Chapter 110: Heavy-Chain Disease

γ-Heavy-chain disease (HCD) is not a specific cytopathologic process; rather, it is a biochemical expression of a mutant B-cell clone. The disease should be considered a serologically determined entity with a variety of clinical and histopathologic features. It is defined by the recognition of monoclonal deleted gamma (γ) chains devoid of light chains.¹

The first case of γ-HCD was described in 1964 by Franklin and colleagues,² who observed a homogeneous band between γ- and β-globulin in an African American patient with generalized lymphadenopathy. Comparison of the proteins in the urine to those in the serum showed that they were the same, a suggestion of the presence of a low-molecular-weight serum γ-globulin, which then was shown to be a fragment of a γ-heavy chain (HC). Since this first description, more than 130 patients with γ-HCD have been described in the literature.^3,4,5

γ-HCD has been described throughout the world. Although initially γ-HCD was reported to occur equally in men and women,⁴ there was a clear predominance of women in a more recent series of 23 patients.⁵ The median age at diagnosis in that series was 68 years (range: 42 to 87 years).

The etiology of γ-HCD is unknown.

Originally, γ-HCD was considered to be a lymphomatous illness. However, γ-HCD has various clinical and pathologic features that can be divided into three broad categories, as described below.

DISSEMINATED LYMPHOPROLIFERATIVE DISEASE

Disseminated lymphoproliferative disease is present in most patients at the time of diagnosis, and various series have reported it in 57 percent to 66 percent of patients.^4,5,6 In two different series,^4,5 lymphadenopathy was present in 56 percent and 62 percent of patients, splenomegaly in 38 percent and 52 percent, and hepatomegaly in 8 percent and 37 percent at the time of diagnosis.

LOCALIZED PROLIFERATIVE DISEASE

In approximately 25 percent of patients, the lymphoproliferative process is localized, which may be extramedullary or may involve only the marrow.^4,5 Cutaneous involvement is the most frequently reported extramedullary presentation.^4,5 Patients may present with extramedullary plasmacytoma of the thyroid or parotid gland or an oropharyngeal mass⁵ and hypertrophic spinal pachymeningitis.⁷

NO APPARENT PROLIFERATIVE DISEASE

A proliferative lymphoplasmacytic disease is not apparent in 9 percent to 17 percent of patients. In most of these patients, an underlying autoimmune disorder has been reported. Autoimmune disorders with or without underlying lymphoid proliferation include rheumatoid arthritis, autoimmune cytopenias, systemic lupus erythematosus, Sjögren syndrome, myasthenia gravis, thyroiditis, and vasculitis.⁵

MOLECULAR BIOLOGY AND GENETICS

Most γ-HCD proteins are dimers of truncated HCs devoid of light chains. The molecular weight of the monomeric unit varies from 27,000 to 49,000. The length of the truncated γ chain varies, but usually it is one-half to three-fourths the length of the normal γ chain. Structural analysis of the defective monoclonal γ-HC of 23 patients with γ-HCD showed several characteristic features (Fig. 110–1). The proteins usually begin with a normal variable region. In most cases, this sequence is short and interrupted by a large deletion encompassing the remainder of the variable region, although four of the HCs shown in Fig. 110–1 appear to have retained most or all of their variable (V), diversity (D), and joining (J) sequences. In all γ-HCD proteins, the entire constant region 1 (C_H1) domain is also deleted, with normal sequence beginning at the hinge or occasionally at the C_H2 domain. C_H1 is responsible for light-chain binding. In the absence of an associated light chain, the C_H1 domain binds to heat shock protein 78 (HC binding protein), and the HC undergoes proteasomal degradation rather than secretion.

In two cases of γ-HCD (OMM and RIV), genomic sequence data are available (Fig. 110–2). The presence of large deletions in the switch/C_H1 regions of these two γ-HCD genes explains why the corresponding HCD proteins lack C_H1. Because the normal C_H1 acceptor splice site is deleted, the donor splice of the leader, or the J region, is spliced directly to the next available functional acceptor splice site at the beginning of the hinge or C_H2 domain.

