Abbreviations used in this article: CHOP, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone, CT, computed tomography, CVP, cyclophosphamide, vincristine, and prednisone, FND, fludarabine, mitoxantrone, and dexamethasone, MGUS, monoclonal gammopathy of undetermined significance, MOPP, nitrogen mustard, vincristine, procarbazine, and prednisone, SPEP, serum protein electrophoresis
The heavy chain diseases represent a proliferative process of lymphoplasma cells involving B cells and are characterized by the production of incomplete heavy chains devoid of light chains. They have been described for the 3 main immunoglobulin classes. The most frequent is α-heavy chain disease; μ-heavy chain disease is rare. The incidence of γ-heavy chain disease is intermediate.
Since the first description of γ-heavy chain disease in 1964 (19), the cases of approximately 100 patients have been reported in the literature (16,17). Although γ-heavy chain disease is considered to resemble a lymphoma-like illness—with lymphadenopathy, splenomegaly, and hepatomegaly in association with a lymphoplasmacytic proliferation similar to that of Waldenström macroglobulinemia—several reports have called attention to its heterogeneity (17,31,46). Our report of 23 patients from a single institution (8 previously published, 15 new patients) emphasizes the diversity of the clinical manifestations and hematopathologic features of γ-heavy chain disease.
Six illustrative cases are described in detail. Case reports of the remaining 17 patients are available in the Appendix.
A 49-year-old man presented in 1974 with a history of burning mouth and dysphagia. On physical examination, superficial erosions of the palate and buccal mucosa were apparent. He was treated with corticosteroids for presumptive pemphigoid. Six months later, dyspnea and bleeding from the tongue developed. On physical examination, a cobblestone granular appearance was noted on the soft palate, tongue, and posterior pharynx. The biopsy specimen showed inflammatory ulceration with a marked plasmacytic response in the ulcer base. Results of bone marrow examination were normal. The patient was treated with azathioprine initially. One year later, therapy was switched to cyclophosphamide and prednisone, and this treatment program was continued until 1978. In 1980, he was hospitalized with nasal obstruction. Examination of tissue from the vocal cords showed a dense submucosal infiltrate of plasma cells that contained γ-heavy chain, which was consistent with γ-heavy chain disease. Immunoelectrophoresis of urine and serum samples was negative for γ-heavy chain. In 1982, at age 57 years, the patient received a diagnosis of γ-heavy chain disease after γ-heavy chain was documented in his serum and urine. Serum protein electrophoresis (SPEP) did not show a monoclonal spike. A 24-hour urine specimen contained 0.17 g of protein with a β-spike of 0.12 g. Results of a work-up for a disseminated lymphoplasma cell proliferative disorder were negative. The patient’s oropharyngeal proliferation was treated with chlorambucil and prednisone. By 1984, there was no clinical evidence of disease, and serum and urine were negative for γ-heavy chain. Therapy with chlorambucil and prednisone was discontinued in 1986. In 1988, the patient returned with an ulceration at the base of the tongue. Pathologic evaluation of tissue from the tongue, right lingual tonsil, and right vallecula showed malignant lymphoma, diffuse mixed small cleaved and large cell type. The tissue revealed selective reactivity for γ-heavy chain without reactivity for other heavy chains or light chains. Urine and serum immunoelectrophoresis results were negative. Local radiation therapy was considered but was not administered. In 1992, there was no evidence of disease on otorhinolaryngologic examination. Results of serial immunoelectrophoresis and immunofixation studies of serum and urine remained negative (last done in November 2000). At latest follow-up, in 2002 (20 years after the diagnosis of γ-heavy chain disease), the patient had no evidence of clinical disease.
Comment: This case exemplifies the presentation of a patient with γ-heavy chain disease as localized extramedullary plasmacytoma; a complete clinical and serologic response to chlorambucil and prednisone occurred with 20 years of follow-up.
A 36-year-old woman received a diagnosis of Coombspositive autoimmune hemolytic anemia in July 1971. She did not have a response to prednisone therapy and required a splenectomy in December 1971. In July 1973, prednisone treatment was resumed for hemolytic anemia and thrombocytopenia (Evans syndrome). In 1974, 2 accessory spleens were removed. Pathologic examination revealed no evidence of lymphoid neoplasia. Subsequent hemolysis and thrombocytopenia responded to therapy with prednisone and azathioprine initially and then to vincristine. In June 1978, at age 42 years and while receiving corticosteroid therapy, the patient presented with headache, fever, and nausea. Cryptococcal meningitis was diagnosed. SPEP showed a monoclonal β-spike of 0.79 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.57 g of protein with a β-spike of 0.15 g (γ-heavy chain). There was no evidence of a lymphoplasma cell proliferative disorder. Results of bone marrow examination were normal. After the diagnosis of γ-heavy chain disease, the γ-heavy chain was absent from the serum in 67 months and from the urine in 110 months. Autoimmune hemolytic anemia continued, requiring continuous treatment with corticosteroids. The patient died of a myocardial infarction in 2000, 22 years after the diagnosis of γ-heavy chain disease. (This patient was previously reported as Case 4 by Kyle et al .)
Comment: This is an example of γ-heavy chain disease in a patient with a 7-year history of a severe autoimmune disorder. γ-Heavy chain disease was diagnosed when she became ill with cryptococcal meningitis. γ-Heavy chain in serum and urine disappeared without specific treatment and never recurred while the autoimmune process continued.
