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Background
Lymphoplasmacytic lymphoma is also known as an immunocytoma. These are low grade Non-Hodgkin's lymphomas and contain small lymphocytes, plasmacytoid lymphocytes, variable numbers of transformed cells, and plasma cells. Currently, Waldenstrom's Macroglobulinemia is considered a variant of this lymphoma, with bone marrow involvement associated with serum IgM paraprotein.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Immunocytoma
Plasmacytoid lymphocytic lymphoma
Waldenstrom's Macroglobulinemia
PATHOGENESIS CHARACTERIZATION PAX 5 GENE
Lack of PAX5 rearrangements in lymphoplasmacytic lymphomas: reassessing the reported association with t(9;14).
Cook JR, Aguilera NI, Reshmi-Skarja S, Huang X, Yu Z, Gollin SM, Abbondanzo SL, Swerdlow SH.
Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.
Hum Pathol. 2004 Apr;35(4):447-54. Abstract quote
A t(9;14)(p13;q32) involving the PAX5 and IGH genes has been described in association with lymphoplasmacytic lymphoma. Although often described as common, the incidence of this translocation in nodal lymphoplasmacytic lymphoma has never been investigated. Recent studies of patients with Waldenstrom's macroglobulinemia (often corresponding to marrow-based lymphoplasmacytic lymphoma) have failed to identify the t(9;14). These studies have suggested that either nodal and marrow-based lymphoplasmacytic lymphomas have distinct pathogenetic mechanisms or that the t(9;14) is less frequent in lymphoplasmacytic lymphoma than was believed previously.
We therefore analyzed a series of nodal or other extramedullary lymphoplasmacytic lymphomas for the presence of the t(9;14) with paraffin section interphase fluorescence in situ hybridization. We developed a BAC contig probe spanning all previously described PAX5 breakpoints and validated this assay with the KIS-1 cell line that expresses a t(9;14). Analysis with the PAX5 probe showed a lack of PAX5 rearrangements in all cases that were analyzed successfully. Similarly, analysis by an IGH fluorescence in situ hybridization probe showed no evidence of translocations involving the IGH locus.
These findings indicate that the t(9;14) is at least uncommon in lymphoplasmacytic lymphoma and should no longer be considered a characteristic finding in this type of lymphoma as defined by World Health Organization criteria.
CLINICAL VARIANTS CHARACTERIZATION GENERAL
- Lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: an evolving concept.
Lin P, Medeiros LJ.
From the Department of Hematopathology, U. T. M. D. Anderson Cancer Center, Houston, Texas.
Adv Anat Pathol. 2005 Sep;12(5):246-55. Abstract quote
The concept of Waldenstrom macroglobulinemia has evolved from the original description of a clinical syndrome to its more recent designation as a distinct clinicopathologic entity, that is, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), in the World Health Organization (WHO) classification and by the participants of consensus meetings on WM.
The diagnosis of LPL/WM, however, remains a challenge in daily practice. Distinguishing LPL/WM from other B-cell lymphomas, especially marginal zone B-cell lymphomas, which share overlapping morphologic features, is difficult.
The traditional practice of separating LPL/WM from other lymphomas by an arbitrary level of serum IgM is no longer considered valid. The characteristic immunophenotype described for LPL/WM by the WHO classification, that is, CD5CD10CD23, is observed in 60-80% of neoplasms, but variations from this pattern of antigen expression are common, with CD23 being detected in up to 40% of cases.
Lack of a distinct molecular genetic hallmark complicates the distinction of LPL/WM from other B-cell lymphomas. Although the t(9;14) is stated to be present in 50% of cases in the WHO classification, translocations involving the Ig heavy chain including the t(9;14) are actually rare in LPL/WM. Deletion of 6q21-q23, a nonspecific finding, is the most common aberration reported in 40-70% of patients. At the molecular level, the neoplastic clone in most cases has undergone Ig variable gene mutation, but not isotype switching, and the clone retains the capability of plasmacytic differentiation.
