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Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study.

BACKGROUND: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. RESULTS: Hematological toxicities (grade > or =3) occurred more frequently in females (P <0.05), and thrombocytopenia and leukopenia were more frequent in patients with high lactate dehydrogenase (LDH) levels (P <0.05). Non-hematological toxicities (grade > or =2) were more frequent in patients with extranodal disease or bone marrow involvement. The overall response rate (ORR) in patients receiving one prior chemotherapy regimen was higher than those receiving two or more regimens (P <0.05). The median PFS was shorter in MCL patients, in those with extranodal disease, or in those receiving two or more prior chemotherapy regimens (P <0.01). The PFS intervals of patients with higher serum rituximab levels (> or =70 microg/ml) immediately before the third infusion were longer than in other patients (P <0.01). CONCLUSIONS: Several prognostic factors and serum rituximab levels are useful for predicting the toxicity and efficacy of rituximab monotherapy.

Adult↗

Diffuse large B-cell non-Hodgkin's lymphoma presenting as a vaginal mass in a patient with a history of intestinal mucosa-associated lymphoid tissue (MALT) lymphoma.

Vaginal involvement in non-Hodgkin's lymphoma is uncommon and is often secondary to disseminated disease. Primary disease at this site is quite rare. We present here an unusual case of a patient who developed a diffuse large B-cell lymphoma presenting as a vaginal mass after having been treated for primary intestinal mucosa-associated lymphoid tissue (MALT) lymphoma 4 years earlier. Combined chemotherapy and radiation therapy for the intestinal MALT lymphoma produced complete remission that lasted for 2 years. Chemotherapy given for the diffuse large B-cell lymphoma with secondary vaginal involvement produced a second complete remission. The second remission was consolidated with high-dose chemotherapy and autologous bone marrow transplantation. Although the patient died from complications related to the transplant procedure, the disease was in complete remission at the time of her death. Given the rarity of primary intestinal MALT lymphoma and primary vaginal lymphoma, no standard treatment has been established. Treatment options have included chemotherapy, radiation therapy, or surgery, given alone or in combination.

Combined Modality Therapy↗

Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA ("Groupe d'Etude des Lymphomes de l'Adulte") study.

Among non-Hodgkin's lymphomas, primary mediastinal large B-cell lymphoma (PMLCL) has been considered a separate entity that has specific clinical and histological aspects and a poor prognosis. In this study, we reexamined the clinicopathologic features and the response to current treatment of 141 PMLCL and compare them with 916 nonmediastinal large B-cell lymphomas (NMLCL) recorded in the same period and treated with similar combined chemotherapy. The clinical features of PMLCL at diagnosis were largely homogeneous and distinct from NMLCL, with a predilection for young women (59% with a mean age of 37 years versus 42% with a mean age of 54 years), bulky tumor (77% versus 7%, p < 10(4)), high serum lactic dehydrogenase (LDH) level 76% versus 51%, p < 10(4)), and frequent intrathoracic extension to adjacent organs such as pleura, pericardium, and lung. By contrast, extrathoracic or hematologic dissemination was uncommon (2% of bone marrow involvement versus 17%). All patients had diffuse large B-cell nonimmunoblastic, nonanaplastic lymphomas. Histological analysis of the 141 PMLCL evaluated two common patterns: the presence of large cells with clear cytoplasm (found in 38% of cases) and the presence of fibrosis (marked in 25% of cases). The presence of clear cells or intense fibrosis did not constitute prognostic indicators. Immunologic and molecular analysis assessed the profile of bcl-2 expression and the presence of Epstein-Barr virus (EBV) in PMLCL: 30% expressed a high level of bcl-2 protein; EBER RNAs were detected by in situ hybridization in only two of the 41 cases tested. Monotypic light chain restriction could be demonstrated in seven of the 41 PMLCL tested on fixed-section. Treated with polychemotherapy regimens without radiotherapy, 79% of PMLCL patients achieved a complete remission compared with 68% in the NMLCL patient group (p = 0.01). Overall, 3-year survival rates were estimated at 66 and 61%, respectively (p = 0.05), and disease-free survival rates were not significantly different (61 versus 64%). Stratified analysis on the International Prognostic Index (based on age, tumor stage, serum LDH level, and performance status) showed no difference in the overall and disease-free survivals between the two lymphoma groups. In conclusion, PMLCL can be combined with other diffuse large B-cell lymphomas on morphologic grounds; it is not associated with EBV. It responds favorably to treatment and should be managed like other high-grade lymphomas of equivalent histology. However, the uncommon clinical presentation makes it a distinct entity.