A 46-year-old man was seen at another institution in 1982 for evaluation of fever, weight loss, splenomegaly, and a 6.5-year history of vasculitis. A diagnosis of γ-heavy chain disease was made at that time. Skin biopsy specimens revealed livedoid vasculitis. Results of periodic bone marrow examinations were normal. The livedoid vasculitis was unresponsive to various forms of treatment (aspirin, dipyridamole, pentoxifylline, dapsone, cyclophosphamide, prednisone, nicotinic acid, and plasmapheresis). The patient was seen at Mayo Clinic in 1988, when he presented for further evaluation of persistent vasculitis. Results of skin biopsy at that time were consistent with livedoid vasculitis and negative for amyloid. Bone marrow examination and metastatic bone survey results were negative. SPEP showed a β-γ-spike of 0.59 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.19 g of protein with a β-spike of 0.16 g (γ-heavy chain). In 1990, congestive heart failure developed (ejection fraction, 20%). Echocardiography was negative for amyloidosis, and repeat immunoelectrophoresis was not available. The vasculitis was unresponsive to therapy, and skin grafting was required for extensive cutaneous ulcerations that developed. The patient died of unknown cause between 1992 and 1994 (exact date unknown).
Comment: This case is another example of γ-heavy chain disease that was diagnosed in a patient who had a therapy-resistant autoimmune disorder.
A 73-year-old woman presented in 1998 with axillary lymphadenopathy and herpes zoster. Her previous history included rheumatoid arthritis of 13 years’ duration and lymphoplasmacytic lymphoma of 1 year’s duration, which was treated with prednisone only. The lymphoma was characterized by follicles that contained CD20+ B lymphocytes, which were negative for Bcl-2, CD23, and CD10, and by interfollicular zones that contained CD2, CD3, CD5, and CD7 T lymphocytes. In addition, results of in situ hybridization studies suggested the presence of Epstein-Barr virus RNA. Computed tomography (CT) scan of the abdomen revealed minimal retroperitoneal adenopathy and mild splenomegaly. Results of bone marrow examination were negative. Results from biopsy of an axillary lymph node showed malignant lymphoma, small lymphocytic type, with extensive plasmacytic differentiation. Immunoperoxidase stain revealed a population of plasma cells that expressed only γ-heavy chain and were negative for CD20, CD10, CD23, CD2, CD3, CD5, CD7, and Bcl-2. SPEP revealed a β-γ-spike of 1.14 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.11 g of protein with a γ-spike of 0.10 g (γ-heavy chain). The patient was treated with chlorambucil and prednisone, but progressive lymphadenopathy developed. Treatment with cyclophosphamide, vincristine, and prednisone (CVP) and fludarabine, mitoxantrone, and dexamethasone (FND) resulted in a temporary response, and in 1999 and 2000 the patient was treated elsewhere with rituximab and had a good response. The patient was alive 3.5 years after the diagnosis of γ-heavy chain disease. No follow-up on the presence or absence of γ-heavy chain in the serum or urine is available.
Comment: In this case, γ-heavy chain disease was associated with a lymphoplasmaproliferative disease as well as an autoimmune disorder. It is of interest that the lymphoplasmaproliferative disease had a response to rituximab therapy, although the immunoperoxidase stain was negative for CD20 at the time of treatment.
A 42-year-old man presented in 1990 with fatigue, weakness, increase in abdominal girth, and an abdominal mass. CT scan of the abdomen revealed marked mesenteric and retroperitoneal lymphadenopathy, producing a large mass. CT scan of the chest showed bilateral pleural effusions and mildly enlarged lymph nodes in the upper pretracheal region. Exploratory laparotomy revealed non-Hodgkin lymphoma, diffuse mixed cell type, with marked plasmacytic differentiation of B-cell phenotype. The neoplastic cells were immunoreactive for γ-heavy chain and negative for κ, λ, μ, α, δ, CD2, CD5, CD20, and CD22. Results of bone marrow examination were not diagnostic; there was no significant increase of plasma cells or lymphocytes, but they stained positively for γ-heavy chain. SPEP showed a β-spike of 3.91 g/dL (γ-heavy chain). A 24-hour urinary total protein excretion was 6.50 g with a β-spike of 4.12 g (γ-heavy chain). The patient was treated with 6 cycles of CVP with a partial response; therapy was continued with oral administration of cyclophosphamide and prednisone for 6 years. His course was complicated by the development of an immune-complex glomerulopathy, which required hemodialysis and, later, a kidney transplant. At latest follow-up in 2000, the patient showed no evidence of lymphoma. The serum and urine were negative for γ-heavy chain at the latest evaluation, in 1996.
Comment: This is another example of a patient with γ-heavy chain disease and an underlying plasmaproliferative disorder. Of note are the large amounts of urinary γ-heavy chain excretion and the absence of clinical and serologic disease at latest follow-up.
In 1989, stage IV chronic lymphocytic leukemia was diagnosed in a woman who was 50 years old. She was treated with chlorambucil and fludarabine. Seven years after chronic lymphocytic leukemia was diagnosed, γ-heavy chain disease was recognized. SPEP showed a β-spike of 1.94 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.49 g of protein with a β-spike of 0.29 g (γ-heavy chain). In 1997, the patient presented to Mayo Clinic with weight loss, dry necrotic papules on the arms and legs, and cervical lymphadenopathy. The total leukocyte count was 13,300 × 109/L, with 86% lymphocytes. Flow cytometric immunophenotyping revealed B lymphocytes expressing CD19, CD20, CD5, CD23, and a small population of bright CD11c/CD22. A CT scan of the chest and abdomen revealed axillary and paratracheal lymph nodes, splenomegaly, and enlarged para-aortic and retroperitoneal lymph nodes. Bone marrow examination findings were consistent with chronic lymphocytic leukemia. Skin biopsy results showed perivascular lymphocytic inflammation consistent with lymphocytic vasculitis. SPEP revealed a β-spike of 2.02 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.60 g of protein with a β-spike of 0.40 g. γ-Heavy chain was present in the urine; in addition, a small λ-light chain was detected. The patient’s course was complicated by severe autoimmune thrombocytopenia. She was treated with corticosteroids, intravenous immunoglobulin, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). She died of complications of the lymphoproliferative syndrome 20 months after the diagnosis of γ-heavy chain disease.
