zone lymphoma gained general acceptance, now referred to as mantle cell lymphoma. Similarities between these entities were emphasized by identification of rearrangement and overexpression of CCND1 (bcl1/PRAD1) gene in the majority of cases. Unlike in all other non-Hodgkin's lymphomas sex distribution demonstrates a striking preponderance of males over females with a ratio of 3:1. Initial parameters in all published series are advanced disease with generalized lymphadenopathy in 90%, bone marrow infiltration in 60-75%, splenomegaly in 55%, hepatomegaly in 35%, gastrointestinal involvement in about 25% and peripheral blood lymphocytosis in 20-30% of patients. In generalized disease, clinical course is characterized by continuous progression with a median survival probability of 3-4 years within most series. Overall response rates of 56-88% with complete remissions in the range of 9-58% are attainable but relapse occurs predominantly within 20 months. At present there is no evidence that any conventional regimen is curative. Prospective multicenter studies are mandatory to overcome this therapeutic dilemma. Patients suitable for some form of maintenance or consolidation therapy should initially be treated intensively by anthracycline-containing regimens. Whether maintenance with interferon or intermittent chemotherapy including new agents, like purine analogues or (un)conjugated monoclonal antibodies are able to influence overall survival is a matter of (ongoing) investigations. Further experimental approaches arise from antisense oligonucleotides or ribozymes blocking the overexpression of bcl-1 especially in this lymphoma entity. At present high-dose myeloablative consolidation radiochemotherapy followed by stem cell rescue in first remission seems to be the most attractive option in younger patients.

Myeloablative therapy with blood stem cell transplantation is effective in mantle cell lymphoma.

Long-term disease-free survival following conventional cytotoxic therapy is extremely rare in patients with advanced-stage mantle cell lymphoma (MCL). High-dose conditioning therapy consisting of hyperfractionated total body irradiation (TBI, 14.4 Gy) and cyclophosphamide (200 mg/kg) was therefore offered to 13 patients (four females/nine males) with advanced-stage MCL. The patients were relatively young with a median age of 49 years (range 30-60). High-dose cytarabine and mitoxantrone with granulocyte colony-stimulating factor (G-CSF) support were given for second-line therapy and mobilization of peripheral blood stem cells (PBSC). During cytokine-stimulated marrow recovery, a median of two leukaphereses (range 1-4) were performed. Using direct immunofluorescence analysis including two-color staining, the proportion of CD19+ B cells and CD34+/CD19+ B lymphoid progenitor cells was found to be extremely low with quantities below detection limit in approximately 50% of the autografts. At the time of autografting, nine patients (pts) were in first partial (five pts) or complete (four pts) remission, while four patients had achieved a second complete remission. Following myeloablative therapy a median number of 7.5 x 10(6) CD34+ cells/kg were autografted. The median time for neutrophil (> or = 0.5 x 10(9)/l) and platelet recovery (> or = 20 x 10(9)/l) was 13 and 10 days, respectively. Hematological recovery was delayed in a patient who received 5.8 x 10(6) positively selected CD34+ cells/kg. There was one toxic death 17 days post-transplantation because of overwhelming interstitial pneumonia. Two patients with a history of previous treatment failure relapsed 10 and 11 months post-transplantation, respectively, at sites of previous disease. Ten patients are disease-free with a median follow-up time of 18 months (range 10-47). The results presented here suggest that PBSC-supported high-dose therapy including TBI may provide long-term disease-free survival for patients with advanced-stage mantle cell lymphoma.

Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIalpha is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIalpha in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975-1985) were investigated immunohistochemically with monoclonal antibodies against topo IIalpha (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIalpha expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIalpha expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIalpha (P<0.001) and Ki-67 (P<0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIalpha as the most important prognostic factor (P<0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

Regulation of the T cell receptor-alpha mRNA expression in the human lymphoblastic T cell line CEM.

We analyzed the transcriptional events involved in the T cell receptor (TcR)-alpha mRNA expression in a human lymphoblastic T-cell line CEM. CD3-negative and CD3-positive CEM subclones that either lack mature TcR-alpha mRNA or express TcR-alpha mRNA were used. Exposure of the TcR-alpha mRNA negative subclones to phorbol 12-myristate 13-acetate (PMA) was followed by 2- to 3-fold increase of transcription, indicating that PMA acts on a transcriptional level. No increase of transcription was observed after blocking protein synthesis with cycloheximide (CHX) or after sequential stimulation with CHX followed by PMA. On the posttranscriptional level, CHX as well as PMA induced a progressive stabilization of TcR-alpha mRNA in the nuclear compartment, which was independent of ongoing transcription. The half-life of the TcR-alpha mRNA upon stimulation was about 6 hours. The accumulation of mature TcR-alpha mRNA seemed to be controlled by nuclear events on a transcriptional as well as posttranscriptional level. The data imply that alterations of TcR-alpha gene transcription are dependent on protein synthesis. DNA-binding proteins enhance transcription and labile nuclear proteins target TcR-alpha mRNA for rapid turnover.