SERUM AND URINE PROTEIN FINDINGS

The serum protein electrophoretic pattern is extremely variable. A monoclonal peak is detected in 60 percent to 86 percent of patients.^4,5 When present, it is most commonly in the β₁ or β₂ region. The median value of the monoclonal spike at diagnosis in 19 patients was 1.59 g/dL (range: 0.40 to 3.91 g/dL).⁵ The diagnosis is established by immunofixation of the serum and a concentrated urine specimen. A modified immunoselection technique for the diagnosis of HCD has been described.⁸ In one case of γ-HCD, low concentrations of free HCs in serum were detected by capillary zone electrophoresis coupled with immunosubtraction.⁹ A heavy/light chain assay to identify truncated immunoglobulin (Ig) HCs was used on serum samples from 15 patients with known γ-HCD. By this method, 20 percent of these patients were shown to also have small amounts of monoclonal free light chains.¹⁰ The amount of HCD protein in the urine usually is small (<1 g/24 h) but may reach 20 g/24 h. An occasional patient with Bence Jones proteinuria has been described.⁵

No standard has been established to identify the subclass of the HC fragment. In reported cases in which the HC fragment subclass has been studied, different methods have been used, ranging from Ouchterlony in the earlier cases to indirect immunofluorescence staining, immunoblotting, amino acid sequence, immunoselection, and enzyme-linked immunosorbent assay.¹¹ IgG subclass distribution shows a lower-than-expected incidence of IgG₂. The most common subclass is IgG₁, which occurs in 65 percent of cases. IgG₃ has been identified in 27 percent of patients, IgG₄ in 5 percent, and IgG₂ in 3 percent.⁴ Although biclonal gammopathy has been reported in 1 percent to 8 percent of all patients with serum monoclonal components, the association between γ-HCD and another monoclonal protein is much higher. In a series of 23 patients with γ-HCD, 7 percent had an IgM-λ intact monoclonal Ig.⁵ No association between γ-HCD and monoclonal IgA has been described, although the IgG-IgA association was the most frequent in several series of biclonal gammopathies. One patient described in the literature was unique in that the serum contained two deleted γ chains of different subclasses (IgG₁ and IgG₂).¹²

HEMATOLOGIC ABNORMALITIES

Anemia is frequent. It is usually normochromic, normocytic, and moderate. Coombs-positive autoimmune hemolytic anemia has been reported in several cases and may be associated with thrombocytopenia (Evans syndrome). The total and differential leukocyte counts are usually normal. Lymphocytosis may occur, and an occasional patient presents with chronic lymphocytic leukemia. In some cases, rare plasmacytoid lymphocytes or plasma cells have been noted in the blood. Plasma cell leukemia has been reported in two patients.^13,14

Marrow aspirates and biopsy specimens often show an increase of plasma cells, lymphocytes, or plasmacytoid lymphocytes, similar to the marrow findings in Waldenström macroglobulinemia. The typical marrow features of myeloma or chronic lymphocytic leukemia are rare. An unusual concurrence of T-cell large granular lymphocytic leukemia with γ-HCD has been reported.¹⁵ Marrow changes consistent with a myeloproliferative neoplasm have been noted in a few patients.⁵

OTHER FEATURES

Bone lesions are rare in γ-HCD. Cytogenetic studies have seldom been reported. No unique abnormalities or characteristics of lymphoma have been found.

HISTOPATHOLOGY

In contrast to α-HCD, γ-HCD has no consistent morphologic pattern and a variety of underlying lymphoproliferative disorders have been described.¹⁶ The most frequent histopathologic finding is a pleomorphic malignant lymphoplasmacytic proliferation in marrow and lymph nodes. These lymphocytoid plasma cells express pan–B-cell markers and cytoplasmic γ-HC without light chains and are negative for CD5 and CD10.¹⁷

Lymphoma without any consistent morphologic type was diagnosed in 18 (38 percent) of 47 patients in whom lymph nodes were examined. A lymphoplasmacytic proliferation was present in 36 percent and hyperplastic nodes and plasmacytoma in 11 percent each; there was one case of Hodgkin lymphoma and one of probable Hodgkin lymphoma.⁶ Plasmacytic infiltration may be found in the salivary glands or thyroid.^4,5,18

All patients presenting with a lymphoplasmacytic proliferative disorder should be evaluated for γ-HCD.

