To the Editor,
Heavy chain disease (HCD) is a rare lymphoproliferative disorder of plasma cells, described for the first time in 1964 by Franklin , characterized by production of incomplete monoclonal immunoglobulin heavy chains without associated light chains .
HCDs involve the three main immunoglobulin classes, the most common α-HCD, γ- and μ-HCD. Originally, Franklin’s disease (γ-HCD) was considered to be a lymphoproliferative disease, however, HCDs have variable clinical presentations and different histopathologic features. γ-HCD has been reported to occur equally in men and women, but in a recently reported series there was a clear female predominance . The diagnosis of γ-HCD requires the evidence of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine . These alterations typically result in loss of a large portion of the constant-1 (CH1) domain of the immunoglobulin heavy chain molecule responsible for light chain binding. In the absence of an associated light chain, the CH1 domain of the normal heavy chain binds to heat-shock protein 78 (hsp78) and undergoes degradation in the proteasome compartment of cells; normal heavy chains unassociated with light chains are therefore never detected in serum or urine. In the HCDs, the altered structure of the CH1 domain prevents the heavy chain from binding both the light chain and hsp78, thereby allowing it to bypass degradation by the proteasome and be secreted into the serum or urine . In addition, the altered heavy chain may function as part of the transmembrane B-cell receptor and facilitate antigen-independent aggregation and downstream signaling by the receptor, thereby conferring a growth advantage to the heavy-chain expressing cells . The clinical course of γ-HCD is extremely variable and ranges from an asymptomatic benign, or stable process to a rapidly progressive neoplasm leading to mortality within a few weeks. Prognosis is variable and the mean survival time has been reported to be 7.4 years (range, 1 month to >21 years) [3, 6].
We describe three cases of γ-HCD associated with chronic lymphocytic leukemia, peripheral T-cell lymphoma, not otherwise specified and small cell lung carcinoma, respectively. All three patients were male. The Ethics Committee of the “Policlinico Universitario A. Gemelli, Roma” approved this study.
The first case is a 75-year-old man, who was admitted to the hospital for a 2-months history of progressive worsening of neurological symptoms, i.e. vision changes, dysphagia and amnesia. He had surgery for adenocarcinoma of the rectum 6 years before, with local recurrence after 5 years. In the last hospital stay before admission, he was treated with radiotherapy and chemotherapy with 5-fluorouracil. Total-body computed tomography scanning was negative for local, nodal or other organ involvement. Franklin’s disease was diagnosed 2 years before with no underlying lymphoproliferative or autoimmune disorder. Laboratory tests, including blood leukocyte count and CD4+ to CD8+ cells ratio, were within normal range, but a severe deficiency of serum IgA (0.39 g/L, 0.70–4.00) and IgM (<0.19 g/L, 0.40–2.30) concentrations and a mild IgG deficiency (6.45 g/L, 7.00–16.00) were found. Serum electrophoresis was negative but serum immunofixation electrophoresis (IFE) showed two γ-heavy chain monoclonal components (MCs) migrating in β, not associated with corresponding light chain, and one MC in the γ-region (small MC IgMλ); urine IFE interestingly showed a typical pattern with a broad band of incomplete γ-heavy chain (Figure 1) .
The second case is a 57-year-old man, negative for human immunodeficiency virus antibodies and hepatitis virus, admitted to the hospital for suspected lymphoproliferative disease. At admission, laboratory tests showed high levels of alanine-transferase (150 IU/L, 7–45), total bilirubin (46.17 μmol/L, 5.13–20.52), γ-glutamyl transferase (205 IU/L 8–61), C-reactive protein (50.4 mg/L <5.0) and β2-microglobulin (4.7 mg/L, 0.0–3.2). Moreover the patient had anemia (74 g/L), leucopenia (1.79×109/L) and thrombocytopenia (36×109/L). Serum electrophoresis displayed an alteration in the γ-region confirmed by IFE that showed a γ-heavy chain MC, not associated with corresponding light chains; urine IFE showed a typical pattern with a broad band of incomplete γ-heavy chains (Figure 1). Normal serum IgA (2.23 g/L) and abnormal IgG concentrations (30.4 g/L), and an IgM deficiency (0.24 g/L) were found. The conditions of the patient rapidly deteriorated. Autopsy documented a peripheral T-Cell lymphoma.