Comment: In this patient, γ-heavy chain disease was diagnosed during the course of chronic lymphocytic leukemia that was complicated by a lymphocytic vasculitis and an autoimmune thrombocytopenia, with death resulting from complications of the lymphoproliferative syndrome.
Between 1976 and 1998, 23 patients with γ-heavy chain disease were evaluated at Mayo Clinic. There were 15 women and 8 men. Twenty-two patients were Caucasian and 1 was Asian (Patient 18). The median age at diagnosis was 68 years (range, 42–87 yr). Eight cases were reported previously (31,55). They are included in this report with additional follow-up information.
At the time of diagnosis, 16 patients had a malignant lymphoplasma cell proliferative disorder (disseminated in 10; localized in 6), 3 had a disseminated lymphoplasma cell proliferative disorder and an autoimmune disorder, 3 had an autoimmune disorder without a proliferative disorder, and 1 had no documented underlying disease (Table 1).
The time from the diagnosis of any associated or underlying disease until the diagnosis of γ-heavy chain disease is summarized in Table 2. In none of the patients did the diagnosis of γ-heavy chain disease precede the diagnosis of a proliferative or autoimmune disorder. One patient in whom γ-heavy chain disease was diagnosed was followed for nearly 3 years, but no proliferative or autoimmune disorder developed. In another patient, γ-heavy chain was documented in tissue derived from the oral pharynx 2 years before a γ-heavy chain was documented in serum and urine.
Physical examination findings
At the time of diagnosis of γ-heavy chain disease, lymphadenopathy was present on clinical examination in 8 patients, splenomegaly in 7, and hepatomegaly in 1 (Table 3). Seven patients had skin manifestations at the time of presentation. Rheumatoid nodules and vasculitis were present in a patient with rheumatoid arthritis. One patient had livedoid vasculitis and another had subcutaneous amyloid nodules. Herpes zoster was present in a patient who was receiving chemotherapy for a lymphoplasma cell proliferative disorder. Disseminated herpes simplex was present in a patient with active Hodgkin disease, and lymphocytoma cutis was present in a patient with angioimmunoblastic lymphoma. One of 2 patients with chronic lymphocytic leukemia presented with a rash and dry necrotic papules, which on pathologic examination were thought to represent a lymphocytic vasculitis.
Two patients presented with an infection: 1 had periorbital cellulitis with a lymphoplasma cell proliferative disorder involving the bone marrow, resulting in an absolute neutropenia; the other had cryptococcal meningitis with an underlying autoimmune hemolytic anemia that was being treated with azathioprine and prednisone.
Hematologic findings at the time of diagnosis of γ-heavy chain disease are summarized in Table 4. The median hemoglobin concentration was 11.2 g/dL (range, 8.4–14.3 g/dL) (results were available for 22 patients); in 8 patients, the hemoglobin concentration was less than 10 g/dL. Two patients had a Coombs-positive autoimmune hemolytic anemia.
The median leukocyte count for 22 patients was 5.7 × 109/L (range, 0.7–20.9 × 109/L). Leukopenia was present in 4 patients and leukocytosis in 3. The median absolute lymphocyte count was 1.6 × 109/L (range, 0.1–3.5 × 109/L). Lymphocytosis was present in 2 patients, lymphocytopenia in 7, and eosinophilia in 4.
The median platelet count for 22 patients was 204 × 109/L (range, 23–431 × 109/L). The platelet count was less than 100 × 109/L in 4 patients. Sedimentation rates were available for 14 patients at the time of diagnosis (median sedimentation rate, 17 mm/1 h; range, 3–80 mm/1 h). Only 2 patients had a sedimentation rate greater than 50 mm/1 h. Two patients had mild hypercalcemia (Patient 7, 10.2 mg/dL; Patient 10, 11.3 mg/dL).
Bone marrow findings
Among the 22 patients who underwent a bone marrow examination, 7 had a lymphoplasma cell proliferative disorder involving the marrow sometime during the disease, with a median involvement of 30% (range, 9%-70%). In 2 patients the marrow involvement was estimated to be at least 50%.
Of the 9 patients with a disseminated lymphoplasma cell proliferative disorder who underwent bone marrow examination, only Patients 10, 11, and 14 had bone marrow involvement. In Patients 2 and 22 the disease was localized to the marrow only. In Patients 6 and 15, who also had localized disease, the bone marrow findings were suggestive but not diagnostic of a lymphoplasma cell proliferative disorder; however, Patient 6 had multiple myeloma at autopsy. In the lymphoplasma cell proliferative/autoimmune disorder group, only Patient 21 had bone marrow involvement. Marrow findings were negative in Patients 3, 4, and 16, who had an autoimmune disorder. Bone marrow results of Patient 8, who had no underlying disease, revealed a nondiagnostic slight increase in plasma and lymphoplasmacytic cells. In Patient 15 a myelodysplastic syndrome developed 15 years after the diagnosis of γ-heavy chain disease. This patient never received treatment for γ-heavy chain disease.
Protein findings at the time of diagnosis of γ-heavy chain disease are summarized in Table 5. A monoclonal spike on SPEP was seen in 19 of 22 patients. SPEP revealed hypogammaglobulinemia in 1 patient and a polyclonal peak in another patient. SPEP results were normal in 1 patient and unavailable in another patient.