Because γ-HCD is a heterogeneous condition, the choice of therapy depends on the clinical findings. In an asymptomatic patient with a monoclonal γ-HC, no therapy is indicated. Any associated autoimmune disease should be managed with standard therapy for that specific disease type. In symptomatic patients with a low-grade lymphoplasmacytic malignancy, a trial of chlorambucil may be beneficial. Melphalan and prednisone can be used, if the proliferation is predominantly plasmacytic. A trial of cyclophosphamide, vincristine, and prednisone with or without doxorubicin is reasonable for patients with evidence of a progressive lymphoplasmacytic proliferative process or high-grade lymphoma. One patient achieved a complete response after six courses of fludarabine.¹⁹ Successful treatment of γ-HCD with low-dose etoposide has been reported.²⁰ CD20 expression has been analyzed in only seven cases and was detected in six of the seven, including one in which CD20 expression appeared transient.^5,21,22,23 Rituximab monotherapy was given in two cases, resulting in clinical responses in both.^5,21 In two other cases, a combination of rituximab with chemotherapy had an antitumor effect in lymphoplasmacytic-type γ-HCD.^22,24 In localized extramedullary plasmacytomas treated with radiation⁴ or surgical removal (or both), complete clinical and serologic remission has been achieved.

The clinical course of γ-HCD is extremely variable and ranges from an asymptomatic, benign, or transient process to a rapidly progressive neoplasm leading to death within a few weeks. Patients with the features of only a monoclonal gammopathy have remained clinically well for 2 to 7 years of followup.^5,25 Spontaneous disappearance of the γ-HCD protein has been reported.⁴ The median duration of survival in a series of 23 patients was 7.4 years (range: 1 month to more than 21 years).⁵

The amount of serum γ-HCD protein usually parallels the severity of the associated malignant process. Disappearance of the monoclonal component from serum and urine associated with apparent complete response has been induced by chemotherapy,¹⁹ radiotherapy,⁴ or surgical removal of a localized process. In some instances, however, the γ-HCD protein does not vary in parallel with the associated process, and relapse can occur without the reappearance of the pathologic protein.⁴

α-HCD is a proliferative disorder of B-lymphoid cells involving the IgA secretory immune system, especially the gastrointestinal tract. It is defined by the recognition of internally deleted monoclonal α chains devoid of light chains.

In the first case description of α-HCD, in 1968 by Seligman and colleagues,²⁶ an Arab woman had severe malabsorption resulting from a lymphoplasmacytic infiltrate in the small bowel. Since then, more than 400 cases have been reported.

The majority of reported cases have been from northern Africa, Israel, and surrounding Middle Eastern countries. A common variable for patients with α-HCD is a low socioeconomic status. In a study of the distribution of monoclonal gammopathies in Tunisia published in 1990, 17 percent of 198 cases were attributed to α-HCD.²⁷ In a later study of 270 cases observed between 1992 and 2000 at the university hospital of Sfax in Tunisia, only 2.2 percent were attributed to α-HCD,²⁸ a finding that might be partially explained by improved socioeconomic conditions. Similarly, a persistent decrease in the incidence of immunoproliferative small intestinal disease (IPSID) since 1986 as a result of improving sanitation has been reported from Iran²⁹ and Greece.³⁰ α-HCD has a predilection for young adults. The prevalence of the disease is slightly higher in males than in females.

The cause of α-HCD is unknown. The disease might be considered a model showing the complex interactions of the environment with genetic factors and the infection–immunity–cancer interrelationships originating from the same proliferating clone. Although the mechanisms leading to the development of a clonal population synthesizing the structurally abnormal IgA are still speculative, the lymphoplasmacytic infiltration of the intestinal mucosa is likely a response of the alimentary tract immune system to protracted luminal antigenic stimulation. A causal relationship between infection and pathogenesis is supported by the observation that α-HCD can respond to broad-spectrum antibiotics. Using molecular strategies, Campylobacter jejuni was detected in five of seven patients with α-HCD.³¹ However, no specific microorganism has been found in other clinical studies. The putative agent may be present only at the onset of the disease and absent at diagnosis.