Adolescent↗

Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study.

PURPOSE: Hyperuricemia and tumor lysis syndrome are well-known complications during induction treatment of aggressive non-Hodgkin's lymphomas (NHLs). Usual prophylaxis and treatment of hyperuricemia consist of hydration, alkalinization, and administration of allopurinol. This study was designed to evaluate the efficacy and the safety of rasburicase (recombinant urate oxidase) in adult patients with aggressive NHL during their first cycle of chemotherapy. PATIENTS AND METHODS: A total of 100 patients from Groupe d'Etude des Lymphomes de l'Adulte centers, with diffuse large B-cell lymphoma (n = 79); anaplastic large-cell lymphoma (n = 6); peripheral T-cell lymphoma (n = 8); transformation of indolent lymphoma (n = 5); Burkitt's lymphoma (n = 1); and lymphoblastic lymphoma (n = 1) were enrolled from May 2001 to June 2002. Before chemotherapy, 66% of patients had elevated lactate dehydrogenase (LDH), including 28% with LDH above 1,000 U/mL. Eleven percent of patients were hyperuricemic (uric acid [UA] > 450 mmol/L or > 7.56 mg/dL). Rasburicase 0.20 mg/kg/d intravenously for 3 to 7 days was started the day before or at day 1 of chemotherapy. UA levels were measured 4 hours after rasburicase injection, then daily during treatment. RESULTS: All patients responded to rasburicase, as defined by normalization of UA levels maintained during chemotherapy. The control of UA was obtained within 4 hours after the first injection of the drug. Creatinine levels and other metabolites were also controlled with the administration of rasburicase. No patient exhibited increased creatinine levels or required dialysis during chemotherapy. CONCLUSION: Rasburicase is the treatment of choice to control UA and prevent tumor lysis syndrome in adult patients with aggressive NHL.

Adult↗

The role of surgery in the treatment of gastrointestinal lymphomas other than low-grade MALT lymphomas.

BACKGROUND AND OBJECTIVE: A bias in clinical investigations on gastrointestinal lymphomas is the lack of testing the intention to treat as to resection, emergency conditions at presentation and selection brought about by the evaluation of feasibility of surgery. DESIGN AND METHODS: A prospective study involved 154 patients with gastrointestinal nodular or high-grade MALT lymphomas, 111 with a gastric and 43 with an intestinal presentation. The decision to resect or treat conservatively was left to clinicians, on condition that it was previously defined for each patient. RESULTS: Failure-free survival was significantly higher in the 106 resected patients than in the 48 unresected ones but did not differ according to either primary intention to treat or emergency surgery/elective treatment. Survival was similar in patients operated on by choice and in those because of an emergency. Intentionally unresected patients had a significantly better survival than those not undergoing surgery despite the initial intention, for a number of clinical reasons. Patients with gastric lymphoma survived longer than those with intestinal disease and prognostic factors were analyzed separately in the two groups. The best predictors of prognosis were performance status and serum lactic dehydrogenase level in gastric lymphomas, resection alone in intestinal ones. INTERPRETATION AND CONCLUSIONS: The prognosis of gastric lymphomas depends on lymphoma-related factors and not on surgical treatment. The prognosis of intestinal ones is exclusively related to surgery. These data support the appropriateness of different clinical approaches to gastric and intestinal lymphomas.

Adolescent↗

Bax mutations are an infrequent event in indolent lymphomas and in mantle cell lymphoma.