Currently, the diagnosis of LPL/WM can only be established by incorporating clinical and pathologic findings and excluding alternative diagnoses. In some cases, in our opinion, distinguishing LPL/WM from marginal zone B-cell lymphomas seems arbitrary using currently recommended criteria.
HISTOLOGICAL TYPES CHARACTERIZATION General Diffuse growth pattern, often with proliferation centers, and is CD5 positive
Presence of plasmacytoid cells, Dutcher bodies, and monoclonal staining for cytoplasmic immunoglobin in the plasmacytoid cells
Lymphoplasmacytic type lacks CD5 and may have an interfollicular growth pattern
VARIANTS Is Lymphoplasmacytic Lymphoma/Immunocytoma a Distinct Entity? A Clinicopathologic Study of 20 Cases
Jo-Ann W. Andriko, etal.
Am J Surg Pathol 2001;25:742-751 Abstract quote
Lymphoplasmacytic lymphoma/immunocytoma (LLI) was defined initially as a small B-cell lymphoma with plasmacytoid or plasmacytic features. Because other types of small B-cell lymphoma, particularly marginal zone B-cell lymphoma may exhibit plasmacytic differentiation, the revised European–American lymphoma classification and World Health Organization has defined LLI more narrowly to exclude other small B-cell lymphomas.
The goal of this study was to reevaluate LLI as a clinicopathologic entity.
Twenty cases were selected from 43 previously diagnosed as ``small lymphocytic lymphoma, plasmacytoid'' or ``immunocytoma'' from 1985 to 1998. Cases fulfilling the criteria for B-cell small lymphocytic lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, or other types of B-cell lymphoma were excluded.
The histopathology and immunoreactivity for CD20, CD79a, CD3, CD43, CD23, CD5, kappa, lambda, and immunoglobulins (Ig's) M, G, and A were reviewed, in addition to available clinical findings.
There were 13 men and seven women, with a mean age of 69 years. Five patients had documented Waldenström's macroglobulinemia (WM).
Three architectural patterns were observed. Pattern A (seven of 20) showed open sinuses, small follicles, and hemosiderosis; pattern B (four of 20) showed hyperplastic follicles; and pattern C (nine of 20) showed diffuse effacement. Epithelioid histiocytes were prominent in patterns B and C but absent in A. Cytologically, six of 20 were polymorphous with 10% to 40% transformed cells; 14 of 20 were lymphoplasmacytic. Five cases showed minor foci of monocytoid B cells. One case showed a composite histology of LLI and small lymphocytic lymphoma. Amyloid was present in two cases. All cases were CD20 and/or CD79a immunoreactive, with two of 20 positive for CD43. Twelve cases were kappa monoclonal and eight cases were lambda monoclonal. Twelve of 17 cases that could be evaluated were positive for IgM and five were positive for IgG. All cases were negative for CD5 and CD23 with the exception of the one case with a composite histology.
Eleven of 20 patients with available follow-up died of disease (median, 48 months), and eight of 20 are alive with disease at a follow-up of 6 months to 2 years.
LLI does appear to represent a distinct clinicopathologic entity even though it shows morphologic heterogeneity and overlapping features with marginal zone B-cell lymphoma and small lymphocytic lymphoma. Recognition of LLI is important because the overall prognosis may be worse than for other types of small B-cell lymphomas.
SKIN Primary cutaneous immunocytoma/marginal zone B-cell lymphoma: a case with unusual course.
Demirkesen C, Tuzuner N, Su O, Esckazan AE, Soysal T, Onsun N.
Department of Pathology, Cerrahpasca Medical Faculty, University of Istanbul, Istanbul, Turkey
Am J Dermatopathol. 2004 Apr;26(2):119-22. Abstract quote
Although primary cutaneous immunocytoma/marginal zone B-cell lymphoma (PCI/MZBL) is considered as an indolent lymphoma with excellent prognosis, extracutaneous spread and even death due to disseminated disease have been reported.
