Kappa Light Chain Restriction Research Articles

Waldenström macroglobulinemia caused by extranodal marginal zone B-cell lymphoma: a report of six cases.

Waldenström macroglobulinemia (WM) and its associated hyperviscosity syndrome (HVS) are generally caused by lymphoplasmacytoid lymphoma or other small B-cell lymphoproliferative disorders. WM associated with extranodal marginal zone B-cell-mucosa-associated lymphoid tissue lymphoma (EMZL/MALT-type) has not been emphasized. We describe 4 men and 2 women (age, 40-79 years) with clinical and laboratory manifestations of WM and EMZL/MALT-type involving one or more sites: lung, pericardium/pleura, ocular adnexa, nasopharynx, minor salivary gland, glossopharyngeal fold, skin, and stomach. The following immunophenotypic patterns were observed: CD20+, 6; CD43+, 3; kappa light chain restriction, 5; and lambda light chain restriction, 1. All were negative for CD5, CD10, and cyclin D1 expression. A clonal paraproteinemia was present in each (IgM kappa, 4; IgM lambda, 1; biclonal IgM kappa/IgA kappa, 1). All 4 patients tested had elevated plasma viscosity; clinical HVS occurred in 3, and 2 required emergency plasmapheresis. These findings suggest that EMZL/MALT-type can cause WM and that the laboratory evaluation of EMZL/MALT-type should include serum protein electrophoresis/immunofixation, and plasma viscosity measurements and urine immunofixation in select cases. EMZL/MALT-type should be considered in the differential diagnosis in patients with clinicopathologic features of WM.

Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit.

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients' serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age > or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration > or =50% (p=0.007), international prognostic index (IPI) > or =3 (p=0.0001), and Morel's scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel's scoring system carry prognostic significance.

Diagnosis of skeletal lymphoma and myeloma by radiology and fine needle aspiration cytology.

Diagnosis of skeletal lymphoma and myeloma by radiology and fine needle aspiration cytology From 1986 to 1998, all patients referred to Karolinska Hospital because of a skeletal destruction of unknown origin routinely underwent radiographic examination and fine needle aspiration cytology (FNAC). Among these, there were 83 patients with solitary lesions of the bone diagnosed and treated for myeloma (plasmacytoma) or non-Hodgkin's lymphoma. Review of the series showed that myeloma could not be distinguished radiographically from lymphoma. Nor could low and high grade lymphoma lesions be discriminated by radiographic appearance. The diagnostic utility of plain radiography in the two conditions seems to be confined to the mere detection of a destructive bone lesion and visual guidance for FNAC. The latter aspect, however, is crucial for the application of FNAC to bone lesions. Review of the cytologic specimens obtained by FNAC showed that they allowed a conclusive diagnosis in all 40 myeloma cases and in 41 of 43 lymphoma cases. In 32 of the 40 myeloma cases, the FNAC material could be used for immunocytochemistry, which disclosed kappa or lambda light chain restriction, corroborating the cytomorphological diagnosis. Thirty-eight lymphomas were characterized immunologically and in 35, a light chain restriction could be demonstrated. Our results show that the use of FNAC in the diagnosis of primary myeloma and lymphoma of bone obviates the need for other diagnostic modalities, including open biopsy. A combined approach based on radiology and FNAC, performed as an out-patient procedure, offers rapid and accurate diagnosis of myeloma and lymphoma among patients with radiographically unclassified destructive bone lesions.

Primary nodal marginal zone B-cell lymphoma arising from more than one clonal neoplastic population.

Primary nodal marginal zone B-cell lymphoma is an uncommon monoclonal B-cell lymphoproliferative disorder. We report a case of a 79-year-old woman who presented with generalized lymphadenopathy. Histologic and immunohistochemical examinations of biopsy sections from an axillary lymph node were consistent with nodal marginal zone B-cell lymphoma. Flow cytometry analysis showed 2 distinct clonal B-cell populations expressing lambda or kappa light chain restriction. Subsequently, genomic deoxyribonucleic acid (DNA) isolated from a paraffin-embedded lymph node section was analyzed for the presence of gene rearrangements. Polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain genes revealed 3 rearranged DNA bands, confirming the presence of more than one clonal B-cell population. These immunophenotypic and genotypic findings have not been previously described in association with this type of lymphoma. To our knowledge, this represents the first reported case of biclonal nodal marginal zone B-cell lymphoma.