BACKGROUND AND OBJECTIVES: The Bax gene is one of the most important genes involved in apoptosis regulation. Recently, it has been proposed that inactivating mutations of this death agonist may contribute to the pathogenesis of human tumors. This study was aimed at defining the status of the Bax gene in indolent lymphomas. DESIGN AND METHODS: Fifty paraffin-embedded biopsies from indolent lymphomas (10 small lymphocytic lymphomas, 5 immunocytomas, 20 follicular lymphomas and 15 marginal zone lymphomas) and 10 mantle cell lymphomas ( MCL ) were studied. All six exons of the Bax gene, together with their flanking sequences, underwent mutational analysis by PCR-SSCP followed by direct sequencing of positive cases. Moreover, Bax protein expression was investigated in all samples by immunohistochemical analysis. RESULTS: All analyzed cases showed wild type Bax gene alleles and variable levels of Bax protein expression. INTERPRETATION AND CONCLUSIONS: This study indicates that deregulation of apoptotic control in indolent lymphomas and MCL is not caused by Bax mutations and that other molecular mechanisms must, therefore, be involved.

Gene Frequency↗

Human herpesvirus-6 in human lymphomas: identification of specific sequences in Hodgkin's lymphomas by polymerase chain reaction.

In search of a possible involvement of the human herpesvirus type 6 (HHV-6) in human Hodgkin's and non-Hodgkin's lymphomas, we studied the levels of anti-HHV-6 antibodies in the sera of 94 cases by an immunofluorescence assay, as well as the presence of HHV-6 sequences in the affected tissues of 66 cases by polymerase chain reaction, using one set of primer oligonucleotides. Our results showed higher anti-HHV-6 antibody titers in human lymphomas than in normal blood donors, but the difference is statistically significant only when normal donors are compared with Hodgkin's lymphoma cases. HHV-6 sequences were detected in 3 of 25 Hodgkin's lymphomas and 0 of the 41 cases of non-Hodgkin's lymphomas studied. The three cases positive for HHV-6 sequences belong to the nodular sclerosis-lymphocyte depletion histologic subtype and share remarkable similarities in their clinical features. Furthermore, Southern blot analysis of total genomic DNA obtained from the neoplastic tissues of two of the three patients showed the same restriction fragment length polymorphism. Our results suggest that: (1) the high level of anti-HHV-6 antibodies in Hodgkin's disease is due to an activation of the immune system not related to the presence of HHV-6 sequences in affected lymph nodes; (2) the presence of HHV-6 sequences in human lymphoid tissues is not a frequent event, rather it is in fact a very rare event in non-Hodgkin's lymphomas, while in Hodgkin's cases it is more frequent than previously reported on the basis of Southern blot analysis; and (3) the presence of HHV-6 sequences in Hodgkin's lymphomas may have a relation with the clinical presentation of the disease.

Adult↗

The gene located at chromosome 18 band q21 is rearranged in uncultured diffuse lymphomas as well as follicular lymphomas.

The karyotypic abnormality t(14;18)(q32;q21) is reported to occur in 75% of follicular lymphomas. This translocation results in the rearrangement of a putative oncogene bcl-2, which resides at chromosome 18 band q21 (the 18q21 gene). Using two human genomic DNA fragments cloned from the chromosome 18 band q21 as probes, we analyzed 65 uncultured human lymphoma samples by the Southern blot technique. The 18q21 gene was rearranged in 18 of 26 (69%) follicular lymphomas, 3 of 5 (60%) follicular lymphomas transformed to large cell lymphomas, 8 of 20 (40%) diffuse large cell lymphomas (DLCLs), and 2 of 7 (29%) small noncleaved cell lymphomas (SNCs). Our analysis detected rearrangement of the 18q21 gene in 10 of 13 (77%) cases in which the t(14;18)(q32;q21) translocation was found by cytogenetic techniques. Our analysis also proved helpful in difficult karyotyping situations: (a) identifying the donor chromosome fragment as chromosome 18 band q21 in 4 of 9 (44%) cases that cytogenetically displayed a 14q+ chromosome of unknown origin, and (b) identifying a rearrangement of chromosome 18 band q21 in 12 of 18 (67%) cases that cytogenetically yielded no cells in metaphase. We also demonstrated three cases of submicroscopic rearrangement of the 18q21 gene. In our studies, patients with DLCLs and rearrangement of the 18q21 gene had a significantly higher incidence of extranodal involvement when compared with patients with DLCLs and no 18q21 gene rearrangement (P = 0.03).