The monoclonal protein peak was located in the following areas: β in 11 patients; β-γ in 4; γ in 3; and α in 1. The median monoclonal protein peak at diagnosis in 19 patients was 1.59 g/dL (range, 0.37–3.91 g/dL). Among the 19 patients who had a follow-up SPEP sometime during the disease, the monoclonal peak increased in 7, remained unchanged in 1, decreased in 4, and was no longer present in 7.
The median serum IgG level at diagnosis in 21 patients was 1,940 mg/dL (range, 462–5,280 mg/dL). The serum IgG level decreased in 6 patients, increased in 3, and remained unchanged in 1.
γ-Heavy chain was present in the serum in all patients. Two patients had an additional monoclonal gammopathy, IgM-λ. γ-Heavy chain disappeared from the serum in Patients 1, 4, 7, 8, 11, and 18. All these patients except Patient 8 were treated. After the γ-heavy chain disappeared, it did not reappear. In 6 patients, the median time from diagnosis of γ-heavy chain disease until the disappearance of γ-heavy chain was 36 months (range, 15–78 mo). At the time of diagnosis of γ-heavy chain disease, no monoclonal light chains were documented in any patient.
A monoclonal spike on urine protein electrophoresis was seen in 19 patients at the time of diagnosis. The monoclonal protein peak was located in the β area in 12 patients, and in the γ area in 7.
The median monoclonal urinary protein excretion at diagnosis in 19 patients was 0.23 g/24 h (range, 0.02–4.12 g/24 h). Among 14 patients who had follow-up urinary protein studies, urinary protein excretion increased in 4, decreased in 9, and was no longer present in 1.
The median 24-hour total protein excretion at diagnosis in 21 patients was 0.34 g (range, 0.04–6.50 g). Protein excretion was mainly γ-heavy chain. In Patient 18, with a total 24-hour urinary protein excretion of 6.50 g, albumin was 2.38 g. Results of a renal biopsy revealed changes consistent with a lymphoproliferative disorder and an immunologically mediated glomerulopathy consistent with membranous nephropathy. In 10 patients, the 24-hour urinary protein excretion decreased; in 5 patients it increased.
γ-Heavy chain was documented in the urine of 18 of 22 patients within 6 months after the diagnosis of γ-heavy chain disease. In an additional patient (Patient 23), γ-heavy chain was documented in the urine 11 months after the diagnosis of γ-heavy chain disease. In Patients 2 and 3, γ-heavy chain was not documented in the urine. γ-Heavy chain was no longer present in the urine in 5 patients (Patients 1, 4, 7, 11, and 18), who were treated for their disease, and was present in the urine in 1 patient with no underlying disease (Patient 8). During the course of disease, 2 patients had urinary light chains: Patient 13 had a small κ-light chain that was no longer present after 10 months without treatment, but the γ-heavy chain persisted in the urine and serum; Patient 21 had a small λ-light chain that was documented at latest follow-up.
Chromosome studies were done in 7 patients. Results were normal on bone marrow specimens in 5 patients. In 1 patient, direct, 24-hour, and 48-hour chromosome studies of unstimulated cultures from the lymph node revealed 47,XX,-D,+2 markers. The markers were a large acrocentric and a large submetacentric abnormality.
In the other patient, the results of conventional cytogenetic studies for bone marrow and blood were not informative because only a few normal metaphases were observed. The results of chromosome studies on cells from spleen cultured for 24 hours in media without mitogens showed 13 metaphases each with a structurally abnormal chromosome 4. The banding patterns of these metaphases were not adequate to define accurately the abnormal chromosome 4.
Metastatic bone survey
A metastatic bone survey was done in 5 patients. Findings were negative for all 5.
Treatment and response
Sixteen of 23 patients were treated for either an underlying lymphoplasma cell proliferative disorder or an associated autoimmune disorder. For 5 patients, treatment was thought to be unnecessary (Patients 2, 6, 8, 15, and 22), and Patients 5 and 9 were thought to be too sick for treatment.
Of 19 patients with a lymphoplasma cell proliferative disorder (disseminated or localized), 13 were treated: 11 had chemotherapy (Patients 1, 7, 10, 11, 13, 17, 18, 19, 20, 21, and 23), 1 had a splenectomy (Patient 14), and 1 had a thyroidectomy followed by radiation therapy (Patient 12). Three patients with an autoimmune disorder and no underlying lymphoplasma cell proliferative disorder were treated with chemotherapy for either vasculitis (Patients 3 and 16) or refractory Evans syndrome (Patient 4).
Chemotherapeutic regimens included chlorambucil and prednisone (Patients 1, 7, 11, 17, and 19), chlorambucil only (Patient 3), melphalan and prednisone (Patient 19), cyclophosphamide and prednisone (Patient 16), CVP (Patients 4, 7, 10, 17, 18, 19, and 23), CHOP (Patients 13, 19, 20, and 21), FND (Patient 17), rituximab (Patient 17), and azathioprine (Patient 4).
Of the 16 patients treated, 6 had a complete clinical response (in Patients 1 and 18, γ-heavy chain was no longer present; in Patients 3 and 20, it persisted; and for Patients 12 and 17, no serologic follow-up was available), and 10 had persistence of clinical disease, leading to death due to progressive disease or disease-related complications in Patients 13, 19, 21, and 23 (in Patients 4, 7, and 11, γ-heavy chain was no longer present; in Patients 13, 14, 16, 19, 21, and 23, it persisted; and for Patient 10, no serologic follow-up was available).