Development of a Biologically Distinct EBV-Related Lymphoproliferative Disorder Following Autologous Bone Marrow Transplantation for an EBV-Negative Post-Renal Allograft Burkitt's Lymphoma

Post-transplant lymphoproliferative disorder (PTLD) is a known complication of both solid organ transplantation and allogeneic bone marrow transplantation (BMT) but is rarely seen following autologous BMT. We report the case of a 45 year-old female who developed Burkitt's lymphoma eight years after a renal allograft. This PTLD was found to have lambda light chain restriction, contained del(8)(q24) and add(14)(q32), and was negative for EBV on immunohistochemical and DNA-based PCR analyses. Immunoglobulin heavy chain (IgH) PCR studies revealed a prominent clonal rearrangement. She responded to intravenous cyclophosphamide and proceeded to high-dose chemoradiotherapy and mafosfamide-purged autologous BMT. Thirty-nine days post-BMT she presented with cough and fever and developed hepatic dysfunction; abnormal lymphoplasmacytoid cells were noted in the peripheral blood. Investigations revealed kappa light chain restriction, an oligoclonal IgH rearrangement, a normal karyotype and PCR studies for EBV were positive, consistent with a clinically and biologically distinct PTLD. She initially improved following discontinuation of immunosuppression, but then deteriorated abruptly and died 58 days post-BMT. It is likely that the two separate episodes of PTLD in this patient, one of which was atypical, arose as a result of both the chronic use of cyclosporine and the impairment of cell-mediated immunity associated with autologous BMT. The sequence of events in this patient should contribute to a better understanding of late-onset, EB V-negative PTLD.

Paraffin immunohistochemistry as an adjunct to hematopathology.

In the past two decades, there have been a number of dramatic advances in immunology that have subsequently affected immunohistochemistry. These have had a substantial impact on all phases of laboratory medicine, especially surgical pathology. Many hospital laboratories use immunohistochemical analysis on paraffin-embedded tissue sections as routinely as other special histochemical techniques. Hematopathology, in particular, has become increasingly reliant on the immunohistochemical antibody technique. This method aids in the identification of lineage-associated or lineage-restricted antigens in hematolymphoid neoplasms. The demonstration of kappa or lambda light-chain restriction is a good indicator of monoclonality in B-cell processes, aiding in the distinction between benign reactive hyperplasia and malignant lymphoma. Increasing numbers of antibodies that react to cluster differentiation cell surface antigens have become available for use in paraffin-embedded sections, obviating the need for frozen tissue in many cases. This facilitates the collection, processing, shipping, and storage of tissue specimens for immunohistochemical studies. This report will discuss the basic concepts in the immunohistochemical technique and show its applicability to hematopathology. It will also describe the most relevant antigens/antibodies and how they are used in antibody panels for the diagnosis of benign and malignant hematolymphoid lesions.

Primary extramedullary plasmacytoma of the liver.

Extramedullary plasmacytoma of the liver is a rare tumour, only two cases of which have been reported so far. A third case arising in a 22 year old woman, who...

B-cell monoclonality in salivary lymphoepithelial lesions

It is well recognised that lymphoma may arise in a lymphoepithelial lesion of the salivary glands. Although the histological features of this lesion are well described, it is not clear what proportion contain monoclonal populations of lymphocytes at outset. In this study, 22 routinely processed lymphoepithelial lesions in parotid glands were examined for B-cell monoclonality using the polymerase chain reaction (PCR) to amplify the immunoglobulin heavy chain gene and using in situ hybridisation or immunohistochemistry to detect kappa or lambda light chain restriction. B-cell monoclonality was identified in 17/22 (77.3%) cases using a combination of the three methods. The detection rate for B-cell monoclonality was highest using PCR with 15/22 (68%) cases containing monoclonal immunoglobulin heavy chain gene rearrangements. In a proportion of cases the results of in situ hybridisation and immunohistochemistry were judged to be inadequate and this was probably a reflection of variations in fixation. In 7 patients, sequential biopsies were available from other sites and 6 of these also showed B-cell monoclonality. The results confirm the high prevalence of B-cell monoclonality in lymphoepithelial lesions of the major salivary glands. Furthermore, these results would suggest that PCR is a more reliable technique to identify B-cell monoclonality in routinely processed lymphoepithelial lesions compared to in situ hybridisation and immunohistochemistry.

Primary Cutaneous Plasmacytoma—Report of Two Cases and Review of the Literature

Primary cutaneous plasmacytomas are very rare. In this report, we describe two such cases and review the literature on this entity. Both patients presented with a slowly growing, painless, and solitary mass on the chest wall. Histologically, one case was composed of mature-looking plasma cells, while the other was composed of immature and anaplastic plasma cells, infiltrating the dermis. The epidermis was spared. Kappa light-chain restriction was demonstrated by immunohistochemical techniques in both cases. There was no evidence of marrow disease even on repeated marrow biopsies, although extracutaneous lesions were detected in one patient. One remained in complete remission 6 years following local irradiation. The other patient was treated with local irradiation and systemic chemotherapy, with a complete response, but this was followed by multiple cutaneous recurrences and further remissions by treatment with cytotoxic agents. The present cases and those reported in the literature illustrate well the variable clinical course of primary cutaneous plasmacytoma. Although cure can apparently be achieved in some patients by local radiation therapy, more than half of the cases relapse or progress to myelomatosis. The disease-related mortality is at least 40%. Thus cutaneous plasmacytoma appears to be more aggressive than noncutaneous extramedullary plasmacytomas and should be separately categorized from them in future studies.