This is a case report of a PCI/MZBL showing dissemination to the regional lymph node and bone marrow, 22 months after the initial diagnosis. Furthermore, in the lymph node, there were focal areas of high-grade transformation. On the other hand, the bone marrow involvement displayed low-grade morphology.
We suggest that it should be kept in mind that there is still a possibility of systemic involvement in PCI/MZBL.
SPECIAL STAINS/
IMMUNOHISTO-CHEMISTRYCHARACTERIZATION
Sergej Konoplev, MD, PhD, L. Jeffrey Medeiros, MD, Carlos E. Bueso-Ramos, MD, PhD, Jeffrey L. Jorgensen, MD, PhD, and Pei Lin, MD
We retrospectively reviewed the immunophenotypic profile of 75 cases of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) analyzed by flow cytometry.
All patients had monoclonal IgM (median, 2,100 mg/dL [21 g/L]) in serum and were considered clinically to have WM. The neoplastic cells, in all cases, expressed monoclonal immunoglobulin light chain (k, 55; l, 20) and CD19, and every case assessed was positive for CD20 (n = 68) and CD52 (n = 60). The results for other antigens assessed in decreasing frequency of positivity were as follows: surface IgM (26/28 [93%]), CD79b (11/13 [85%]), CD11c (13/16 [81%]), CD25 (5/7 [71%]), CD23 (17/28 [61%]), CD38 (24/50 [48%]), FMC7 (11/29 [38%]), CD22 (4/12 [33%]), CD5 (3/65 [5%]), and CD10 (1/38 [3%]).
These results show that the immunophenotype of LPL/WM is variable and overlaps with other B-cell lymphoproliferative disorders. CD23, usually of dim intensity, and CD11c are expressed commonly in LPL/WM. Rare CD5+ and CD10+ cases of LPL/WM also exist.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES MARGINAL ZONE LYMPHOMAS SMALL B-CELL LYMPHOMAS p27Kip1 Immunostaining for the Differential Diagnosis of Small B-Cell Neoplasms in Trephine Bone Marrow Biopsies
Marcus Kremer, M.D., Stephan Dirnhofer, M.D., Anna Nickl, Heinz Hoefler, M.D., Leticia Quintanilla-Martínez, M.D. and Falko Fend, M.D.
Institute of Pathology (MKHH, FF), Technical University Munich, Germany; Institute of Pathology (SD), University of Innsbruck, Austria; Institute of Pathology (MK, AN, HH, LQM), GSF-National Research Center for Environment and Health, Neuherberg, Germany; and Institute of Pathology (SD), University of Basel, Switzerland.
Mod Pathol 2001;14:1022-1029 Abstract quote
The distinction between mantle cell lymphoma (MCL) and other small B-cell non-Hodgkin lymphomas (NHL) is important because MCL has a more aggressive clinical course. In bone marrow (BM) biopsy specimens, this distinction can be particularly difficult. Although cyclin D1 immunostaining and molecular detection of the t(11;14) translocation are highly specific markers for MCL, they fail to detect a proportion of cases.
We have recently described that MCL typically lacks detectable expression of the cyclin-dependent kinase inhibitor p27kip1 protein by immunostaining, which is expressed at high levels in most small B-cell NHL inversely correlated to the proliferation rate. We therefore examined whether p27kip1 immunostaining could be a useful adjunct for the differential diagnosis of small B-cell NHL infiltrates in the BM.
