Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents.

Multiple myeloma (MM) comprises 1% of all malignancies and 13% of hematological malignancies in the Caucasian population. Yearly incidence is 4/100,000 in the US and is higher in blacks and males [1]. The pathogenesis of the disease is relatively unknown; several chromosomal abnormalities have been related to the development of the disease,but none is characteristic of MM. Cyclin-D1 is a protein encoded by the CCND1 (bcl-1) gene on chromosome 11q13, and is an important regulator of G1 to S phase progression.

A unique case of IgD-only splenic marginal-zone lymphoma with mutated immunoglobulin genes: ontogenetic implications.

Splenic marginal zone lymphoma (SMZL) is a rare indolent lymphoma subtype which accounts for less than 1% of all non-Hodgkin's lymphomas. We here report a unique case of IgD-only SMZL with mutated immunoglobulin variable region genes and discuss possible ontogenetic derivation.

Splenic marginal-zone lymphoma: one or more entities? A histologic, immunohistochemical, and molecular study of 42 cases.

We analyzed 42 splenic marginal-zone lymphoma (SMZL) cases diagnosed on splenectomy specimens after established World Health Organization criteria. A predominantly nodular growth pattern was observed in 24 cases; the remainder showed predominantly (11/42) or exclusively (7/42) diffuse infiltration. Twenty-one cases showed the "classic" biphasic appearance; 13 cases exhibited marginal-zone morphology; finally, 8 cases were composed predominantly of small cells. CD21 and CD35 were expressed by 12/42 and 17/38 cases, respectively. DBA.44 was detected in 24/42 cases. Seventeen of 37 cases were surface IgD (SIgD)-positive. Twenty-one of 22 analyzed cases were SIgM-positive (12/21 coexpressed SIgD). Five of 37 cases were SIgG-positive. CD27 staining was observed in 21/35 cases; 7/18 CD27-positive cases coexpressed SIgD; 7/14 CD27-negative cases were SIgD-positive. Forty IGHV-D-J rearrangements were amplified in 34/42 cases: the IGHV4-34 gene predominated, followed by IGHV1-2. Using the 98% homology cut-off, 25/40 (62.5%) IGHV sequences were considered as "mutated": 10/11 cases with monomorphous, marginal-zone morphology were IGHV-mutated; in contrast, 4/6 cases with monomorphous, small-cell morphology were IGHV-unmutated. Five of 7 cases expressing IGHV1 subgroup genes had biphasic morphology, whereas 6/9 IGHV3-expressing cases had monomorphous, marginal-zone morphology. Most IGHV-mutated cases (14/20; 70%) were SIgD-negative; in contrast, 8/11 IGHV-unmutated cases expressed SIgD. CD27 was detected in 10/17 IGHV-mutated and 6/10 IGHV-unmutated cases. Seven of 11 CD27-negative cases were IGHV-mutated; 5/7 CD27-negative/IGHV-mutated cases expressed DBA.44. These results confirm the considerable histologic, immunohistochemical, and molecular heterogeneity of SMZL and indicate an origin from the diverse resident B-cell populations of the normal SMZ.

Extranodal non-Hodgkin's lymphoma presenting as an abdominal wall mass. A case report and review of the literature.

Soft tissue lymphoma is a very rare clinical entity with varying presentation characteristics and atypical clinical and imaging features. The present report describes a patient who presented with a painless soft tissue mass on the posterolateral surface of the abdominal wall, simulating a neoplasm of mesenchymal origin. After complete surgical excision, the tumor was diagnosed as a diffuse large B-cell lymphoma. No B-symptoms were present and clinical staging did not reveal other sites of disease (stage I EA). The International Prognostic Index score was equal to 1 and classified the patient to the good risk group. Post-operatively the patient was treated with immuno-chemotherapy consisting of rituximab plus cyclophosphamide, epirubicin, vincristine and prednisolone and is currently free of disease for 10 months. The case is discussed with a brief review of the literature on the diagnosis, treatment and outcome of soft tissue lymphomas.

Discordant response or progression in patients with myeloma treated with thalidomide-based regimens.