In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy.

To identify prognostic factors alternative or additional to P-glycoprotein (Pgp), we studied the impact of the multidrug resistance-related protein (MRP), bcl-2 (flow cytometry), mutant p53 (single-strand conformation polymorphism), and heat-shock protein 27 (HSP27, Western blotting) in myeloid blasts obtained at the time of diagnosis in patients with de novo acute myeloid leukemia (AML). We collected bone marrow samples from untreated AML patients, prepared the cells as well as the cellular protein, and froze all the material. We then analyzed 20 patients who responded with complete remission (CR) and 20 patients who had blast persistence (BP). The purpose of the study was to determine whether leukemic blasts from patients with BP were more resistant to chemotherapy than those from patients with CR. There was no significant correlation between the expression of any of these proteins alone and treatment outcome in both groups studied. In contrast, there was a significant correlation between the coexpression of at least two of these proteins and response (p = 0.0298), which turned out to be a significant independent prognostic factor for treatment failure (p = 0.0329, relative risk = 1.5) according to multivariate analysis. We conclude that drug resistance in AML is multifactorial. Thus, coexpression of different resistance mechanisms may be responsible for the primary drug resistance in de novo AML.

Molecular analysis of an ataxia telangiectasia T-cell clone with a chromosomal translocation t(14;18)--evidence for a breakpoint in the T-cell receptor delta-chain gene.

We established a clonal T-cell line with a reciprocal chromosomal translocation t(14;18)(q11;q23) from a patient with ataxia telangiectasia (AT) and T-cell chronic lymphocytic leukemia (T-CLL). The tumor cells and the derived T-cell line were compared with respect to phenotype, karyotype, and rearrangement pattern. Restriction fragment analyses of the T-cell receptor (TCR)-delta gene, which is located within the TCR-alpha gene on chromosome 14q11, indicated that the breakpoint is located within the TCR-delta locus, splitting the TCR-delta gene between the variable and joining segments. This specific chromosomal translocation was only detected in the derived T-cell line and may be involved in the genesis of T-cell malignancies in AT.

[POEMS syndrome. A rare variant of osteosclerotic multiple myeloma with polyneuropathy, organomegaly, endocrinopathy, M-gradient and skin lesions]. / POEMS-Syndrom. Seltene Variante des osteosklerotischen multiplen Myeloms mit Polyneuropathie, Organomegalie, Endokrinopathie, M-Gradient und Hautläsionen.

BACKGROUND: A rare multi-organ involvement in plasma-cell dyscrasias has been named POEMS-syndrome: it is a synopsis of monoclonal gammopathy (M-gradient), osteosclerotic bone lesions, peripheral polyneuropathy, organomegaly, endocrinopathy and skin lesions. CASE REPORT: A patient is presented who had a classical manifestation of this disease known mainly in Japan. A monoclonal IgA-lambda-gammopathy was determined as cause of a gradually progressive polyneuropathy. The patient had a hypergonadotropic hypogonadism, hyperprolactinaemia, and sclerotic bone lesions. In addition, he showed a changing organomegaly, and hyperpigmentation of the skin. CONCLUSION: As yet, aetiology and pathophysiology are not fully understood. Irradiation or surgical resection of one or several osteosclerotic bone lesions may improve the polyneuropathy or may even lead to a complete remission of all symptoms. Thus, monoclonal immunoglobulins should be searched for in any unclear polyneuropathy, as should be for other symptoms of the POEMS-syndrome.

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma.

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (P<0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, P<0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.

[R.E.A.L. classification of non-Hodgkin lymphoma from the clinico-oncologic viewpoint]. / R.E.A.L.-Klassifikation der Non-Hodgkin-Lymphome aus klinisch-onkologischer Sicht.

