Mu Heavy Chain Disease 

Updated: Nov 16, 2019
Author: Jessica Katz, MD, PhD, FACP; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Heavy chain diseases (HCDs) are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains: alpha, gamma, or mu. The clinical manifestations vary with the heavy chain isotype and range from an asymptomatic presentation to aggressive lymphoma.[1]

HCDs characteristically involve production of a mutated immunoglobulin heavy chain that is incapable of either partnering with light chains to form a complete immunoglobulin molecule or incapable of being degraded by a proteasome. Their defining feature is the presence of an abnormal heavy chain in the urine and/or serum without an associated light chain.[2]

Normal immunoglobulin molecules are symmetrical and consist of 2 pairs of polypeptide chains, designated the light and heavy chains, which are interconnected by disulfide bonds. The heavy chains are the larger polypeptide subunits; they are specific and distinctive structures that distinguish the major classes of immunoglobulins.

B cell proliferative disorders that are characterized by an anomalous serum, and sometimes urinary, protein (from free light chain) that is immunochemically related to the Fc fragment of the immunoglobulin molecule are known as HCDs. The isotype of the mutated immunoglobulin heavy chain (α, γ, or µ) determines the nomenclature of HCD subtypes. When the anomalous protein structurally resembles the heavy chain fragment of the immunoglobulin M (IgM) molecule, it is designated as mu-HCD. Ballard and colleagues first described this entity in 1970.[3]

This article focuses on mu-HCD; however, other heavy chain diseases are described (eg, see Heavy Chain Disease, Gamma).

Pathophysiology

The pathogenesis of mu-HCD is not completely understood. No viruses, chemical, physical, or genetic factors have been identified.[4] Most patients have a concurrent lymphoproliferative disorder resembling chronic lymphocytic leukemia/ small lymphocytic leukemia. There are also single reports of mu-HCD associated with myelodysplastic syndrome, amyloidosis, and diffuse large B cell lymphoma.

In mu-HCD the altered heavy chains contain deletions, insertions, and point mutations that are acquired during somatic hypermutation. These alterations typically result in loss of a large portion of the constant-1 (CH1) domain of the heavy chain, which is responsible for light chain binding. Additionally, this abnormal domain on the heavy chain is also unable to bind to the heat-shock protein 78 (hsp78), which would otherwise promote proteosomal degradation of the aberrant heavy chain. The heavy chain thus bypasses degradation and is instead secreted into the serum, where it can be detected.[2, 5, 6]

Epidemiology

Mu-HCD is the least common of the HCDs. Fewer than 50 cases have been reported in the literature.[7] However, many cases likely have not been reported, especially in the past decade. Given the difficulty in diagnosing this disorder, most reports are from the United States, Western Europe, and Scandinavia.

Mu-HCD is predominantly reported in white men in the 5th and 6th decades of life. However, reports also exist in black and Asian patients, with ages ranging from 15-80 years.

Prognosis

The course of mu-HCD is variable. Survival ranges from a few months to several years, with a median survival of 24 months in well-studied cases.[8] Possible complications include pathologic fracture secondary to osteolytic lesions. Renal insufficiency occasionally is associated with mu-HCD. Etiologies include cast glomerulopathy, nodular glomerulosclerosis, and amyloidosis. Cytopenias requiring transfusion are possible in advanced disease.

 

Presentation

History

The presenting signs and symptoms of mu heavy chain disease (mu-HCD) are generally secondary to the associated lymphoproliferative disorder, such as chronic lymphocytic leukemia (CLL), lymphoproliferative disorder, or myeloma. Patients may show evidence of systemic disease, such as weight loss, fever, night sweats, and recurrent infection.[9]

Initial reported cases of mu-HCD had a clinical picture consistent with CLL; however, with better diagnostic procedures and a high index of suspicion, the defining protein abnormality has been noted in a broader range of clinical settings. Currently, only one third of patients with mu-HCD appear to have CLL. In 150 consecutive patients with CLL, thorough investigation of serum proteins failed to identify a single instance of mu-HCD, which suggests an incidence of less than 1% in this population.[10]

Other clinical presentations vary, one of which may be essential monoclonal gammopathy with no clinical symptoms of B-cell lymphoma (20%).[11] In 10% of cases, an intact IgM protein was simultaneously detected in the serum. Another 10% of cases were associated with clinical multiple myeloma or plasmacytoma. Mu-HCD is also reported to be associated with systemic amyloidosis in rare instances.[9]

Physical Examination

Physical examination findings are variable in patients with mu-HCD, but may include the following:

  • Splenomegaly is almost universal.
  • Hepatomegaly is noted in 75% of cases.
  • Peripheral lymphadenopathy is present in 40% of cases.
  • Bone pain from lytic lesions is present in 40% of cases.
  • Pallor may be noted if significant anemia is present, which is usually observed only in advanced disease.

 

 

DDx

 

Workup

Laboratory Studies

Laboratory studies should include the following:

  • Complete blood cell count with differential
  • Renal function studies (ie, blood urea nitrogen [BUN] and creatinine)
  • Liver function studies (ie, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase)
  • Calcium levels
  • Beta-2 microglobulin values
  • Serum protein electrophoresis (SPEP) and immunofixation
  • Urine protein electrophoresis (UPEP) and immunofixation

Anemia is the most common lab finding in mu-HCD, followed by thrombocytopenia and lymphocytosis. Renal complications are infrequent, with cast nephropathy and renal failure reported in a single case.[12] Two patients, including the first reported case, have had amyloidosis with renal impairment.[9]

The diagnosis of mu-HCD often can be difficult to establish. Consulting a hematopathologist is appropriate to facilitate an appropriate and adequate workup.

