B-Cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins)

Among 78 patients with persistent cold agglutinins, 31 had lymphoma, 13 had macroglobulinemia of Waldenström, six had chronic lymphocytic leukemia and 28 had chronic cold agglutinin disease. The average age was over 60 years. Patients with chronic cold agglutinin disease had more hemolytic crises, bleeding and Raynaud's phenomena, and less frequently lymphadenopathy or hepatosplenomegaly. The frequency of anemia, positive Coombs test results, cryogtobulinemia and Bence Jones proteinuria was similar in the various groups. Survival time from diagnosis was on average two years in lymphoma, two and a half years in Waldenström's macroglobulinemia, more than six years in chronic lymphocytic leukemia and more than five years in chronic cold agglutinin disease. Anti-I were common in chronic cold agglutinin disease (74 percent) and rare in other groups (32 to 33 percent). Anti-I and other cold agglutinins were rare in chronic cold agglutinin disease and common in lymphoma and Waldenström's macroglobulinemia. In chronic cold agglutinin disease, and in Waldenström's macroglobulinemia, cold agglutinins usually had κ light chains—92 percent and 71 percent, respectively—whereas in lymphoma, 71 percent of cold agglutinins had λ light chains. The type of light chains related to the specificity of cold agglutinins: 58 percent of IgM/κ were anti-i, 75 percent of IgM/λ had other specificities. Cold agglutinins were cytotoxic to autologous and allogeneic lymphocytes. Occasionally, more autologous than allogeneic cells were killed implying that the former may be precoated in vivo with the antibodies. In conclusion, conditions with persistent cold agglutinins are a spectrum that varies from “benign” autoimmune-like chronic cold agglutinin disease to malignant lymphoma. Marked differences in the light chain type of cold agglutinins, specificity toward membranous antigens and severity of clinical manifestations were noted in benign and malignant varieties.     

Acquired C1 inhibitor deficiency associated with lymphoproliferative disorders: four cases

INTRODUCTION: Acquired C1 inhibitor deficiency is sometimes associated with lymphoproliferative disorders. EXEGESIS: We report four cases of acquired C1 inhibitor deficiency in association with lymphoproliferative disorders. Three of them were asymptomatic; one was associated with abdominal pain. Four women (median age, 66 years) presented either two non-Hodgkin lymphoma or two chronic lymphocytic leukaemia. C1 inhibitor deficiency was detected fortuitous (n = 1) or during investigation of arthralgia (n = 2), or Gougerot-Sjogren syndrome (n = 1). The deficit was acquired in all cases type I. Auto-immune disorders were associated with: Gougerot-Sjogren syndrome (n = 1), cryoglobulinemia (n = 2), IgM lambda monoclonal gammopathy (n = 1), Coombs positive test (n = 2), IgG anti-cardiolipine antibodies (n = 1). C1 inhibitor deficiency was not modified after lymphoproliferative disorders treatment (radiotherapy, splenic ablation) in two cases but patients were not in complete remission. C1 inhibitor raised normal level in one case, after five chemotherapy regimens, but decreased complement level and C4 split persist. CONCLUSION: Acquired C1 inhibitor deficiency associated with lymphoproliferative disorders is sometimes asymptomatic. Diagnosis could be delay in spite of clinical manifestations. Deficit correction is not constant after lymphoproliferative disorders treatment.     

The clinical aspects of biclonal gammopathies. Review of 57 cases

Between 1966 and 1979, biclonal gammopathy was recognized in 57 patients. Clinical and laboratory features differentiated three groups: biclonal gammopathy of undetermined significance, 37 cases (65 percent); multiple myeloma, nine cases (16 percent); and lymphoproliferative disease--including lymphoma, macroglobulinemia, chronic lymphocytic leukemia and unclassified lymphoproliferative disorders--11 cases (19 percent). With biclonal gammopathy of undetermined significance, symptomatic multiple myeloma developed after two years in one patient; the others remained stable. One patient with multiple myeloma had osteosclerotic myeloma and a severe sensorimotor peripheral neuropathy, and another presented with plasma cell leukemia. In the remainder response to therapy and survival were much the same as in patients with multiple myeloma with a monoclonal protein. Patients with lymphoproliferative disease responded to chemotherapy like that for monoclonal gammopathy. Of the 57 patients, 30 (53 percent) had IgG and IgA components, 15 (26 percent) had IgG and IgM, six had two IgG components, three had IgA and IgM, one had IgA proteins, one had IgA and IgE and 1 had triclonal gammopathy. Of the 115 light chains, 70 percent were kappa; the chains were both kappa and lambda in 63 percent of biclonal pairs. In many cases, serum electrophoresis produced only a single band on the acetate strip, and the biclonal gammopathy was not recognized until immunoelectrophoresis was done. Although the clinical features of biclonal gammopathy and its response to therapy are similar to those of monoclonal gammopathy, this subject is of importance because of the lack of clinical data in the literature.     