In 1994 the International Lymphoma Study Group (ILSG) published the "Revised European-American Classification of Lymphoid Neoplasms" (R.E.A.L. Classification). Lymphomas were classified according to their presumed normal counterparts, to the extent possible. Within both T- and B-cell categories differentiation between lymphomas and/or leukemias of "precursor" or "peripheral" neoplasms are defined arising from antigen independend or antigen reactive cell proliferation. Lymphomas undoubtedly characterized by currently available morphologic, immunologic, and genetic technics represent "real" disease entities. Provisional categories include lymphomas that have been described in some detail, but without consensus within the ILSG. Proposed names are based predominantly on established usage. With respect to similar treatment approaches and difficulties of the ILSG members in subclassifying large cell lymphomas, centroblastic, immunoblastic and large cell anaplastic lymphomas of B-cell type were "lumped" together as large B-cell lymphomas. Within a prospective treatment trial overall survival was significantly better in centroblastic as compared to B-cell immunoblastic lymphoma diagnosed by optimal histomorphology according the criteria of the Kiel Classification. Thus the R.E.A.L. Classification fails to identify patients who may require other than standard treatment. Future studies will demonstrate whether subclassifying the proposed "peripheral" T-cell lymphomas, unspecified into T-zone lymphoma, lymphoepitheloid (Lennert's) lymphoma and pleomorphic, small, medium, and large cell lymphomas according the Kiel Classification is of clinicopathologic relevance. On the contrary the subtypes of chronic lymphocytic leukemia of T-cell type form two distinct entities within the R.E.A.L. Classification separating T-CLL/prolymphocytic leukemia from large granular lymphocyte leukemia of T- and NK-cell type. Within the R.E.A.L. Classification the lymphoplasmacytoid immunocytoma of the Kiel Classification will be subsumed together with the prognostically significantly better B-cell chronic lymphocytic leukemia. Opposite to the original intention of the ILSG two proposals are developed on clinical grouping of entities. Clinical indolent lymphoid neoplasms usually have "low grade" histologic appearances, with a predominance of small cells subsuming with the exception of the mantle cell lymphoma all of the low grade lymphomas of the Kiel classification. Aggressive lymphomas (intermediate risk) are defined as tumors whose survival if untreated is measured in months, highly or very aggressive lymphomas and/or leukemias will kill untreated patients within weeks. Unlike the Kiel Classification proposed categories subsume lymphomas irrespective of cytomorphology, thus grouping together potentially curable and uncurable diseases. Undoubtedly the R.E.A.L. Classification forms at present the best compilation of existing knowledge upon neoplasms of the immune system, enabling cooperation between clinicians and scientists all over the world. According to the ILSG this proposal should be considered a starting point for future periodic reevaluations.

[Catheter break in an implantable central venous infusion system with embolization in the pulmonary artery]. / Katheterbruch eines implantierbaren zentralvenösen Infusionssystems mit Embolisation in die Arteria pulmonalis.

A central venous catheter with a subcutaneous infusion port was implanted for chemotherapy into a 64-year-old woman with gastric lymphoma. Six weeks later, two weeks after a trivial trauma with hyperextension of the shoulder joint, it was found that the catheter had broken and its tip portion had embolized into the pulmonary artery: it was retrieved without difficulty via the femoral vein. This event suggests that pressure between clavicle and first rib can cause material fatigue in a silicon catheter. Such catheters should therefore not be implanted via the subclavian vein.

Lysosomal acid phosphatase: difference between normal and chronic lymphocytic leukaemia T and B lymphocytes.

Lysosomal acid phosphatase was assayed in homogenates of isolated normal and B cell type chronic lymphocytic leukaemia (B-CLL) T and B lymphocytes by biochemical means. Unlike the results of cytochemical studies reported in the literature enzyme activity was considerably higher in normal B lymphocytes than in corresponding T cells. This finding offers the possibility to use acid phosphatase as a marker for normal B lymphocytes. The diminution of acid phosphatase in unseparated B-CLL lymphocytes depends predominantly upon a loss of enzyme activity in the B cell fraction indicating an intrinsic abnormality of these neoplastic lymphocytes.

[Bone marrow biopsy investigation: an important prognostic factor in aplastic anaemia (author's transl)]. / Knochenmarkhistopathologie: Bedeutender prognostischer Faktor beim aplastischen Syndrom.

In thirty-five patients with aplastic anaemia initial bone marrow biopsy investigations were performed. 25 patients showed partial bone marrow aplasia whereas in ten patients complete myeloid aplasia could be demonstrated. Probability of survival was approximately ten times higher in patients with partial than in patients with complete bone marrow aplasia. The results of bone marrow biopsy investigations had a greater predictive value than the degree of diminution of single cellular blood components. Initial bone marrow biopsy investigation facilitates the selection of poor risk patients who should be treated by bone marrow transplantation rather than by conventional therapy.

Frequent association of idiopathic myelofibrosis with plasma cell dyscrasias.