Bone Marrow Cells↗

Frequent nonrandom chromosome abnormalities in 27 patients with untreated large cell lymphoma and immunoblastic lymphoma.

Fresh tumor samples from 27 patients with large cell lymphoma, either previously untreated (26 patients) or minimally treated (one patient), were processed for cytogenetic studies. Cytogenetic abnormalities were observed in all patients, most commonly in chromosomes 1, 3, 7, 12, 14, 17, and 18. Nine chromosomal breakpoints appeared frequently: 14q32 in 14 instances; 18q21 in seven; 9p13-21, 17p11-13, and 3q21-23 in six each; 1p11-21 in five instances; 1p36 in four; and 2p21-23 in three. The most common structural abnormalities were t(14;18)(q32;q21) in seven patients (26%) and 17p- in six (22%). The presence of 17p- was associated with a significantly higher proliferative capacity as manifested by the percentage of S phase = 22% versus 11% for cases without 17p-(P less than 0.05). Trisomy 12, typical of small lymphocytic lymphoma, was seen in five patients in this series, all of whom had diffuse large cell lymphoma; frequently, it appeared simultaneously with t(14;18). The two patients with immunoblastic lymphoma of B-cell type had an abnormality involving chromosome 2p21-23. Deletions in the long arm of chromosome 6, previously described as typical of diffuse large cell lymphoma and B-cell immunoblastic lymphoma were observed infrequently in this series. However, this abnormality has been present in 50% of patients with large cell lymphoma previously exposed to therapy, suggesting that it may be related to effects of chemotherapy or to clonal evolution.

Chromosome Aberrations↗

Signet ring cell lymphoma. A rare morphologic and functional expression of nodular (follicular) lymphoma.

Nodular lymphomas and diffuse lymphomas of corresponding cellular composition have been shown to arise from follicular center cells. This paper describes a rare functional and morphological expression of malignant lymphomas arising from follicular center cells, namely, immunoglobulin production, an observation for which no detailed description or nanlysis is available in the literature. Furthermore, the unusual signet ring-like appearance of the lymphoma cells, which is due to retention of immunoglobulins within the cytoplasm, may result in an erroneous interpretation of metastatic adenocarcinoma or liposarcoma. Therefore, we are presenting a detailed analysis of light microscopic, histochemical, immunocytochemical, and ultrastructural observations. The lymphomas of all seven patients in our series showed nodular growth patterns; in all but one, diffuse areas were also observed. Five of the lymphomas were classified as poorly differentiated lymphocytic type and two as mixed cell type, according to Rappaport's classification. In four of the seven patients, the majority of the neoplastic cells had a clear vacuolated cytoplasm, and in three of these cases, a few of the neoplastic cells showed immunoperoxidase positivity for monoclonal IgG. This group in particular closely simulated metastatic carcinoma composed of so-called signet ring cells. In the remaining three cases, most of the neoplastic cells contained PAS-positive, Russell body-like monoclonal IgM. Ultrastructurally, the monoclonal IgG appeared as even-sized electron-dense spherules or irregular electron-dense clumps, while the monoclonal IgM appeared as membrane bound, homogeneous, electron-dense material. The implications of these findings and the morphologic features which are helpful in the identification of these lymphomas are discussed.

Aged↗

Frequent expression of shared idiotypes in mantle cell lymphoma and extranodal small lymphocytic/non-mantle cell diffuse small cleaved lymphoma.