Hyperreactive malarial splenomegaly in a European returning from Africa]

INTRODUCTION: Hyper-reactive malarial splenomegaly (HMS) syndrome related to abnormal immunologic response to repeated malarial infections is unusual in European expatriates. EXEGESIS: We report the case of a 72-year-old white male patient who had been residing in the Congo and developed a typical clinical features of hyperactive malarial syndrome characterized by massive splenomegaly with hypersplenism, high titers of malarial IgM antibodies, IgM macroglobulinemia, liver and medullary lymphocytic proliferation, and a clinical and immunological response to long-term chloroquine therapy. CONCLUSION: Criteria for the diagnosis of hyper-reactive malarial splenomegaly are useful. However, making a distinction from malignant lymphoproliferative disorders is difficult, as a sustained response to chloroquine is required. Therefore, chloroquine appears to have a regulatory effect on the immune system.     

Hairy cell leukemia and other "hairy-cell" lymphoproliferative disorders (LPD-HC): the significance of morphologic, histologic and immunologic studies

In this report the clinical, morphologic, histologic and immunologic findings of 41 patients with hairy lymphoid cells in peripheral blood and/or bone marrow are analyzed. In 27 patients the diagnosis of hairy cell leukemia was established. 14 patients had other variants of lymphoproliferative disorders: malignant lymphoma with hairy cells--7, chronic lymphocytic leukemia with hairy cells--5, and T cell lymphoproliferative disorder with hairy cells--2 patients, respectively. Several variants of malignant lymphoma with hairy cells were defined: lymphocytic, centrocytic and lymphoplasmacytic. The importance of combined use of bone marrow biopsy and immunophenotyping for the correct diagnosis of hairy cell leukemia and other "hairy-cell" lymphoproliferative disorders is stressed. The obtained data suggest relationship between characteristic clinical manifestation (isolated splenomegaly), presence of hairy cells and CD11c-antigen expression.     

Malignant Lymphoma of the Transverse Colon Associated with Macroglobulinemia

We present an unusual case of a malignant lymphoma of the transverse colon associated with macroglobulinemia. A 73-yr-old man was incidentally discovered to have high serum γ-globulin on a regular check-up. Serum immunoquantitation revealed an IgM level of 3490 mg/dl. Kappa-type Bence-Jones protein was positive in the urine. Immunoelectrophoresis identified the abnormal protein as IgM-kappa. After hospitalization an abdominal tumor was detected with barium and CT, identified as a tumor of the transverse colon. Partial resection of the transverse colon was carried out. His-topathologically the tumor were confirmed as small lymphocytic non-Hodgkin lymphoma of B-cell origin, based on the Working Formulation. According to flowcytometric analysis, the tumor cells were positive for IgM-kappa. The lymphoma cells produced monoclonal IgM, giving rise to macroglobulinemia.     

Minimal Change Nephrotic Syndrome Associated With Non-Hodgkin Lymphoid Disorders: A Retrospective Study of 18 Cases

Few studies have examined the occurrence of minimal change nephrotic syndrome (MCNS) in patients with non-Hodgkin lymphoma (NHL). We report here a series of 18 patients with MCNS occurring among 13,992 new cases of NHL. We analyzed the clinical and pathologic characteristics of this association, along with the response of patients to treatment, to determine if this association relies on a particular disorder. The most frequent NHLs associated with MCNS were Waldenström macroglobulinemia (33.3%), marginal zone B-cell lymphoma (27.8%), and chronic lymphocytic leukemia (22.2%). Other lymphoproliferative disorders included multiple myeloma, mantle cell lymphoma, and peripheral T-cell lymphoma. In 4 patients MCNS occurred before NHL (mean delay, 15 mo), in 10 patients the disorders occurred simultaneously, and in 4 patients MCNS was diagnosed after NHL (mean delay, 25 mo). Circulating monoclonal immunoglobulins were present in 11 patients. A nontumoral interstitial infiltrate was present in renal biopsy specimens from 3 patients without significant renal impairment. Acute kidney injury resulting from tubular lesions or renal hypoperfusion was present in 6 patients. MCNS relapse occurred more frequently in patients treated exclusively by steroid therapy (77.8%) than in those receiving steroids associated with chemotherapy (25%). In conclusion, MCNS occurs preferentially in NHL originating from B cells and requires an aggressive therapeutic approach to reduce the risk of MCNS relapse.     