In most cases, patients who have α-HCD present with the digestive form. The disease is characterized by malabsorption manifested by diarrhea, weight loss, and abdominal pain. Ascites, tetany, edema, and clubbing may be present. Hepatosplenomegaly and peripheral lymphadenopathy are infrequent. Fever is uncommon. Amenorrhea, alopecia, and growth retardation in children and adolescents correlate with the duration and the severity of the malabsorptive process. α-HCD may be confined to the respiratory tract, but this is extremely rare, as is a lymphomatous form characterized by generalized lymphadenopathy. α-HCD has been reported in a patient with a goiter from a plasmacytoma of the thyroid³² and in a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin lesions (POEMS).³³

MOLECULAR BIOLOGY AND GENETICS

Most α-HCD proteins consist of multiple polymers. The molecular weight of the basic monomeric unit varies from 29,000 to 34,000. The length of the basic polypeptide subunit differs from patient to patient and in most instances is between one-half and three-fourths that of a normal α chain. Sequence data are available for several α-HCD proteins (Fig. 110–3). In all cases of α-HCD studied, the α-HCD protein belonged to the α₁ subclass. Common features of the defective α chain include deleted V regions, missing C_H1 domains, and the absence of light chains. Most of the proteins have short, non–Ig-related sequences of unknown origin at the amino terminus. The complete sequences of the genes encoding 3 α-HCD proteins are shown in Fig. 110–4. These three genes show striking similarity in their position and extent of the two main deletions, which encompass sequences in the V/J and the switch/C_H1 region.

SERUM, URINE, AND INTESTINAL FLUID PROTEIN FINDINGS

In contrast to other monoclonal gammopathies, the characteristic sharp spike of a monoclonal gammopathy is not found on serum protein electrophoresis in α-HCD. In about half of cases, an abnormal broad band is found in the α₂- or β-globulin region, which is probably related to polymerization of the α chains. In the other half of cases, serum protein electrophoresis shows no evidence of an abnormal protein. Identification of the α-HCD protein depends on immunoselection or immunofixation. The pathologic protein may easily escape detection by immunoelectrophoresis when its serum concentration is low. In most patients, the α-HCD protein can be found in the serum. During the course of the disease, the progressive diminution of mature plasma cells and their replacement by immature immunoblasts likely is followed by a progressive decrease in the serum concentration of α-HCD protein. α-HCD protein hyposecretion also may be found during the early stage of the disease.

In most cases, the α-HCD protein also is found in the jejunal secretions.³⁴ α-HCD protein has been found in the intestinal or gastric fluid in a few cases when it was undetectable in serum and urine. The concentration of α-HCD protein in the urine is low. Bence Jones proteinuria has never been documented.

Synthesis of the α-HCD protein by the proliferating cells has been demonstrated by immunohistochemical or immunocytochemical methods and by biosynthesis studies in vitro.³⁵ These techniques are helpful in the recognition of nonsecreting forms of α-HCD.

HEMATOLOGIC AND METABOLIC ABNORMALITIES

Mild to moderate anemia is often found. Hypokalemia, hypocalcemia, hypomagnesemia, and hypoalbuminemia are common. The intestinal isoenzyme fraction of the alkaline phosphatase level may be increased. Results of tests to indicate malabsorption are usually positive.

IMAGING PROCEDURES

Abnormal radiographic findings of the small intestine include hypertrophic and pseudopolypoid mucosal folds, occasionally associated with strictures and filling defects. The extent of the disease should be evaluated with computed tomography.

ENDOSCOPY

α-HCD intestinal lesions nearly always affect the duodenum and jejunum, making endoscopy with biopsy a useful tool in the evaluation of patients in whom α-HCD is suspected. Several endoscopic patterns have been defined. The infiltrated pattern is the most specific, followed by the nodular pattern. Other primary lesions (ulcerations, mosaic pattern, and mucosal fold thickening alone) are nonspecific.

HISTOPATHOLOGY

In the digestive form of α-HCD, the proliferation involves at least the proximal half of the small intestine and adjacent mesenteric lymph nodes. The whole length of the small bowel, the gastric, and the colorectal mucosae that belong to the IgA secretory system may be involved.

The disease progresses in three histopathologic stages according to Galian and colleagues.³⁶ In stage A, a mature plasmacytic or lymphoplasmacytic infiltration of the mucosal lamina propria is noted. Villous atrophy is variable. Stage B is characterized by the presence of atypical plasmacytic or lymphoplasmacytic cells and more or less atypical immunoblast-like cells extending at least to the submucosa. Subtotal or total villous atrophy is present. Stage C corresponds to an immunoblastic lymphoma. Similar to the changes described in the small intestine, three histologic stages (A, B, C) have been described in the mesenteric lymph nodes. Involvement of liver, spleen, and peripheral lymph nodes is uncommon. The histologic lesions may progress at any given site from stage A to stage B or from stage B to stage C. However, different stages can be found at the same time in different organs or even at different sites in the same organ. Thus, accurate pathologic staging of α-HCD requires a laparotomy with sampling of multiple sites in all patients with α-HCD in whom no stage C lesions are found on peroral biopsy. This recommendation is based on the observation that mesenteric lymph nodes may harbor malignant lymphoma when the intestinal mucosa reveals only a benign-appearing cellular infiltrate that one might be tempted to treat with antibiotics alone.³⁷ A staging system based on anatomical spread of the disease, which is complementary to the Galian staging system has been published;³⁸ however, most physicians use the Galian staging system for determining prognosis and therapeutic strategies.