A panel of 14 anti-shared idiotype (Sid) monoclonal antibodies selected according to their high cross-reactivity to various lymphomas was immunohistologically tested for reactivity with seven reactive lymphoid tissue specimens and 227 B cell lymphoma specimens obtained from Japanese patients. In the reactive lymphoid tissues, the anti-Sld antibodies each reacted with a subpopulation of cells in the mantle zone and interfollicular areas; they rarely reacted with cells in the germinal center. In the B cell lymphomas, 13 anti-Sld antibodies reacted with a total of 78 of 186 (42%) specimens bearing immunoglobulin; none of the antibodies reacted with 41 specimens not bearing immunoglobulin. In mantle cell lymphomas (15/19, 79%) and extranodal small lymphocytic/non-mantle cell diffuse small cleaved lymphomas (11/15, 73%), the reactivity of the antibodies was high compared with that in the other lymphomas (52/152, 34%; P = 0.0002 and 0.004, respectively), including follicular lymphomas (11/42, 27%; P = 0.002 and 0.002, respectively). Since idiotypes are associated with the hypervariable regions and antigen-binding sites of immunoglobulin, these findings may reflect the differences in the regions/sites in each of these diseases.

Antibodies, Monoclonal↗

[Occurrence of follicular small cleaved cell lymphoma following chemotherapy for diffuse large cell lymphoma].

A 59-year-old man was admitted in July, 1985 because of generalized lymphadenopathy and hypercalcemia. The biopsy specimen of the left inguinal lymph node showed diffuse large cell lymphoma. He achieved a complete remission (CR) in July, 1986 by CHOP therapy. In January, 1992, he visited the outpatient clinic with splenomegaly, and swelling of the left axillary and left supraclavicular lymph nodes. The biopsy specimen of the axillary lymph node showed follicular small cleaved cell lymphoma. Because the spleen and the lymph nodes regressed after the biopsy, he has been followed up without any specific treatment for lymphoma. Histologic change from low-grade lymphoma into more aggressive histologic pattern is well documented. However the converse phenomenon, occurrence of low-grade lymphoma after intermediate-, or high-grade lymphoma has rarely been reported. Histological examination is mandatory when a patient with diffuse large cell lymphoma is suspected to have relapsing disease after the long-term CR.

Antineoplastic Combined Chemotherapy Protocols↗

Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin's lymphoma.

The Revised European-American Lymphoma (REAL) classification has been criticized for its emphasis on the unproven clinical relevance of immunophenotype. A worse prognosis for peripheral T-cell non-Hodgkin's lymphomas (PTCLs) has been inconsistently reported in part because the definition of PTCL has been imprecise (eg, T-cell-rich B-cell non-Hodgkin's lymphomas [TCRBCLs] have been misdiagnosed as PTCLs in the past) and because its correlation with other known prognostic factors has not been studied by multivariate analysis. We analyzed six protocols from 1984 to 1995 with Working Formulation intermediate grade and immunoblastic lymphomas (exclusive of mantle cell) and selected only those cases in which immunophenotyping was performed and was conclusive. Of a total of 560 evaluable patients, 68 were PTCLs (12%) and the remaining 492 (88%) were B-cell non-Hodgkin's lymphomas, including 16 TCRBCLs (3% of total). The 5-year failure-free survival (FFS) for PTCLs and B-cell large-cell lymphomas (BCLCLs) is 38% and 55%, respectively (P < .0001) and the 5-year overall survival (OS) is 39% and 262%, respectively (P < .001). The M.D. Anderson prognostic tumor score (MDATS) and International Prognostic Index (IPI) for all patients was calculated. With MDATS of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 56% and 69%, respectively (P = .01), and the 5-year OS is 64% and 77%, respectively (P = .06). With MDATS of greater than 2 (poor prognosis), 5-year FFS for PTCL and BCLCL is 26% and 38%, respectively (P = .03), and the 5-year OS is 24% and 41%, respectively (P = .02). With an IPI of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 49% and 64%, respectively (P = .001), and the 5-year OS is 55% and 71%, respectively (P = .013). With an IPI greater than 2 (poor prognosis), the 5-year FFS for PTCL and BCLCL is 11% and 35%, respectively (P = .044), and the 5-year OS is 10% and 40%, respectively (P = .011). Multivariate analysis shows that MDATS, IPI, and T-cell phenotype are totally independent and are the most significant predictors of FFS and OS. The 68 PTCLs include 45 PTCLs unspecified, 10 Ki-1 anaplastic (ALCL), 8 angioimmunoblastic, and 5 angiocentric lymphomas. Angiocentrics were usually refractory (1 of 5 remissions only). ALCL rarely relapsed late. We conclude that the immunophenotypic basis of the REAL classification is clinically relevant and that, although other prognostic features also influence outcome, the T-cell phenotype still remains an independent and significant prognostic factor.