Autocrine expression of platelet-derived growth factor B in B cell chronic lymphocytic leukemia

Platelet-derived growth factor (PDGF) regulates clonal proliferation of malignant pre-B cell lines, but little is known about its role in normal B lymphocyte differentiation and malignant transformation. To understand the expression of PDGF-A, PDGF-B and the beta-receptor (PDGF-Rbeta) in B cell lymphoproliferative disorders, we used an immunohistochemical method to stain formalin-fixed, paraffin-embedded tissues in 5 patients with reactive lymphoid hyperplasia, 15 with non-Hodgkin's lymphoma and 23 with B cell chronic lymphocytic leukemia (B-CLL). Abundant PDGF-A, rather than PDGF-B, was expressed in normal B cell differentiation. There was no difference in the expression of PDGF-A and PDGF-B between patients with reactive lymphoid hyperplasia and patients with malignant lymphoproliferative disorders. Among the patients with B-CLL, the expression of PDGF-B was much stronger than the expression of PDGF-A, and 18 of the patients had coexpression of PDGF-B and PDGF-Rbeta. A larger proportion of patients with B-CLL than with non-Hodgkin's lymphoma had expression of PDGF-B and PDGF-Rbeta. In conclusion, PDGF-A expression in all stages of B lymphocyte differentiation suggests that it is important in B cell differentiation and proliferation. Expression of PDGF-B and PDGF-Rbeta suggests that autocrine signaling of PDGF may be important in malignant transformation of B-CLL. However, further studies are necessary to confirm these conclusions.     

Granulocyte antibodies in leukaemic chronic lymphoproliferative disorders

The anti-granulocyte activity of serum from patients with B-cell chronic lymphocytic leukaemia (CLL) and other lymphoproliferative disorders was investigated. Granulocyte-binding IgG was measured in 34 patients with CLL, 13 patients with hairy cell leukaemia, one patient with prolymphocytic leukaemia, two patients with Sézary cell leukaemia, and seven patients with chronic T-cell lymphocytosis who had a predominance of circulating large granular lymphocytes. Anti-granulocyte activity was absent in CLL and its variants, but present in the majority of granulocytopenic patients with chronic T-cell lymphocytosis. In one of these patients, granulocytopenia was associated with complement-activating IgG granulocyte antibody. Thus, antibody-mediated granulocyte injury appears to be an unusual occurrence in chronic lymphocytic leukaemia, but is a frequent complication of chronic T-cell lymphocytosis.     

The treatment of Waldenström macroglobulinemia and the therapy of diseases caused by monoclonal IgM gammaglobulin

Waldenstr?m macroglobulinemia is defined by the presence of IgM type monoclonal immunoglobulin and histologi cal prove of lymphoplasmocytary lymphoma in the bone marrow. Alkylating cytostatic drugs, chlorambucil or cyclofosfamide in monotherapy have been typically used for its treatment. Similarly to other lymphoproliferative diseases with a low degree of aggressiveness, purine analogues (fludarabine and 2-chlordeoxyadenosine) have a faster treatment response and a higher number of treatment responses, especially if administered in combination with alkylating drugs. The monoclonal antibody rituximab (R) also brings considerable improvement to patients suffering from the disease. It is good for cytopenic patients on monotherapy, and for non-cytopenic patients, in combination with other drugs, both with R-CHOP and with a purine analogue and an alkylating cytostatic drug. In recent years, new drugs for the treatment of this disease have been tested (bortezomib, thalidomid, revlimid and others). High-dose chemotherapy with autologous transplantation has a higher treatment response rate than classical chemotherapy. It is recommended in case of insufficient effect of conventional treatment or early relaps. Young patients with suitable profile and insufficient response to conventional treatment can also qualify for allogenic transplantation; graft response against the disease has been observed in almost all patients who underwent allogenic transplantation. However, treatment is often necessary also in diseases caused by IgM monoclonal immunoglobulin, irrespective of it being formed by a malignant or a benign clone, because the characteristics of IgM monoclonal immunoglobulin may endanger the patient's integrity. The article provides an overview of treatment options for Waldenstr?m macroglobulinemia and diseases caused by monoclonal IgM.     