In the past, confusion existed over whether Mediterranean lymphoma and α-HCD were different conditions. In 1976, a consensus panel concluded that α-HCD and Mediterranean lymphoma constitute a spectrum of disease, and the term immunoproliferative small intestinal disease (IPSID) came into use. This term is applied to small intestinal lesions whose pathologic features are identical to those of α-HCD, regardless of the type of Ig synthesized.^34,39 The pattern of α-HCD pathologic lesions often includes clear lymphoepithelial lesions composed of centrocytic-like cells. This indicates that α-HCD can be considered a subtype of lymphoma arising from mucosa-associated lymph node tissue.⁴⁰ The pathologic changes in the few cases of the respiratory form of α-HCD are poorly documented. In a case of the lymph node or lymphomatous form, lymph node biopsy showed diffuse plasmacytic lymphoma.

CYTOGENETICS

Cytogenetic abnormalities have been found in the lymphoid cells of patients with α-HCD. The clonal proliferation in this disease appears to be associated with frequent alterations of chromosome 14 at band q32 resulting from translocations that differ from those observed in the vast majority of other lymphomas. Abnormal karyotypes were reported in three of four patients.⁴¹ Two patients had a rearrangement of 14q32 resulting from a t(9;14)(p11;q32) and a t(2;14)(p12;q32). Cloning and sequencing of the der(14) breakpoint of a chromosome translocation involving the 14q32 Ig locus in 1 of these patients suggested that the translocation originated from a local pairing of the two chromosomes, 9 and 14.⁴² One case showed complex rearrangements, including t(5;9). No abnormalities were found in the intestinal tumor of the fourth case with immunoblastic lymphoma.

The digestive form of α-HCD must be differentiated from lymphoma, although this is an uncommon diagnosis in the age range typical of α-HCD. Other causes of malabsorption need to be considered, especially celiac disease. Enteric presentation of γ-HCD, variable immunodeficiency, and acquired immunodeficiency syndrome with clinicopathologic features simulating IPSID should be excluded.

Patients with stage A lesions limited to the bowel and to the mesenteric lymph nodes should be treated initially with oral antibiotics. In the absence of a documented parasite, tetracycline, metronidazole, or ampicillin is appropriate. Patients with stage B or C lesions or stage A lesions without improvement after a 6-month course of antibiotic treatment should be given chemotherapy. The treatment regimens are those commonly used to treat lymphoma. There have been few controlled clinical trials. In a prospective randomized study, a doxorubicin-based regimen (cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) provided a higher response rate than a non–doxorubicin-containing protocol (cyclophosphamide, vincristine, procarbazine, and prednisone) or total abdominal irradiation.⁴³ Similar results were noted in a retrospective study.⁴⁴ Good results have been reported with cyclophosphamide, doxorubicin, teniposide, and prednisone, sometimes alternating with bleomycin, vinblastine, and doxorubicin⁴⁵ and with cyclophosphamide, epidoxorubicin, vincristine, prednisolone, ifosfamide, methotrexate, etoposide (VP-16), and dexamethasone.⁴⁶ Surgical resection should be considered for focal or bulky transmural lymphomatous tumors and extramedullary plasmacytoma. Autologous hematopoietic stem cell transplantation has been recommended for patients with advanced or refractory disease,³⁴ but to our knowledge there are no reports in the literature demonstrating the usefulness of this approach. Previous trials have not incorporated immunotherapy with rituximab, an anti-CD20 monoclonal antibody, in the management of IPSID. As expected, the centrocyte-like cells are CD20-positive, but the plasma cells are not. In light of the extreme plasma cell differentiation and the plasmacytic nature of large-cell IPSID lymphoma, there is interest in investigating the value of treating patients with IPSID with the novel agents (thalidomide, lenalidomide, bortezomib, pomalidomide, or carfilzomib).