Antineoplastic Combined Chemotherapy Protocols↗

Sinusoidal CD30-positive large B-cell lymphoma: a morphologic mimic of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) has been recognized recently as a distinct clinicopathologic entity, restricted to a subset of CD30-positive diffuse large cell lymphomas of T/null lineage. Some of the characteristic features of ALCL, such as CD30 antigen expression and the presence of large pleomorphic lymphoid cells infiltrating lymph node sinuses, can be found rarely in diffuse large B-cell lymphomas. We collected 11 such cases, and their clinical, morphologic, and immunophenotypic features are reviewed. The age of the patients ranged from 36 to 82 years (mean, 63.2 years) with a male to female ratio of 1:1.2. All neoplasms were nodal with a sinusoidal infiltrative pattern, although four neoplasms also had foci of confluent growth. Eight tumors were composed predominantly of large pleomorphic cells with occasional Reed-Sternberg-like cells. The other three tumors had a higher proportion of large monomorphic lymphoid cells. Necrosis and admixed granulocytes were other common features. Immunophenotypically, all cases were positive for CD30 and CD20 or CD79a. All eight cases examined for anaplastic lymphoma kinase-1 immunoreactivity were negative. In situ hybridization for Epstein-Barr virus RNA was performed in eight cases; two were positive. Excluding one consultation case with no available clinical follow-up data, six patients died of the disease within 3 years and one had disease relapse within 1 year. We conclude that an unusual variant of diffuse large B-cell lymphoma can closely mimic ALCL. However, these neoplasms can be distinguished from ALCL by virtue of their B-lineage and lack of anaplastic lymphoma kinase-1 expression. Evidence of Epstein-Barr virus infection can be found in a small subset of these neoplasms.

Adult↗

Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas.

This study reports the first use of gene array technology for the identification of a tumor-specific marker in lymphoid neoplasms. The differential gene expression of 31 hematopoietic cell lines, representing most major lymphoma subgroups of B- and T-cell origin, was assessed by hybridizing labeled complementary DNA to Atlas human expression arrays containing 588 genes. Genes known to be specific for B, T, or myelomonocytic lineages were appropriately identified in the arrays, validating the general utility of this approach. One gene, clusterin, not previously known to be expressed in lymphoid neoplasms, was specifically found in all 4 anaplastic large-cell lymphoma (ALCL) cell lines, but not in any of the 27 remaining tumor lines. Using a monoclonal antibody against clusterin, its differential expression was confirmed by Western blotting and immunohistochemistry. A total of 198 primary lymphomas (representing most major lymphoma subtypes), including 36 cases of systemic ALCL, were surveyed for clusterin expression by immunohistochemistry and Western blotting. All of the 36 ALCL cases marked for clusterin, with most cases showing moderate to strong staining in the majority of neoplastic cells. Clusterin expression was not related to expression of anaplastic lymphoma kinase-1. With 2 exceptions, none of the remaining 162 non-ALCL cases marked with the clusterin antibody, including Hodgkin disease and primary cutaneous ALCL. In reactive lymphoid tissues, only follicular dendritic cells and fibroblastic reticular cells exhibited staining. Clusterin is a highly conserved glycoprotein implicated in intercellular and cell matrix interactions, regulation of the complement system, lipid transport, stress responses, and apoptosis. Although its function in ALCL is unknown, the unique expression of clusterin within this category of lymphoma provides an additional marker for the diagnosis of ALCL. This study illustrates the enormous potential of gene array technologies for diagnostic marker discovery. (Blood. 2000;96:398-404)

Biomarkers, Tumor↗

Activity and isoenzymes of acid phosphatase in human B-cell lymphomas of low-grade malignancy: a novel aid in the classification of malignant lymphoma.