UNLABELLED: Thalidomide-based regimens (TBR) are now widely used for the treatment of refractory multiple myeloma and have shown significant activity in newly diagnosed patients. In some patients with secretory disease, we observed discrepancies between the reduction of the monoclonal protein levels and the plasma cell infiltration in the bone marrow and/or extramedullary sites of relapse after treatment with TBR. The purpose of this study was to assess the incidence and analysis of this phenomenon in all myeloma patients treated with TBR in our Institution. PATIENTS AND METHODS: We studied all patients who received TBRs and had a follow up time of at least 6 months. Partial response (PR) was defined as at least 50% reduction of serum myeloma protein and soft tissue plasmacytomas and/or > 90% reduction of Bence Jones protein excretion and minor response as a > 25% reduction of the serum myeloma protein or > 50% reduction of the Bence Jones myeloma protein. RESULTS: Between July 1999 and July 2002 we treated 94 patients with advanced myeloma and 9 patients with newly diagnosed disease with TBR. Sixty-seven patients (66%) achieved either partial or minor response. In 4 patients (3 with advanced and 1 with newly diagnosed myeloma) the bone marrow was heavily infiltrated by plasma cells, despite a decrease of the paraprotein levels ranging from 38% to 68%. This discordance between monoclonal protein levels and bone marrow plasmacytosis was noted in 6% of patients rated as responders and in 11% of responding patients who actually had a repeat bone marrow assessment. Furthermore 6 responding patients, after achieving a PR which lasted between 5 and 9 months, relapsed with bone marrow (all cases), and extramedullary (2 cases) plasmacytosis, without increase of serum and/or urine monoclonal protein. This hyposecretory conversion was noted in 12.5% of relapsing patients. CONCLUSION: Our data indicate that after treatment with TBR some patients with myeloma show discordant responses of the monoclonal protein levels and the bone marrow or extramedullary plasmacytosis. If our data are confirmed, they may have practical implications for assessment of response and follow up of patients treated with TBR.

Treatment of relapsed/refractory multiple myeloma with thalidomide-based regimens: identification of prognostic factors.

We evaluated the predictive value of several parameters, including the International Staging System (ISS) for myeloma, in patients with advanced disease treated with thalidomide-based regimens (TBR). We analyzed 119 patients, from 3 phase II studies. Patients with pretreatment beta2 microglobulin<3.5 mg/l and albumin 3.5 g/dl were scored ISS stage 1, patients with beta2 microglobulin<3.5 mg/l and albumin<3.5 g/dl or beta2 microglobulin 3.5-5.5 mg/l regardless of albumin levels were scored ISS stage 2, patients with beta2 microglobulin>5.5 mg/l ISS stage 3. ISS stage was 1, 2 and 3 in 45, 32 and 23% of patients respectively. Seventy-four patients (62%) achieved at least partial response. Median progression-free and overall survival were 8 months and 19.5 months respectively. ISS stage, serum LDH and performance status were independent predictive factors for survival. Based on these 3 variables a scoring system was developed with survival times of 38.1, 28.8 and 5.8 months for scores 0, 1 and 2 respectively. The ISS staging system was highly predictive for overall survival of patients with advanced myeloma treated with TBR. With the addition of performance status and serum LDH, a simple scoring system was developed which may help select patients likely to benefit from TBR.

Autoimmune manifestations in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a disorder characterized by decreased serum immunoglobulin concentrations and increased incidence of recurrent infections. Interestingly 20-25% of patients with CVID develop clinical features suggestive of an autoimmune disease. Although this association is well established, the immunodeficiency background of CVID patients manifesting autoimmune disorders is often overlooked. This study describes three CVID patients displaying a variety of autoimmune manifestations. The pathophysiologic mechanisms of autoimmunity in CVID are also reviewed.

Non-gastric extra-nodal marginal zone lymphomas--a single centre experience on 76 patients.

In the present study, we assessed the clinical and pathological data of 76 patients with the diagnosis of non-gastric extranodal marginal zone B-cell lymphoma. The most commonly affected sites were salivary glands, skin, ocular adnexa, lung, intestine and Waldeyer's ring. Ann Arbor stage I disease was present in 39 patients (51%), stage II in 10 (13%) and stage IV in 27 (36%). In 17 cases (21%), the lymphoma presented at multiple mucosal sites. Lymph node and bone marrow involvement were present in 21% and 16%, respectively. Most cases were in the low or low-intermediate risk group. Treatment was heterogeneous and included chlorambucil in 59% either alone or in combination with other agents. Complete and partial remission was achieved in 79% and 7%, respectively, with an overall response rate of 86%. The 5- and 10-year overall survival and cause-specific survival rates were 94%, 82% and 95%, 91%, respectively. The 5- and 10-year progression free survival was 56% and 41%, respectively. The only feature associated with inferior outcome was disease localisation to the lung.