The course of α-HCD is variable but generally progressive in the absence of therapy. Followup should include a periodic search for α-HCD protein in serum and urine and, if negative, in the intestinal secretions. Bowel radiography, ultrasonography, and esophagogastroduodenojejunal endoscopy should be performed. A second-look laparotomy may be necessary.³⁴ Relapses may occur after treatment at any stage of the disease. The long-term prognosis for patients with α-HCD remains imprecise because of the lack of large series with prolonged followup. In a small prospective Tunisian study,⁴⁵ including eight patients with stage A disease and 15 with stages B and C, the survival of the total group was 90 percent at 2 years. A series from Turkey⁴⁷ reported 5-year treatment results of 23 patients with IPSID, including five with secretion of α chains. In patients with stage A disease, tetracycline yielded a 71 percent complete response. The 5-year overall survival rate for the entire group was 70 percent. However, the median overall survival for 3 patients with immunoblastic lymphoma was only 7 months.

Thirteen patients were studied who had IPSID associated with α-HCD.⁴⁸ Six patients, two with high-grade lymphoma and four with low-grade disease, received chemotherapy or radiotherapy or both. One patient died at 76 months, and five were alive at an average of 92 months. Five patients with low-grade disease received conservative therapy (antibiotics and in some cases prednisone). All five patients were alive at an average of 40 months after presentation. Three of these five patients achieved remission at 5, 6, and 27 months. Two of the five patients had persistent disease at 20 and 25 months. Two patients did not receive treatment and died of high-grade lymphoma.

Another study⁴⁹ described six patients who had α-HCD with lymphoma. All patients responded poorly to chemotherapy; the median duration of survival was 10.5 months.

A subsequent study⁵⁰ described 12 patients with secretory and nonsecretory IPSID. Six patients presented with stage A disease. Four patients responded to antibiotic or glucocorticoid therapy. In two patients, stage A disease evolved into stage C. Three patients presented with stage B disease. Two of these patients responded completely to chemotherapy, and the third refused treatment and died after 16 months. Three patients with stage C disease at diagnosis received aggressive combination chemotherapy and remained in complete remission with a median followup of 2.2 years.

Preliminary results suggest that flow cytometric analysis of S-phase fraction⁵¹ and certain immunomarkers, such as syndecan, Bcl6, and p53,⁵² may be useful prognostic indicators in the clinical management of patients with IPSID. Patients with a poor prognosis have a higher fraction of cells in S phase, lower syndecan-1 expression, and higher Bcl6 expression than those with a good prognosis.

μ-HCD is a proliferative disorder of B lymphocytes defined by the recognition of monoclonal deleted μ-HCs. In the first reported case, in 1969 by Forte and colleagues,⁵³ the patient had chronic lymphocytic leukemia. Since then, approximately 34 additional cases have been reported.^54,55,56,57

μ-HCD is extremely rare. In a series of 27 patients, the majority were white (76 percent) and male (55 percent). The median age at diagnosis in 27 patients was 57.5 years (range: 15 to 80 years).⁵⁴

The cause of μ-HCD is unknown.

The most common presenting symptoms of patients with μ-HCD are those of a lymphoproliferative malignancy. An associated lymphoplasmacytic proliferative disorder was noted in 22 of 27 patients at some time during the disease and designated as chronic lymphocytic leukemia, lymphoma, Waldenström macroglobulinemia, or myeloma.⁵⁴ μ-HCD protein has been described in one patient each with systemic lupus erythematosus, hepatic cirrhosis, hepatosplenomegaly with ascites, pulmonary infection, splenomegaly with pancytopenia,⁵⁴ and myelodysplasia.⁵⁵ Three cases of μ-HCD associated with amyloidosis have been reported.⁵⁸

Splenomegaly and hepatomegaly are common in μ-HCD and were noted in 21 of 22 and 15 of 21 patients, respectively.⁵⁴ Peripheral lymphadenopathy was described in 10 of 25 patients.⁵⁴

MOLECULAR BIOLOGY AND GENETICS

The molecular weight of the μ-HCD protein determined in eight patients ranged from 26,500 to 158,000. The higher molecular weights are thought to be the result of polymerization of the μ-chain fragments. The μ-HCD fragments from 6 patients were subjected to detailed chemical analysis. Figure 110–5 depicts the structure of these six μ-HCD proteins compared with that of normal μ-HC. The V_H domain is absent in all cases. The normal sequence began with C_H1 in three cases, C_H2 in two cases, and C_H3 in one case. There are sequence data for only 1 gene coding for a μ-HCD protein (Fig. 110–6).