Activity and isoelectric focusing (IEF) pattern of lysosomal acid phosphatase (E.C.3.1.3.2.) were investigated in 55 cases of low-grade malignant B-cell lymphoma, classified as chronic B-lymphocytic leukemia (B-CLL), centroblastic/centrocytic follicular lymphoma (CB/CC), lymphoplasmacytic/lymphoplasmacytoid lymphoma (Immunocytoma, IC), and plasmacytoma (PC), applying the criteria of the Kiel classification. The results show (1) that the four lymphoma types present a characteristic range of enzyme activity in an increasing order: B-CLL, BC/CC, IC, and PC. B lymphocytes, germinal center cells, and plasmacytes are the main constituents of these lymphomas. This sequence might reflect one possible mode of B-cell transformation into plasmacytes traversing an amplification stage in germinal centers under normal conditions. (2) All cases showed the basic IEF pattern of normal B lymphocytes with 12 bands localized in three regions between pH 6.1 and 3.9. This finding supports the B-cell origin and the close phenotypical relationship among the investigated lymphomas. (3) The IEF patterns of B-CLL and CB/CC did not differ from that of normal B lymphocytes, whereas two additional isoenzymes were encountered in cases of IC and seven in PC; this suggests that the higher enzyme activity of IC and PC is at least partly due to the appearance of "new" isoenzymes. The results support the validity of the underlying classification and indicate the individually, B-cell origin, and close relationship among the four lymphoma entities investigated.

Acid Phosphatase↗

Malignant lymphomas of follicular center cell origin in humans. V. Incidence, clinical features, and prognostic implications of transformation of small cleaved cell nodular lymphoma.

Seventy-five cases of small cleaved cell nodular lymphoma (SCC-N) were reviewed. Thirty-four cases underwent repeat biopsy a median of 54 months after diagnosis (range, 7-116 months) because of progressive or recurrent disease. Histologic conversion to a transformed (noncleaved) cell lymphoma was found at re-biopsy in 13 of 34 cases (38%). Neither age, gender, stage, visceral sites of disease, nor symptoms at presentation were predictive of subsequent conversion. Similarly, none of the clinical features analyzed at the time of rebiopsy were predictive of whether the rebiopsy would show stable histology or transformation. Documentation of transformation was of significant prognostic value. Although rebiopsies were performed at the time of progressive disease, survival following re-biopsy was 37.5 months for patients found to have cleaved cell lymphoma at re-biopsy, and only 2.5 months for those with transformed cell lymphoma at re-biopsy. Two of the cases which had immunoglobulin surface markers studied at diagnosis and at transformation, showed retention of heavy and light chain markers. This implies that the change in appearance involves the original neoplastic clone and was not due to a second neoplasm. Development of transformed cell lymphoma is one of the most common features of the aggressive phase of indolent lymphoma. Repeat biopsy in all patients with indolent lymphoma who have relapsing or progressive disease is recommended.

Adult↗

B-cell lymphomas morphologically resembling T-cell lymphomas.

Seven cases of B-cell lymphoma that morphologically resembled T-cell lymphoma are described. These cases are of four morphologic types: atypical poorly differentiated lymphocytic lymphoma (PDLL) with convoluted nuclei, "Lennert's" lymphoma, mixed lymphocytic-"histiocytic" lymphoma with large variation in size of abnormal cells, and "histiocytic" lymphoma with large multilobed nuclei. These cases add further support to the belief that morphologic criteria alone are not sufficient for accurate immunologic classification of the malignant lymphomas since they may represent a distinct clinicopathologic entity.

B-Lymphocytes↗