Translocation detection in lymphoma diagnosis by split-signal FISH: a standardised approach.

Lymphomas originating from the lymphatic system comprise about 30 entities classified according to the World Health Organization (WHO). The histopathological diagnosis is generally considered difficult and prone to mistakes. Since non-random chromosomal translocations are specifically involved in different lymphoma entities, their detection will be increasingly important. Hence, a split-signal fluorescence in situ hybridisation (FISH) procedure would be helpful in discriminating the most difficult classifications. The Euro-FISH programme, a concerted action of nine European laboratories, has validated a robust, standardised protocol to improve the diagnostic approach on lymphoma entities. Therefore, 16 fluorescent probes and 10 WHO entities, supplemented with reactive cases, were selected. The results of the Euro-FISH programme show that all probes were correctly cytogenetically located, that the standardised protocol is robust, resulting in reliable results in approximately 90% of cases, and that the procedure could be implemented in every laboratory, bringing the relatively easy interpretation of split-signal probes within the reach of many pathology laboratories.

Myelofibrosis-associated massive splenomegaly: a cause of increased intra-abdominal pressure, pulmonary hypertension, and positional dyspnea.

We describe a patient with myelofibrosis, giant splenomegaly, and pulmonary hypertension related to increased intra-abdominal pressure. Focusing on alterations in hemodynamic studies, we conclude that in patients with myelofibrosis, dyspnea, and hypoxemia, the measurement of intra-abdominal pressure should be included in the initial evaluation. It is an inexpensive, non-invasive diagnostic tool that can provide crucial information about the cause of dyspnea and disclose the pathogenetic link between massive splenomegaly and pulmonary compromise in myelofibrosis.

Molecular analysis of B-cell clonality in Helicobacter pylori gastritis.

The aim of our study was to identify PCR-detectable clonal B-cell population in Helicobacter pylori gastritis and assess their relation to the Wotherspoon-Isaacson (W-I) grade for gastric lymphoid infiltrates. Amplified DNA was obtained from thirty four H. pylori positive gastritis dyspeptic patients and thirty four H. pylori negative matched controls. Clonal bands were observed in 6 (2/17 W-I Grade 1, 2/13 W-I Grade 2, and 2/4 W-I Grade 3 lesions) and polyclonal smears in 24 cases (15 W-I Grade 1, 7 W-I Grade 2, and 2 W-I Grade 3). Four additional W-I Grade 2 samples with clonal bands were associated with background polyclonal smear and were not reproducible. Clonal bands were not recorded in controls. B-cell clonality was not related to W-I grades. We conclude that certain H. pylori positive gastritis patients show PCR-detectable monoclonality, which is independent of the W-I grade of gastritis and cannot be taken as evidence of an existing neoplastic lesion.

Immunoglobulin heavy- and light-chain repertoire in splenic marginal zone lymphoma.

The considerable heterogeneity in morphology, immunophenotype, genotype, and clinical behavior of splenic marginal zone lymphoma (SMZL) hinders firm conclusions on the origin and differentiation stage of the neoplastic cells. Immunoglobulin (IG) gene usage and somatic mutation patterns were studied in a series of 43 SMZL cases. Clonal IGHV-D-J rearrangements were amplified in 42/43 cases (4 cases carried double rearrangements). Among IGHV-D-J rearrangements, IGHV3 and IGHV4 subgroup genes were used with the highest frequency. Nineteen IGHV genes were unmutated (> 98% homology to the closest germline IGHV gene), whereas 27/46 were mutated. Clonal IGKV-J and IGLV-J gene rearrangements were amplified in 36/43 cases, including 31 IGKV-J (8/31 in lambda light-chain expressing cases) and 12 IGLV-J rearrangements; 9/31 IGKV and 6/12 IGLV sequences were mutated. IGKV-J and IGLV-J rearrangements used 14 IGKV and 9 IGLV different germline genes. Significant evidence for positive selection by classical T-dependent antigen was found in only 5/27 IGHV and 6/15 IGKV+IGLV mutated genes. These results provide evidence for the diverse B-cell subpopulations residing in the SMZ, which could represent physiologic equivalents of distinct SMZL subtypes. Furthermore, they indicate that in SMZL, as in other B cell malignancies, a complementarity imprint of antigen selection might be witnessed either by IGHV, IGKV, or IGLV rearranged sequences.