Clinical, Biologic, and Histologic Features of Late Relapses in Diffuse Large Cell Lymphoma

After completing chemotherapy and achieving a complete remission (CR), patients with diffuse intermediate-grade lymphoma and immunoblastic lymphoma are usually considered cured if they are able to maintain that remission continuously for 24 months. Recently, we observed a number of patients with these disorders who relapsed after a continuous CR of greater than or equal to 30 months from the beginning of therapy or 24 months from completing chemotherapy. This finding led us to examine 503 consecutive cases to determine the risk of late relapse and their clinical and biologic features. We found that the overall risk of late relapse of those who attained CR was 6.8%, but several features at presentation were associated with a high risk: (1) the presence of a divergent histology; (2) a sclerosing large cell lymphoma; (3) a diagnosis based on an extranodal site with no nodal tissue available for examination. When none of these features were present, the risk of late relapse was minimal (only 3%). When any of these features was present, the risk was 14%. Most striking was the 43% late relapse rate of patients with divergent histology. All but one of the eight B-cell tumors studied at relapse showed kappa light chain restriction. Five of these eight has a low S phase at the time of relapse, suggesting chemotherapeutic selection of a clone of cells with a low proliferative potential that could have given rise to the late relapse. Nucleic acid flow cytometry and immunophenotypic studies on three tumors at initial diagnosis and after relapse failed to support the hypothesis of a second de novo lymphoma and were consistent with a true recurrence of the original tumor. The results of salvage chemotherapy in this group of late relapses showed a high CR rate (57%) but no evidence of a trend for cure in the time to treatment failure curve. In contrast to the experience with Hodgkin's disease, retreatment with the same or a similar regimen used for the original induction was not associated with durable response. Clinicians should be aware of the potential for a late relapse in cases with divergent histology and the need for new treatment strategies for such cases.

Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma

After completing chemotherapy and achieving a complete remission (CR), patients with diffuse intermediate-grade lymphoma and immunoblastic lymphoma are usually considered cured if they are able to maintain that remission continuously for 24 months. Recently, we observed a number of patients with these disorders who relapsed after a continuous CR of greater than or equal to 30 months from the beginning of therapy or 24 months from completing chemotherapy. This finding led us to examine 503 consecutive cases to determine the risk of late relapse and their clinical and biologic features. We found that the overall risk of late relapse of those who attained CR was 6.8%, but several features at presentation were associated with a high risk: (1) the presence of a divergent histology; (2) a sclerosing large cell lymphoma; (3) a diagnosis based on an extranodal site with no nodal tissue available for examination. When none of these features were present, the risk of late relapse was minimal (only 3%). When any of these features was present, the risk was 14%. Most striking was the 43% late relapse rate of patients with divergent histology. All but one of the eight B-cell tumors studied at relapse showed kappa light chain restriction. Five of these eight has a low S phase at the time of relapse, suggesting chemotherapeutic selection of a clone of cells with a low proliferative potential that could have given rise to the late relapse. Nucleic acid flow cytometry and immunophenotypic studies on three tumors at initial diagnosis and after relapse failed to support the hypothesis of a second de novo lymphoma and were consistent with a true recurrence of the original tumor. The results of salvage chemotherapy in this group of late relapses showed a high CR rate (57%) but no evidence of a trend for cure in the time to treatment failure curve. In contrast to the experience with HodgkinAfter completing chemotherapy and achieving a complete remission (CR), patients with diffuse intermediate-grade lymphoma and immunoblastic lymphoma are usually considered cured if they are able to maintain that remission continuously for 24 months. Recently, we observed a number of patients with these disorders who relapsed after a continuous CR of greater than or equal to 30 months from the beginning of therapy or 24 months from completing chemotherapy. This finding led us to examine 503 consecutive cases to determine the risk of late relapse and their clinical and biologic features. We found that the overall risk of late relapse of those who attained CR was 6.8%, but several features at presentation were associated with a high risk: (1) the presence of a divergent histology; (2) a sclerosing large cell lymphoma; (3) a diagnosis based on an extranodal site with no nodal tissue available for examination. When none of these features were present, the risk of late relapse was minimal (only 3%). When any of these features was present, the risk was 14%. Most striking was the 43% late relapse rate of patients with divergent histology. All but one of the eight B-cell tumors studied at relapse showed kappa light chain restriction. Five of these eight has a low S phase at the time of relapse, suggesting chemotherapeutic selection of a clone of cells with a low proliferative potential that could have given rise to the late relapse. Nucleic acid flow cytometry and immunophenotypic studies on three tumors at initial diagnosis and after relapse failed to support the hypothesis of a second de novo lymphoma and were consistent with a true recurrence of the original tumor. The results of salvage chemotherapy in this group of late relapses showed a high CR rate (57%) but no evidence of a trend for cure in the time to treatment failure curve. In contrast to the experience with Hodgkin's disease, retreatment with the same or a similar regimen used for the original induction was not associated with durable response. Clinicians should be aware of the potential for a late relapse in cases with divergent histology and the need for new treatment strategies for such cases. s disease, retreatment with the same or a similar regimen used for the original induction was not associated with durable response. Clinicians should be aware of the potential for a late relapse in cases with divergent histology and the need for new treatment strategies for such cases.