SERUM AND URINE PROTEIN FINDINGS

A monoclonal spike was found on serum protein electrophoresis in less than half of a series of patients with μ-HCD (eight of 19).⁵⁴ The diagnosis of μ-HCD is made by documentation of the abnormal HC. Immunofixation of both serum and urine should be done. When these procedures yield ambiguous results, two-dimensional gel electrophoresis is a useful additional tool. The combination of capillary immunotyping electrophoresis and high-resolution two-dimensional electrophoresis has been used successfully for the detection of μ-HCD in one patient,⁵⁹ whereas in another capillary zone electrophoresis failed to detect the μ-HCD protein.⁶⁰ Three of 33 reported patients with μ-HCD had a biclonal gammopathy. Hypogammaglobulinemia was noted in 10 of 22 patients.⁵⁴ Hypergammaglobulinemia with a polyclonal pattern in the γ-globulin fraction was described in one case.⁵⁵ In contrast to γ- and α-HCD in which there usually is no detectable monoclonal light chain in the serum and urine, Bence Jones proteinuria was found in more than half the cases of μ-HCD (14 of 22 patients).⁵⁴ μ-HCD protein was found in the urine of only two patients.⁵⁴ Three cases of nonsecretory μ-HCD have been reported.^61,62,63 μ-HCs were documented by immunofluorescence on the cell surface of proliferating lymphocytes in 1 case and in marrow plasma cells of two others.

HEMATOLOGIC ABNORMALITIES

Anemia is frequent, but lymphocytosis and thrombocytopenia are uncommon. One patient had a positive direct antiglobulin test.⁵⁵ Examination of the marrow usually shows an increase in lymphocytes, plasma cells, or plasmacytoid lymphocytes. Plasmacytosis was noted in 18 of 20 cases; in 13 of these, vacuolated plasma cells were found.⁵⁴ The presence of vacuolated plasma cells in the marrow of a patient with a lymphoplasmacytic proliferative disorder should always suggest the possibility of μ-HCD.

OTHER FEATURES

Lytic bone lesions were described in three of 15 patients⁵⁴ and osteoporosis was mentioned in three others. No cytogenetic studies have been reported.

HISTOPATHOLOGY

In a literature review that included 27 documented cases of μ-HCD, 22 patients (81 percent) had an associated lymphoplasmacytic proliferative disorder designated as chronic lymphocytic leukemia, lymphoma, Waldenström macroglobulinemia, or myeloma.⁵⁴

The differential diagnosis of μ-HCD includes all lymphoplasmacytic proliferative disorders. Without a suspicion for the disease, μ-HCD is difficult to diagnose. The finding of Bence Jones proteinuria in a patient with a lymphoproliferative disorder and vacuolated plasma cells in the marrow deserves further investigation for possible μ-HCD.

There is no specific therapy for μ-HCD. The finding of a μ-HCD protein in the serum of an apparently normal patient should be considered to represent monoclonal gammopathy of undetermined significance, and the patient should be followed closely for the development of a symptomatic lymphoplasmacytic proliferative disorder. Once this develops, chemotherapy is indicated. Various agents have been used. Initially, a combination of cyclophosphamide, vincristine, and prednisone with or without doxorubicin is a reasonable choice. The use of fludarabine has been reported in two patients with μ-HCD; one had an “apparent hematologic response,”⁶⁴ and the other had a partial response.⁵⁶ Vincristine, cyclophosphamide, prednisolone, and doxorubicin in combination with rituximab led to complete resolution of tumoral lesions in one patient with μ-HCD.⁶⁵

The course of μ-HCD is variable. Because of the rarity of the disease, no large series of patients treated systematically in a single center has been reported. The median duration of survival from the time of diagnosis is 24 months (range: <1 month to 11 years).⁵⁴ Because several of the reported patients had findings consistent with μ-HCD before recognition of the μ-HCD protein, the course is probably longer than reported in most patients. In one patient, the hematologic abnormalities became normal and the μ-HC disappeared after 2 years without specific treatment.