In a retrospective analysis of 199 cases of myeloproliferative diseases a concomitant plasma cell dyscrasia was found in three out of 46 patients with idiopathic myelofibrosis. Chronic myeloid leukemia, polycythemia vera or unclassifiable myeloproliferative disorders were in no case associated with monoclonal gammopathy. One patient with idiopathic myelofibrosis had primarily coexistent IgG-lambda paraproteinemia and increasing osteolytic lesions; histologic evidence of multiple myeloma, however, was insufficient. In the second patient the interval between diagnosis of idiopathic myelofibrosis and IgG-kappa paraproteinemia was 11 years. After a stable period of 9 years' duration the paraprotein level rapidly increased, associated with depression of normal background immunoglobulins and progressive bone marrow failure. The exact nature of this patient's malignant plasma cell dyscrasia remained uncertain. In the third case benign monoclonal gammopathy of the IgM-lambda type was diagnosed 13 years after idiopathic myelofibrosis. A review of the literature confirms a remarkably high incidence of monoclonal gammopathies in idiopathic myelofibrosis. Benign monoclonal gammopathy seems to occur in at least 8% of the patients while only a few cases of concomitant multiple myeloma have been reported. It may be speculated that plasma cell dyscrasias in idiopathic myelofibrosis reflect involvement of the lymphoid lineage in the neoplastic stem cell disorder.

Extramedullary manifestation of the blastic phase of chronic myelocytic leukemia: A chromosome study.

Two patients with extramedullary manifestation of the blastic phase of chronic myelocytic leukemia (CML) are reported. 100% of the metaphases derived from extranedullary sites were aneuploid. Despite the absence of blastic changes in the bone marrow and the peripheral blood, a significant proportion of the metaphases derived from these tissues also showed aneuploidy. It is suggested that maturation and differentiation of aneuploid myeloblasts are influenced by their environment.

[Diagnosis of primary non-Hodgkin lymphomas of the central nervous system]. / Zur Diagnostik primärer Non-Hodgkin-Lymphome des Zentralnervensystems.

In literature, primary malignant lymphomas (PML) of the central nervous system (CNS) have been known for many years under different names, although diagnosis was almost exclusively made via autopsy. It is only since the existence of computed tomography (CT) that there is a possibility of identifying or at least presuming intra vitam such malignancy and of securing the diagnosis via brain biopsy. This is most important because it enables an early treatment of patients by means of radiation and chemotherapy. We are documenting a new approach to identify the PML of CNS by four case histories of our own patients. This consists in the specific manner in which these tumours react to high doses of corticosteroid therapy. Under this treatment they diminish in size or even disappear completely. This can even be seen in other diseases, but when such behaviour of an intracerebral lesion is seen in a CT scan it should be of help in the evaluation of differential diagnosis and should be regarded as an important pointer towards achieving early diagnosis of PML of the CNS.

[High-dose cytarabine treatment: a promising therapy modality in acute resistant myeloid leukemias in recurrence]. / Hochdosierte Cytarabin-Behandlung: Erfolgversprechende Therapie-modalität bei resistenten akuten myeloischen Leukämien im Rezidiv.

High dose Cytarabin in relapsed and refractory acute leukaemia. High dose cytarabin can be very effective for the treatment of acute leukaemia resistent to conventional cytarabin doses. Therefore 10 patients (6 males, 4 females) with ages ranging from 18 to 58 years (median: 34 years) refractory to conventional induction therapy were treated with 1 hour infusions of high dose cytarabin (3 g/m2 q 12 h for 6 days) 2 patients got additional 20 mg/m2 doxorubicin on days 7 to 9. According to this treatment, in 5 of the 10 patients complete remissions could be achieved. Without further treatment 3 patients relapsed after 4, 7 and 15 months leading to death in 2 or 3 months. 19 months after treatment 1 patient is in complete remission, though demonstrating meningosis leukaemica 5 months after high dose cytarabin. Another patient relapsed 14 months after high dose cytarabin, reaching another complete remission after treatment according to a ALL/AUL protocol [7]. 2 patients died in bone marrow aplasia and 2 patients did not show any response, dying 11 months after high dose cytarabin application. All patients demonstrated vomiting, nausea, diarrhea and allopecia. Bone marrow was profoundly depressed in all patients with severe granulocytopenia and thrombocytopenia for periods from 7 to 34 days. 3 to 5 days after the end of high dose cytarabin therapy 3 patients developed acute ceratitis and 2 patients conjunctivitis. 3 patients showed erythrodermia of their skin with epidermolysis in 2 of these patients.