Localization of immunoglobulin-containing cells in human endometrium in the first trimester of pregnancy and throughout the menstrual cycle

The distribution of immunoglobulins in normal human endometrium throughout the menstrual cycle and in early pregnancy has been studied with an immunoperoxidase technique. In first-trimester decidua, IgG was detected within many cells of differing morphology and size. Large IgG-containing cells were often binucleate and were believed to be decidual cells. Examination of serial sections showed no kappa or lambda light-chain restriction, suggesting absorption of the immunoglobulin content. Medium-sized, irregular, IgG-containing cells were macrophages. An additional substantial population of small hyperchromatic IgG-containing cells were prominent around arterioles and adjacent to endometrial glands. From examination of adjacent sections stained with phloxine tartrazine, it was concluded that these represented endometrial granulocytes. Labelling for light chains again suggested absorption of the immunoglobulin content. In contrast, in non-pregnant endometrium immunoglobulin-containing stromal cells were uncommon, although IgG and IgA were detected in gland epithelium and secretions and in the stromal interstitium particularly in the secretory phase. These results support the notion that human endometrium lacks a classical secretory immune system and highlight the requirement for correlation between studies of cell surface markers, morphology and cell surface receptors.

Small noncleaved cell lymphoma: An immunophenotypic study of 18 cases and comparison with large cell lymphoma

Eighteen cases of small noncleaved cell lymphoma (SNCL) were studied with a large panel of monoclonal antibodies applied to tissue frozen sections and compared with 18 cases of immunoglobulin-expressing diffuse large cell lymphoma (DLCL). Immunoglobulin expression was seen in all cases of SNCL, with a predominance of cases showing lambda light chain restriction. Expression of mu and delta heavy chains was common, but gamma and alpha chain expression was uncommon. In the cases of SNCL T015, B1, B2, 41H, BA-1, BA-2, Ia, CALLA, and OKT10 were generally expressed, and a large percentage of cells expressed Ki-67. Only rare expression of T05, Leu-8, and Leu-9 was seen, and in no case was reactivity with anti-Tac antibodies observed. In contrast, the immunoglobulin-expressing DLCLs showed the typical predominance of cases of kappa light chain restriction, a lower proportion of cases with mu or delta expression, and a higher proportion of cases with gamma expression. A lower incidence of Leu-8, T05, and Tac expression and a higher incidence of BA-1, CALLA, Ki-67 and OKT10 were seen in the SNCLs as compared with the DLCLs. It is concluded that immunologic studies may be of considerable aid in the differential diagnosis of SNCL and DLCL.

Oligoclonal IgG antibody response in the central nervous system to different measles virus antigens in subacute sclerosing panencephalitis.

Agarose electrophoresis of cerebrospinal fluid from two patients with subacute sclerosing panencephalitis revealed in both cases several homogeneous bands in the intermediate and basic gammaglobulin region. The bands were identified as IgG with various degrees of kappa or lambda light-chain restriction in crossed immunoelectrophoresis. Homogeneous IgG bands were separated by preparative agarose electrophoresis and were found to represent measles virus-specific antibodies. Antibody activities against different virus products (hemolysin, hemagglutinin, and nucleocapsids) were carried by different populations of IgG. In both cerebrospinal fluid materials, antibodies to the virus hemolysin and to virus nucleocapsids were found to be relatively more basic than the antibodies to virus hemagglutinin, which appeared in the basic intermediate gammaglobulin region. We conclude that the oligoclonal IgG bands in cerebrospinal fluid of patients with subacute sclerosing panencephalitis represent homogeneous measles virus antibodies. In some instances, the IgG bands appeared to fulfill criteria of monoclonality on the basis of their electrophoretic homogeneity, selective light-chain type, and specific antibody activity.