Sjögren's syndrome associated with multiple myeloma

Sjögren's syndrome (SS) is a chronic autoimmune disease of unknown etiology characterized by lymphocytic infiltration of the exocrine glands and a polyclonal B-cell activation; it is demonstrated by the presence of multiple autoantibodies against organ- and non-organ-specific autoantigens. SS is associated with malignant lymphomas, Waldenstrom's macroglobulinemia and benign monoclonal gammopathy, while its relationship with multiple myeloma is extremely rare. The association between multiple myeloma and rheumatoid arthritis and other autoimmune diseases has been established, but it is not clear why a B-cell proliferation like myeloma occurs more rarely than other B-cell disorders in patients with SS. We describe a patient who presented with multiple myeloma and SS that might have existed for at least 2?years prior to the appearance of myeloma.     

CD5-Negative,CD10-Negative small B-cell leukemia: Variant of chronic lymphocytic leukemia or a distinct entity?

CD5- and CD10-negative chronic lymphocytic leukemias are quite uncommon as compared to the CD5-positive CLL. We reviewed 250 sequential cases of peripheral blood lymphocytosis to characterize cases of small B-cell lymphoproliferative disorders, submitted with a clinical diagnosis of chronic lymphocytic leukemia exhibiting a non-classic immunophenotypic profile. Six cases of CD5-, CD10-negative chronic lymphocytic leukemias and no tissue involvement were identified that revealed high-density surface-membrane immunoglobulin and CD20 expression, with variable expression of CD11c, CD23, and CD25. Most had a profound leukocytosis (mean WBC 180 x 10(9)/L) with proliferation of mature-appearing lymphocytes. Subsequent bone marrow biopsies showed diffuse infiltration by neoplastic cells in all evaluated patients. The clinical course appeared indolent, with follow-up revealing three patients alive (survival time 38-68 months), while two died of unrelated causes and one was lost to follow-up soon after diagnosis. These cases may represent somewhat unusual chronic lymphoproliferative disorders, with morphologic features and immunophenotypic profile not readily classifiable, but which are certainly atypical for classic chronic lymphocytic leukemia. Some of these features are reminiscent of those seen in marginal-zone lymphoma. However, it is most unusual for this known to be tissue-based disease to present primarily as leukemia rather than lymphoma.     

Frequency and role of low molecular weight IgM in systemic lupus erythematosus

Summary Low molecular weight IgM (LMW IgM) is the monomeric subunit of the naturally occurring pentameric IgM. It is not seen in health but has been previously observed in systemic lupus erythematosus (SLE) particularly in those patients with active disease and may reflect an adverse prognostic finding. We have therefore studied the presence of LMW IgM in 33 Chinese or Malay SLE patients (Singapore) and 21 Caucasian patients (Adelaide). LMW IgM was measured using filtration chromatography or by a sensitive immunoblotting technique. LMW IgM was observed in all patients in the Adelaide group and in 32 patients in the Singapore group with slightly greater quantities being seen in the Adelaide group. LMW IgM constituted up to 15.3% of the total IgM and was frequently associated with the presence of other low molecular weight IgM oligomers. In both groups LMW IgM correlated significantly with the total IgM levels (P<0.01). In a more detailed study in the Singapore group LMW IgM also correlated significantly with the IgM anticardiolipin levels (P=0.02) but not with IgG anticardiolipin or with IgG or IgM anti-DNA levels or with rheumatoid factor. Patients with more extensive organ involvement had higher levels of LMW IgM but not at a significant level. We conclude that circulating LMW IgM occurs almost universally in SLE, is closely related to the total IgM levels and appears independent of ethnic background. The significance of LMW IgM in this disorder is unclear.     

B-chronic lymphocytic leukemia, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma, including Waldenstr?m's macroglobulinemia: a clinical, morphologic, and biologic spectrum of similar disorders.