Of the 7 patients who were not treated, Patient 5 died within 1 month after diagnosis and Patient 9 died within 5 months after diagnosis; Patients 8 and 22 had no evidence of clinical disease at latest follow-up, although γ-heavy chain persisted in urine or serum or both; and Patients 2 and 15 had no change in their clinical and serologic status. Patient 6 died of septic shock, probably related to the underlying disease, 15 months after the diagnosis of γ-heavy chain disease. γ-Heavy chain persisted in serum and urine. Clinical and laboratory findings at latest follow-up are summarized in Table 6.
Duration of follow-up
The median duration of follow-up for 23 patients from the time of diagnosis of γ-heavy chain disease was 2.75 years (range, 1 mo-21.75 yr).
At latest follow-up, 15 patients were dead. The cause of death was known in 12 patients and was not related to the underlying disease in 7 (Table 7). The median survival of the 23 patients was 7.4 years (range, 1 mo to more than 21 yr). Kaplan-Meier estimates of patient survival are depicted in Figure 1.
Heavy chain diseases are B-cell lymphoproliferative disorders that are characterized by the production of monoclonal immunoglobulins, which have the immunochemical characteristics of truncated heavy chains without associated light chains. Heavy chain diseases involving the 3 main immunoglobulin classes (IgA, IgM, IgG) have been described. The most common is α-heavy chain disease, which usually occurs as intestinal malabsorption in young adults of low socioeconomic status from the Mediterranean area or from the Middle East (53). Patients with μ-heavy chain disease are rarely encountered and are clinically similar to patients with B-cell non-Hodgkin lymphoma that produces an abnormal heavy chain (52). The incidence of γ-heavy chain disease is intermediate. The diagnosis of these conditions depends on the detection of structurally abnormal immunoglobulin molecules in the serum or urine. γ-Heavy chain disease should be considered in any patient who has an atypical lymphoplasma cell proliferative disorder, especially if proteinuria or abnormal SPEP results are present.
γ-Heavy chain disease has been described throughout the world, occurring with no apparent epidemiologic pattern. Patients with γ-heavy chain disease are predominantly middle-aged. In our 23 patients the median age at diagnosis was 68 years, which is somewhat older than in the series of 16 patients reported by Fermand et al (17) (60 yr) and in a previous literature review cited by Fermand et al (17) (58 yr). Although a slight predilection for men has been reported (17), there was a clear predominance of women in our series (15 women and 8 men).
Patients with γ-heavy chain disease can present with various clinical and pathologic features, which usually precede the serologic diagnosis of γ-heavy chain disease. The diagnosis of a lymphoplasma cell proliferative disorder or an autoimmune disorder (or both) was made in 21 of 23 (91%) of our patients before the diagnosis of γ-heavy chain disease.
In concordance with other reports (17,55), our results show that most of our patients (83%) had an underlying lymphoplasma cell proliferative disorder, with disseminated disease being more common than localized disease; 57% had disseminated disease in our series, as compared with 63% in the series reported by Fermand et al (17). Although the most common clinical presentation of patients with a disseminated lymphoplasma cell proliferative disorder consists of constitutional symptoms with lymph-adenopathy, the frequency of these findings in patients with γ-heavy chain disease depends on the treatment status of the disease at the time of the serologic detection of the γ-heavy chain.
In patients with localized lymphoplasma cell proliferative disorder, the proliferation may be extramedullary or medullary. Extramedullary locations described in the literature include the skin (5,12,21,27,28,31,32,39,45,46), thyroid (31,37,40,48,56), parotid gland (19), oropharyngeal area (4), and the gastrointestinal tract (3,25,41,47,50). Our series included 1 patient with amyloid nodules confined to the skin and 1 patient each with an extramedullary plasmacytoma involving the tongue and soft palate, submandibular area, and thyroid. Two of our patients had a lymphoplasma cell proliferative disorder involving only the bone marrow.
Our findings are consistent with previous reports showing that a lymphoplasmacytoid proliferation, as seen in Waldenström disease, is the most common malignant proliferation in patients with γ-heavy chain disease, although different types of lymphoma, including Hodgkin disease, can be associated with γ-heavy chain disease (8,11,46).
The occurrence of autoimmune disorders, with or without an associated underlying lymphoid proliferation, has been reported in 26% of patients with γ-heavy chain disease (17). Three of our patients (13%) had a previously diagnosed autoimmune disorder, and 3 others had a disseminated lymphoplasma cell proliferative disorder that was associated with an autoimmune disorder. Rheumatoid arthritis has been reported in about a dozen patients with γ-heavy chain disease (9,12,17,22,30,36,57), and our series included 2 patients with long-standing rheumatoid arthritis. Vasculitis with or without associated rheumatoid arthritis (17,30,49), livedoid vasculitis (7), and Sjögren syndrome (51) has been associated with γ-heavy chain disease.
Conditions in several patients with γ-heavy chain disease and no features of a lymphoplasma cell proliferative process or an autoimmune disorder have been classified as benign monoclonal gammopathy or as monoclonal gammopathy of undetermined significance (MGUS) (2,20,35,56). One of our patients (Patient 8) met the criteria for MGUS.
The diagnosis of γ-heavy chain disease depends on the documentation by immunofixation or immunoelectrophoresis of a γ-heavy chain fragment in serum or urine. Because SPEP findings vary and a monoclonal peak cannot always be detected, γ-heavy chain disease is probably underdiagnosed. A monoclonal peak, albeit small and apparently inconsequential, was detected on SPEP in 19 of 22 patients (86%), a percentage that is higher than previously reported in the literature (17). The mobility ranged from α to γ, with the β region being the most common location.