The third case is a 75-year-old man, with hepatosplenomegaly. A bone marrow biopsy revealed a highly increased cellularity, a low percentage of neutrophil granulocytes (11.0%) and erythrocytes (6%, RI 15%–35%) and a high percentage of lymphocytes (83%, RI 3%–15%). Clinical chemistry testing showed elevated β2-microglobulin (12 mg/L) and lactate dehydrogenase (LDH) (1766 IU/L) values. Immunophenotyping of the lymphocytes resulted in the diagnosis of chronic lymphocytic leukemia: typical expression of monotypic surface proteins CD5 (15% of proliferating lymphocytes), CD19 (53%), CD23 (52%), and CD38 (15%), with the evidence of a B-cell lymphoproliferative disorder presenting a λ clone in 15% of the mononuclear cells. The search for monoclonal proteins showed the presence in serum of an abnormal broad band of γ-heavy chains not associated with a corresponding light chain in the β-region. Urine IFE showed the same pattern (Figure 1). Four months later, blood cell count showed macrocytic anemia (hemoglobin 110 g/L, hematocrit 33.9%) and leukocytosis.
Diagnosis of HCD is commonly confirmed by the evidence of serum unbound heavy chain on IFE performed with anti-Fab and anti-Fc antisera or by immunoselection methods. Use of IFE simplifies the diagnostic procedure but offers only indirect evidence for the presence of a free heavy chain as some light-chain molecules in multiple myeloma (IgA and IgD) may not react with antibodies to form precipitates because the antigenic determinants are hidden . The absence of a light-chain precipitin band may also be a prozone phenomenon, attributable to either a high antigen concentration or low antibody titers. In addition, light-chain antisera frequently have lower avidity and affinity than heavy-chain antisera. Two methods have been used to confirm the presence of a monoclonal heavy chain. Kaleta et al.  described utility of a nephelometric assay to identify truncated IgG and by indirect measurement calculated γ-HCD with (Gκ+Gλ)/IgG total ratio. Luraschi et al.  proposed capillary electrophoresis analysis coupled with immunosubtraction to detect and characterize low-concentration free heavy chains in serum.
Our findings show how HCD diagnosis can be established by serum or urine IFE using specific antisera in combination with an immunoselection technique. 10 μL serum and urine are incubated with 200 μL of a mixture anti-κ (100 μL) and λ (100 μL) bound antiserum (polyclonal rabbit anti-human κ and λ light chains, DAKO-Agilent Technologies, USA) overnight at 4°C, independent of the concentration of HC; subsequently they are centrifuged at 12,000 rpm in an ultra-centrifuge. To make sure all the immunoglobulins, except for the possible free heavy chain in the patient’s serum, are precipitated by the light-chain antisera, a control sera with total immunoglobulin bound was applied as a specimen with suspected heavy-chain disease. All samples are analyzed using commercially available IFE (Sebia, France and Interlab, Italy). Serum and urine supernatant immunofixed with anti-κ (bound), anti-λ (bound) and anti-γ confirm the presence of free heavy chains not reacting during antiserum incubation (Figure 1). This modified immunoselection technique is simple and convenient as commercially available IFE and light chain antiserum can be used. Unfortunately, it requires an overnight reaction. As HCDs are rare, this procedure is only performed in a few cases but the results appear to be specific.
Harris NL, Isaacson PG, Grogan TM, Jaffe ES. Heavy chain diseases. In: Swerdlow SH, Campo E, Harris NL, editors. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC Press, 2008:196–9. Google Scholar
Zhang L, Sotomayor EM, Papenhausen PR, Shao H, Moscinski LC, Sandin RL, et al. Unusual concurrence of T-cell large granular lymphocytic leukemia with Franklin disease (gamma heavy chain disease) manifested with massive splenomegaly. Leuk Lymphoma 2013;54:205–8. Web of ScienceCrossrefPubMedGoogle Scholar
Tasca G, Iorio R, Basile U, Lauriola L, Tartaglione R, Mirabella M, et al. Progressive multifocal leukoencephalopathy in a patient with Franklin disease and hypogammaglobulinemia. J Neurol Sci 2009;284:203–4. CrossrefWeb of ScienceGoogle Scholar
Kaleta E, Kyle R, Clark R, Katzmann J. Analysis of patients with γ-heavy chain disease by the heavy/light chain and free light chain assays. Clin Chem Lab Med 2014;52: 665–9. Web of SciencePubMedGoogle Scholar
About the article
Published Online: 2017-06-29
Published in Print: 2017-11-27
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.