Among small lymphocyte cell disorders, B-chronic lymphocytic leukemia (B-CLL), small lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma/Waldenstr?m's macroglobulinemia (LPL/MW) are included. B-CLL patients always have blood and bone marrow (BM) involvement by a CD5+ B lymphocyte. They frequently present with lymphadenopathy and/or hepatosplenomegaly, although in a considerable number of patients, no abnormal physical findings are found. They are prone to develop hypogammaglobulinemia, autoimmune hemolysis, or autoimmune thrombocytopenia. The typical immunophenotype of the malignant cell is CD5+, surface immunoglobulin (slg)+ (weak), CD23+, CD79b-, and FMC7-. Trisomy 12 and 13q deletions are frequent chromosomal abnormalities. The bcl-2 protein is usually overexpressed. SLL patients present with lymphadenopathy, usually generalized. Lymphocytosis is by definition absent and BM involvement, usually nodular, is found in 25% to 50% of patients. The lymph node lymphocytes are CD5+ and have a similar immunophenotype with CLL, but frequently express the LFA-1 adhesion molecule. Patients are at low risk to develop hypogammaglobulinemia, autoimmune hemolysis, or autoimmune thrombocytopenia. LPL/MW patients may present either with an accidental discovery of IgM gammopathy, symptoms related to paraproteinemia, or lymphadenopathy and/or splenomegaly. The BM is frequently involved and a leukemic picture may be found. A monoclonal gammopathy of IgM class is by definition present in MW and is frequently accompanied by hypogammaglobulinemia. Immunophenotypic studies usually reveal a CD5-, slg+ (moderate), cytoplasmic immunoglobulin (clg)+, FMC7+, and CD38+ cell. A significant proportion of cases carry the translocation t(9;14)(p13;q32) involving the PAX-5 gene. All of these disorders may potentially undergo transformation to large-cell lymphoma or Richter's syndrome. Prognostic factors have been extensively studied in B-CLL, but more studies are needed for SLL and LPL/MW. These entities should be differentiated from other B-chronic small lymphocyte cell disorders, particularly when the latter are leukemic.     

Varied manifestations of a familial lymphoproliferative disorder

In a sibship of nine adults, four died of lymphocytic or histiocytic lymphomas, and one of Waldenström's macroglobullnemia (immunoglobulin M [IgM], kappa type) complicated by adenocarcinoma of the lung. In the next generation, one member died of Hodgkin's disease; four of nine healthy persons had impaired lymphocyte transformation in vitro in response to phytohemagglutinin-P (PHA-P), and three of these had polyclonal elevations in IgM levels. Subsequent to these observations, adenocarcinoma of the lung developed in one woman with immune defects, and lymphocytic leukemia developed in her 3 year old grandson. The findings in this family point to a genetically regulated defect of immunity expressed as diverse lymphoproliferative disorders, including polyclonal and monoclonal IgM gammopathies. The occurrence of pulmonary adenocarcinoma in two members suggests genetic and immunologic determinants in these instances.     

Malignant Evolution of Asymptomatic Monoclonal IgM after Seven and Fifteen Years in Two Siblings of a Patient with Waldenström's Macroglobulinemia

ABSTRACT. This paper reports a rare familial occurrence of Waldenström's macroglobulinemia (WM) in siblings (two brothers and one sister). Examination of the siblings of a patient suffering from WM in 1965 showed that a brother and a sister had an “asymptomatic” monoclonal IgM in their sera without clinical or hematological features. Follow-up demonstrated a malignant transformation into WM after 7 years in the brother and after 15 years in the sister. This unusual incidence makes the true existence of asymptomatic gammopathies of IgM class questionable.     