In most of our patients (91%) γ-heavy chain was documented in the urine during the course of their disease. A small monoclonal light chain was detected in 2 of our patients during the course of their disease: 1 κ and 1 λ. As far as we know, only 2 other patients with γ-heavy chain disease and Bence Jones proteinuria have been described in the literature (6,24). The amount of γ-heavy chain protein excreted in the urine was less than 1 g/24 h in 16 of 19 patients (84%). In 1 patient (Patient 18), γ-heavy chain excretion reached 4.12 g/24 h; his 24-hour urine protein excretion at that time was 6.50 g. An immune-complex glomerulopathy requiring hemodialysis and kidney transplantation complicated this patient’s disease.
Two of our patients with a localized plasmaproliferative disease (Patient 15, amyloid of the skin, and Patient 22, bone marrow involvement only) had an associated IgM-λ monoclonal gammopathy. In a literature review (31) of 56 cases of γ-heavy chain disease, 9 cases of biclonality (IgM or IgG) were identified (16%). The associated monoclonal immunoglobulin was IgM (9,15,17,29,38,43,47,50,54) or IgG (1,18,23,26,30,33,34). No association between γ-heavy chain disease and a monoclonal IgA has been described.
Hematologic data in patients with γ-heavy chain disease are difficult to assess because many patients receive chemotherapy for an underlying lymphoplasma cell proliferative or autoimmune disorder before γ-heavy chain disease is diagnosed. Twenty-two of our patients underwent a bone marrow examination, with only 7 (32%) revealing involvement by a lymphoplasma cell proliferative disorder. In previous series, bone marrow involvement was reported in 58%-63% of cases (17). In 1 of our patients, bone marrow findings were consistent with a myelodysplastic syndrome. This patient had never received any chemotherapy. A few patients with a myelodysplastic disorder and γ-heavy chain disease have been reported in the literature (13,42,55).
Cytogenetic abnormalities have been recognized infrequently in γ-heavy chain disease. Abnormalities were found in 2 of our 7 patients in whom chromosome studies were done. Of 13 patients reported in the literature who underwent cytogenetic evaluation, aneuploidy was found in 3 (17,36,46). Three others had trisomy 7 (39), trisomy 21 (44), and multiple chromosome abnormalities (17). Three of these patients (17,36) had received chemotherapy, which may have been responsible for some of the chromosomal abnormalities. No chromosome abnormalities were found in 7 other patients (10,14,17,19,22,57).
Because γ-heavy chain disease is a heterogeneous condition, the choice of therapy should rely entirely on the underlying disorder and the pathologic findings. In an asymptomatic patient with MGUS, no therapy is indicated. Any associated autoimmune disorder should be managed with standard therapy without taking into account the existence of the abnormal monoclonal component. Common regimens described in the literature and used in our patients with a low-grade lymphoplasmacytic malignancy are chlorambucil or melphalan and prednisone if the proliferation is predominately plasmacytic. CVP may be helpful in patients with evidence of progressive disease. Patients with aggressive lymphomas should receive a regimen containing an anthracycline. One of our patients (Patient 17) was treated with rituximab and had a good response. There have been no reports of the usefulness of immunotherapy in γ-heavy chain disease. However, when immunophenotyping of malignant cells was done in 4 of our patients, 3 expressed CD20. Therefore, we suggest that immunophenotyping be done in all patients who have γ-heavy chain disease and an underlying lymphoplasma cell proliferative disorder. Treatment with rituximab should be considered for patients whose neoplastic cells express CD20.
In general, therapeutic responses vary according to the aggressiveness of the underlying disease, and clinical and serologic responses do not necessarily occur together. Only 2 of our patients had complete clinical and serologic treatment responses: 1 (Patient 18) who had a disseminated lymphoplasma cell proliferative disorder and was treated with CVP and 1 (Patient 1) who had a localized plasmacytoma of the tongue and soft palate and was treated with chlorambucil and prednisone. A complete clinical response with persistence of γ-heavy chain was achieved in 2 of our patients (Patients 3 and 20). In Patients 4, 7, and 11, γ-heavy chain was no longer present in serum and urine despite persistence of the underlying disease. These variable clinical and serologic responses are in agreement with therapeutic responses previously described (17,31,55).
Because γ-heavy chain disease may range from an asymptomatic, benign process to a rapidly progressive neoplasm, the range of survival is large. The median survival of our 23 patients was 7.4 years (range, 1 mo to more than 21 yr), which is longer than the 12 months (range, 1–264 mo) previously reported (31).
In accordance with other reports, we found that γ-heavy chain disease is commonly associated with a neoplastic proliferative disorder or an autoimmune disorder, or both, although patients can also present with MGUS. No specific lymphoproliferative or other disease process corresponds consistently to the serologically determined diagnosis of γ-heavy chain disease. Therefore, the diagnosis of γ-heavy chain disease has little implication in regard to the patient’s underlying disease, treatment, and prognosis. In addition, the usefulness of γ-heavy chain as a serologic marker for the activity of an underlying disease is limited, because γ-heavy chain may no longer be present in serum and urine while the associated disease persists.
APPENDIX. CASE REPORTS OF REMAINING 17 PATIENTS
A 77-year-old woman presented in 1993 with a periorbital cellulitis due to an absolute neutropenia (0.12 × 109/L). Bone marrow evaluation revealed a lymphoplasma cell proliferative disorder. Results of chloroacetate esterase and peroxidase staining were positive; results of butyrate esterase staining were positive in less than 5% of lymphocytes. There was no evidence of other organ involvement. SPEP showed a monoclonal β-spike of 1.67 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.09 g of protein (mainly albumin). γ-Heavy chain could not be documented in the urine. No therapy was given. At latest follow-up, 17 months after the diagnosis of γ-heavy chain disease, the patient was alive with no infection despite persistent neutropenia. However, her health was poor because of other medical problems (diabetes mellitus, coronary artery disease, and congestive heart failure).