Electrophoresis and Immunofixation

Serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) and immunofixation are essential tests. While SPEP is typically normal, immunofixation detects monoclonal mu IgH in polymers of different sizes without an associated light chain.[7] Performing a combination of electrophoretic, immunoelectrophoretic, and immunofixation techniques can help establish the diagnosis.

When developed with specific anti-heavy and anti-light sera, the immunoelectrophoretic pattern reveals a heavy chain–specific band that does not react with either anti-kappa or anti-lambda antisera on immunofixation. IgM M-proteins sometimes do not react with certain anti–light chain (kappa or lambda) sera. In these cases, isolating the monoclonal proteins from the serum, treating them with reducing agents to cleave disulfide bonds, and subjecting them to gel electrophoresis to determine the size of the immunoglobulin heavy chain polypeptide may be necessary to confirm mu-HCD.

More commonly, the proteins are present in smaller amounts and show a heterogeneous pattern on electrophoresis. One study reported a detectable monoclonal spike in 8 of 19 patients, and 3 of 28 patients had a biclonal gammopathy.  Immunofixation with a panel of anti-heavy/anti-light antibodies can strongly suggest the diagnosis.[11]

Urinary excretion of the mu fragment has been noted in very few patients, presumably because the polymers of the carboxy-terminal mu fragment are too large to be filtered by intact renal glomeruli. Monoclonal light chains have been found in the urine in two thirds of cases. Thus, Bence Jones (free light chain) proteinuria is common in patients with this disorder. Nonetheless, renal complications are infrequent. Immunoglobulin light chains capable of producing amyloid are found in approximately 12% of cases, an incidence that is similar to that observed in patients with multiple myeloma.

Maisnar et al presented a case study in which they used immunofixation electrophoresis, capillary zone electrophoresis with immunotyping, and high-resolution two-dimensional electrophoresis to detect and characterize monoclonal mu-heavy chains in a patient with multiple malignancies.[13] The investigators were able to determine the molecular weight of the mu heavy chains; their patient's abnormally high serum protein concentration, 38 g/L, appears to be the highest reported in the literature.[13]

Procedures

Almost all patients should undergo bone marrow aspiration and biopsy. Certain histologic features, as outlined below, may aid in making the diagnosis of mu-HCD.

When mu-HCD is not considered, based on the patient's presentation (as is commonly the case), biopsy of the appropriate involved area (eg, lymph node mass) is required to establish the diagnosis of a lymphoproliferative disorder.

Imaging Studies

No definitive guidelines are available regarding the extent of imaging studies that should be performed for suspected mu-HCD. Performing a chest radiograph is reasonable, and a skeletal survey is considered essential given the fact that 40% of patients present with osteolytic lesions.

Obtaining computed tomography (CT) scans of the thorax and abdomen is appropriate because hepatosplenomegaly and lymphadenopathy are common. CT scan findings help to objectively quantify disease and are useful for assessing response to therapy.

Histologic Findings

Marrow involvement is characterized by infiltration with lymphocytes and plasma cells. Cells that often are described as lymphocytic plasmacytes or plasmacytoid lymphocytes are prominent. Although the marrow of almost all patients contains the multivacuolated plasma cells described in the index case, the vacuoles are not universally apparent. The identification of these vacuoles sometimes offers a clue to the diagnosis, which requires confirmation by appropriate electrophoretic and immunoelectrophoretic studies.[14]

On immunophenotypic analysis, associated cells lack light chain expression but are positive for the following[8] :

  • CD19
  • CD20
  • CD38
  • Cytoplasmic IgM
  • CD5 (rare)

Staging

Given the rarity of mu-HCD, a clinical staging system has not been developed. Accompanying lymphoproliferative disorders such as CLL, non-Hodgkin lymphoma, and multiple myeloma should be appropriately staged.

 

Treatment

Approach Considerations

Because of the paucity of cases, no standard treatment has been established for mu heavy chain disease (mu-HCD). Currently, the finding of a mu-HCD protein in the serum of an apparently healthy patient should be considered a monoclonal gammopathy of undetermined significance, and the patient should be monitored closely for the development of a symptomatic lymphoproliferative disorder.

Once a lymphoproliferative disorder develops, chemotherapeutic agents are used as appropriate for the patient's disorder, stage, and clinical situation (eg, combinations of proteasome inhibitors, steroids, and immunomodulatory agents for multiple myeloma; purine analogs, alkylating agents, and monoclonal antibodies for chronic lymphocytic leukemia). Successful treatment with fludarabine has been reported in two cases.[15] The details of some of these therapies can be found in Chronic Lymphocytic Leukemia and Multiple Myeloma.

If no overt lymphoproliferative disorder is found, the patient should be evaluated every few months to assess the abnormal protein. Reasonable follow-up intervals are every 3 months in the first year following diagnosis, every 4 months for the next year, and every 6 months thereafter. The patient should be evaluated earlier if symptoms occur. If the patient is symptomatic in any way, then radiologic assessment and other diagnostic procedures for lymphoproliferative disorders are essential.

Surgical care usually is not required, although special circumstances may require surgery (eg, surgery needed to fix a pathologic fracture). Occasionally, consultation with a radiation oncologist may be required to treat a pathologic fracture site after surgical correction or to prophylactically treat a site of bony involvement to prevent a pathologic fracture.