Sjögren syndrome associated with multiple myeloma of the IgA κ-type

We report a case of a 62-year-old female patient with Sjögren syndrome (SS) who developed multiple myeloma (MM) of the IgA κ-type. In 1986, the patient was admitted to our hospital with a facial rash, keratoconjunctivitis sicca, and xerostomia. She was diagnosed as having discoid lupus erythematosus (DLE) and SS. She was treated with bromhexine hydrochloride for SS and with topical fluorinated steroid for DLE. In 1992, she developed compression fractures of the lumbar vertebrae and was readmitted to our hospital. DLE was not recognized. Laboratory findings revealed IgA 2046 mg/dl, IgG 529 mg/dl, and IgM 21 mg/dl. Anti-SS-A antibody was 1 : 32 and anti-SS-B antibody was 1 : 2. M protein of IgA κ was demonstrated by immunoelectrophoresis. Aspiration biopsy of the bone marrow revealed 20.2% plasma cells. A bone scintigram demonstrated many hot spots at the cervical and lumbar vertebrae. She was diagnosed as having SS and MM of the IgA κ-type. After chemotherapy for MM, the percentage of plasma cells in the bone marrow and the concentration of serum IgA decreased to 6.2% and 532 mg/dl, respectively. SS is frequently associated with benign monoclonal gammopathy or lymphoproliferative disorders, especially Waldenström's macroglobulinemia or malignant lymphoma. Although benign monoclonal gammopathy has frequently been observed in patients with SS, SS associated with MM is extremely rare.     

Double gammopathies. Incidence and characteristics (83 cases). Clinical correlations (62 cases)

Within 13 years (1969-1981) 1 339 monoclonal gammopathies were recognized and fully investigated. The following were remarked: the high frequency of "double gammopathies": 6,2 p. 100 (83 cases); the high frequency of the association of (G + M): 52,4 p. 100 of double gammopathies of different classes (63 cases); both of these probably in relation of the abnormal frequency of the IgM-gammopathies (35,4 p. 100 in the Anjou province). Clinical correlation of double gammopathies do not appear to be different from those noticed in monoclonal gammopathies. In the 62 cases of obvious diagnosis, chronic lymphoproliferative diseases are the more frequent: 32,3 p. 100, followed by 17,7 p. 100 of multiple myelomas, 14,5 p. 100 of carcinoma, 4,9 p. 100 of other malignant diseases, 22,6 p. 100 of benign disorders and 8 p. 100 of idiopathic cases. In all the cases of multiple myeloma and Waldenstr?m's macroglobulinemia, a reciprocal correlation is remarked between predominant monoclonal immunoglobulin and the diagnosis. In all the other diseases (except for 3 cases) one of the two monoclonal components is an IgM.     

Systemic vasculitis in association with human immunodeficiency virus infection

Fourteen cases of vasculitis associated with human immunodeficiency virus infection have thus far been described. Five of these cases may be classified as angiocentric immunoproliferative disorders, including benign lymphocytic angiitis, lymphomatoid granulomatosis, and angiocentric lymphoma. We report a case of benign lymphocytic angiitis of T cell lineage. Extensive studies found no evidence of viral antigens in the inflammatory infiltrates, and immunologic evaluation of the pathologic lesions revealed the infiltrating cells to be predominantly CD3+, CD8+, CD4-. A significant number of these lymphocytes demonstrated a deletion of T cell antigen receptor determinants. We believe that in certain cases of human immunodeficiency virus disease, there occurs a spectrum of lymphoproliferative disorders with angiocentric features that lead to the clinical picture of systemic necrotizing vasculitis. Clinicians should be aware of this association.     

Large quantities of low molecular weight IgM in mixed cryoglobulinaemia.

Low molecular weight (LMW) IgM is the monomeric subunit of pentameric IgM. It was not found in the sera of 20 healthy subjects but was detected in all six patients with mixed cryoglobulinaemia with a mean value of 1.4 g/l, representing 34% of the total IgM. In three of four patients studied LMW IgM was monoclonal and of the same light chain type (kappa) as the pentameric monoclonal IgM rheumatoid factor (RF) observed in the cryoprecipitate. LMW IgM was proportionately under-represented, however, in the cryoprecipitate compared with the corresponding serum, possibly because of the lower valency of the LMW molecule. Immunoblot analysis of sera showed the presence of other oligomers of IgM in addition to monomeric IgM, suggesting that a disorder of IgM assembly was responsible for its occurrence, and this was supported by the secretion of large proportions of LMW IgM in vitro by peripheral blood mononuclear cells (PBMC) from one patient with this disorder but not from healthy controls. In conclusion, the occurrence of large quantities of monoclonal LMW IgM in mixed cryoglobulinaemia was observed, and it is suggested that this is unlikely to have a direct pathogenic significance. It is postulated that its presence reflects a disturbance of assembly of the monomeric IgM subunits that occurs during the polymerization of the pentameric molecule.