Rheumatoid arthritis was diagnosed in a 26-year-old woman in 1935. In 1969, Sjögren syndrome and Felty syndrome developed, and a vasculitis occurred which was treated with chlorambucil. In 1980, at age 70, she presented with a right malleolar ulcer, multiple skin lesions (rheumatoid nodules), and findings that were consistent with vasculitis. SPEP showed a monoclonal γ-spike of 1.51 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.06 g of protein (mainly albumin). γ-Heavy chain could not be documented in the urine. There was no evidence of an underlying proliferative disorder on clinical or laboratory examination. Her skin lesions and vasculitis responded to therapy with chlorambucil. The γ-heavy chain in the serum persisted at 54 months of follow-up.
A 78-year-old man presented in 1980 with weakness and fatigue. He had a history of papillary carcinoma of the bladder, prostate cancer, and coronary artery disease. On physical examination, he had cervical, axillary, and inguinal lymphadenopathy. Results of a lymph node biopsy revealed a lymphoproliferative disorder (angioimmunoblastic lymphadenopathy) with γ-heavy chain secretion on immunoperoxidase studies. Results of a bone marrow study, CT scan, and bone survey were negative. SPEP showed hypogammaglobulinemia. γ-Heavy chain was documented in the serum. A 24-hour urine specimen contained 0.56 g of protein with a γ-spike of 0.30 g (γ-heavy chain). Treatment with corticosteroids was planned; however, the patient died of a myocardial infarction 26 days after the diagnosis of γ-heavy chain disease. (This patient was previously reported as Case 8 by Wester et al .)
A 63-year-old man had splenomegaly and an absolute neutropenia (hypersplenism) during hospitalization in 1974 for Guillain-Barré syndrome. Five years later he presented with an extramedullary plasmacytoma in the left submandibular area. SPEP showed a broad-based γ-band of 2.17 g/dL and a small localized β-γ-band (γ-heavy chain). A 24-hour urine specimen contained 0.85 g of protein with a γ-spike of 0.65 g (γ-heavy chain). Results of a bone marrow examination were suggestive but not diagnostic of a lymphoplasma cell proliferative disorder. The patient received no treatment; he died of septic shock 15 months after the diagnosis of γ-heavy chain disease. Autopsy results revealed multiple myeloma and replacement of bone marrow (demonstrated in the spine) with extramedullary infiltration of liver, spleen, and lungs. (This patient was previously reported as Case 7 by Kyle et al .)
A 74-year-old woman presented in 1976 with generalized pruritus, skin nodules, and weight loss of 9 kg. The skin nodules had been present since 1972, diagnosed as lymphocytoma cutis, and treated with radiation therapy and prednisone. Pertinent physical findings at the time of presentation included multiple purplish, raised lesions over the body except the scalp; oropharyngeal edema; axillary lymphadenopathy; and a palpable spleen tip. Skin biopsy results showed “early evolution of a lymphomatous process”; lymph node biopsy results showed angioimmunoblastic lymphadenopathy. On lymphangiography, enlarged inguinal and iliac lymph nodes were consistent with lymphoma. Results of bone marrow examination were normal. SPEP showed a monoclonal β-spike of 0.90 g/dL (γ-heavy chain), and a 24-hour urine specimen contained 0.24 g of protein with a β-spike of 0.20 g (γ-heavy chain). The patient was treated initially with CVP and then was treated with chlorambucil and prednisone for 2 years. Treatment with CVP resulted in a complete clinical response within 4 months. Immunoelectrophoresis of the urine was negative for γ-heavy chain in 1978, and immunoelectrophoresis of the serum was negative for γ-heavy chain in 1979. In 1984, 8 years after the diagnosis of γ-heavy chain disease, recurrent lymphadenopathy developed. The patient died between 1984 and 1990; the cause of death was unknown. (This patient was previously reported as Case 2 by Kyle et al .)
A 65-year-old woman presented in 1988 for a routine examination. Physical examination findings were normal. SPEP showed a monoclonal β-spike of 1.75 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.44 g of protein with a β-spike of 0.12 g (γ-heavy chain). A CT scan of the abdomen was negative, and bone marrow examination revealed a slight increase (5%-7%) in plasma cells and lymphoplasmacytic cells. She received no treatment. γ-Heavy chain was no longer in the serum at 1-year follow-up but was present in the urine at the latest testing in 1991. Clinical disease had not developed at 2 years 9 months of follow-up.
A 66-year-old woman presented to Mayo Clinic in 1983 with fever, weakness, and weight loss. In 1977, she received a diagnosis of Hodgkin disease, stage IA, lymphocyte depletion type, for which she was treated with radiation therapy. In 1981, she had stage IVB disease and was treated with nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP). At presentation in 1983, she had marked lymphadenopathy, splenomegaly, disseminated herpes simplex, and ileus. A CT scan of the chest showed bilateral pleural effusions and a pulmonary embolism. A CT scan of the abdomen showed enlarged retroperitoneal lymph nodes and ascites. Bone marrow examination results were normal. SPEP showed a monoclonal β-γ-spike of 2.23 g/dL (γ-heavy chain), and a 24-hour urine specimen contained 3.51 g of protein with a β-spike of 2.26 g (γ-heavy chain). Supportive therapy was given. Five months after the diagnosis of γ-heavy chain disease, the patient died of respiratory failure, a complication of a right hip fracture.