Trephine BM biopsy specimens of 96 patients, including well-characterized MCL (19 cases), B-cell chronic lymphocytic leukemia (27 cases), follicular lymphoma (18 cases), hairy cell leukemia (22 cases), and marginal zone lymphoma (10 cases) as well as 10 reactive BM, including five with benign lymphoid aggregates were investigated. In addition, the presence of a t(11;14) translocation involving the major translocation cluster was studied by PCR in all MCL. All cases of B-cell chronic lymphocytic leukemia, follicular lymphoma, and marginal zone lymphoma revealed a strong p27kip1 nuclear staining in the majority of neoplastic cells. Fourteen (78%) cases of MCL were p27kip1-negative in the tumor cells, whereas four cases revealed a weak nuclear positivity. Seventeen (77%) cases of hairy cell leukemia were also either completely negative for p27kip1 or showed a faint positive staining in a minority of the neoplastic cells. Nine of 19 cases (47%) of MCL showed a bcl1 rearrangement involving the major translocation cluster region.
These findings demonstrate that p27kip1 immunostaining is a valuable additional marker for the differential diagnosis of small B-cell NHL infiltrates in BM biopsies. The reduction or lack of p27kip1 protein expression in MCL, as well as in hairy cell leukemia, might be an important event in the pathogenesis of these disorders.
TREATMENT CHARACTERISTICS GENERAL
Lymphoplasmacytic lymphoma/immunocytoma: towards a disease-targeted treatment?Clavio M, Quintino S, Venturino C, Ballerini F, Varaldo R, Gatto S, Galbusera V, Garrone A, Grasso R, Canepa L, Miglino M, Pierri I, Gobbi M.
Dept. of Internal Medicine, University of Genoa, Genova, Italy.
J Exp Clin Cancer Res. 2001 Sep;20(3):351-8. Abstract quote Lymphoplasmacytic-lymphoplasmacytoid lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) or immunocytoma (IMC) consists of diffuse proliferation of small mature B lymphocytes, plasmacytoid lymphocytes, and plasma-cells. The nosographic definition includes the lack of histological, immunophenotypic, cytogenetic, and molecular markers considered specific of other types of lymphoma. The cells show surface Ig (usually IgM), B-cell-associated antigens and display the CD5-, CD23- and CD10- phenotype, which allows for differential diagnosis from B-CLL and mantle cell lymphoma. t(9;14)(p13;q32) chromosomal translocation has been found in 50% of all LPL cases. The cytogenetic rearrangement juxtaposes the PAX-5 gene, which encodes for an essential transcription factor for B-cell proliferation and differention, to the Ig heavy chain gene.
The combination of chlorambucil and prednisone holds as the standard treatment and seems to guarantee good control of the disease in most patients. Similar therapeutic results have been described with the combination of cyclophosphamide, vincristine, prednisone with (CHOP) or without doxorubicin (CVP), or with a combination of other alkylating agents and prednisone. Nucleoside analogues, alone or in combination with alkylating agents and anthracyclines, provide good salvage therapy for IMC and being increasingly employed as first line therapy.
In a multicentric European trial Foran et al. administered the chimeric anti-CD20-monoclonal antibody (Rituximab) to 28 patients with previously treated IMC. Seven out of 25 evaluable patients (28%) achieved a partial response. Byrd et al. examined the outcome of 7 previously treated WM patients who received weekly infusions of rituximab (375 mg/m2). Therapy was well tolerated by all patients, and there was no decrease in cellular immune function, or significant infectious morbidity. Partial responses were noted in three of these patients, including two with fludarabine-refractory disease. These data suggest that rituximab exerts clinical activity on heavily pre-treated patients with WM. Furthermore, Weide et al. first reported that WM-associated polyneuropathy can be treated effectively with a combination of chemotherapy and the anti-CD20 monoclonal antibody rituximab.
Most published trials exploring the efficacy of high dose treatment as salvage therapy for relapsed or refractory low grade non Hodgkin's lymphoma have included prevalently follicular or lymphocytic lymphomas. In selected high risk patients radioimmunotherapy with autologous stem-cell rescue, and myeloablative therapy followed either by autologous stem cell transplantation (SCT) or allogeneic SCT might represent an alternative strategy.Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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Last Updated October 24, 2005
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