A 69-year-old man presented in 1978 with a 6-month history of severe soreness of the tongue, fever, night sweats, weight loss, lymphadenopathy, hepatosplenomegaly, and parotid and submandibular gland swelling as well as anemia and hypercalcemia. Results of bone marrow examination revealed 30% plasma cells. A renal biopsy specimen showed infiltration by plasma cells and lymphoplasmacytic cells. SPEP showed a monoclonal β-γ-spike of 1.91 g/dL (γ-heavy chain). A 24-hour urine specimen contained 2.98 g of protein with a β-spike of 2.78 g (γ-heavy chain). Treatment with CVP produced improvement; however, the condition relapsed when vincristine therapy was discontinued. The patient subsequently obtained some benefit from treatment with doxorubicin and cyclophosphamide. He died of a cerebrovascular accident 10 months after the diagnosis of γ-heavy chain disease. (This patient was previously reported as Case 1 by Kyle et al .)
A 55-year-old woman presented with bilateral parotid gland enlargement and splenomegaly in 1979. She had a 7-year history of chronic lymphocytic leukemia and a 3-year history of bilateral painful parotid gland swelling. Bone marrow findings were consistent with chronic lymphocytic leukemia. SPEP showed a β-spike of 1.46 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.76 g of protein with a β-spike of 0.71 g (γ-heavy chain). The chronic lymphocytic leukemia was treated with intermittent chlorambucil and prednisone. γ-Heavy chain could not be documented in the serum 34 months after treatment, and no γ-heavy chain was found in the urine 4.5 years after the diagnosis of γ-heavy chain disease. The patient died of congestive heart failure 7.5 years after the diagnosis of γ-heavy chain disease. (This patient was previously reported as Case 5 by Kyle et al .)
An 87-year-old woman presented in 1979 with a rapidly enlarging goiter. Biopsy results showed a mature plasmacytoma. There was no evidence of multiple myeloma on bone marrow examination. SPEP showed an α-spike of 1.05 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.29 g of protein with a β-spike of 0.26 g (γ-heavy chain). The patient was treated with radiation therapy to the thyroid and upper mediastinum. She died of congestive heart failure 2 months after the diagnosis of γ-heavy chain disease. (This patient was previously reported as Case 6 by Kyle et al .)
A 62-year-old woman presented in 1982 for a recheck of her lymphoma. She had a 6-year history of stage IV, welldifferentiated lymphocytic lymphoma that had been treated with chemotherapy. SPEP showed a β-γ-spike of 0.37 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.34 g of protein with a γ-spike of 0.23 g. Urine immunoelectrophoresis showed a γ-heavy chain and a small free κ-light chain. The lymphoma was stable for 2 years and then progressed to a diffuse, large cell lymphoma with spinal cord compression. The patient was treated with CHOP and radiation therapy to the spine. γ-Heavy chain persisted in the serum and urine. The κ-light chain disappeared. Despite progressive disease, the amount of protein in the serum and urine decreased. The patient died of progressive lymphoma 2 years after the diagnosis of γ-heavy chain disease.
A 79-year-old man presented in 1983 with fatigue, weight loss, anorexia, and splenomegaly. He had a history of splenomegaly, pancytopenia, phlebitis, pulmonary embolism, and localized amyloid of the urinary bladder. SPEP showed a γ-spike of 1.97 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.22 g of protein with a γ-spike of 0.14 g (γ-heavy chain). Results of bone marrow examination revealed a lymphoplasma cell proliferative disorder (25% lymphocytes that were slightly atypical). After splenectomy (histopathologic diagnosis: lymphoplasma cell lymphoma), the pancytopenia improved. The size of the monoclonal spike in the serum samples decreased, but γ-heavy chain persisted in the serum and urine. The patient died of unknown cause 20 months after the diagnosis of γ-heavy chain disease.
A 71-year-old woman presented in 1986 with a 20-year history of subcutaneous skin nodules, 1–4 cm in diameter, involving the lumbosacral area, buttocks, and thighs. Biopsy specimens of these nodules revealed tumefactive deposits of amyloid in subcutaneous tissue with increased numbers of plasma cells in the background. Bone marrow examination, which was negative for amyloid, showed 8%-10% mature plasma cells. An echocardiogram showed no evidence of amyloidosis. SPEP showed a β-spike of 1.32 g/dL. Immunoelectrophoresis of the serum revealed a biclonal gammopathy (γ-heavy chain and IgM-λ [614 mg/dL]). A 24-hour urine specimen contained 0.04 g of protein with a γ-spike of 0.02 g (γ-heavy chain). Fifteen years after the diagnosis of γ-heavy chain disease, a myelodysplastic syndrome developed and the patient required blood transfusions. She continued to have amyloid skin lesions, and the biclonal gammopathy persisted. The patient died of chronic renal failure along with a myelodysplastic syndrome and a coagulopathy 15.5 years after the diagnosis of γ-heavy chain disease. She had received no therapy other than supportive measures.
A 63-year-old man presented in 1990 with fatigue, night sweats, and axillary lymphadenopathy. Laboratory tests revealed Coombs-positive autoimmune hemolytic anemia. CT scans of the chest and abdomen were negative. Bone marrow examination revealed atypical lymphocytic aggregates but no evidence of lymphoma or myeloma. Results of immunocytochemical staining for common acute lymphocytic leukemia antigen (CALLA, CD10) were negative. Axillary node biopsy results showed an extensive plasma cell infiltrate that was consistent with a plasma cell proliferative disorder. SPEP showed a γ-spike of 2.44 g/dL (γ-heavy chain). A 24-hour urine specimen contained 2.31 g of protein with a γ-spike of 0.66 g (γ-heavy chain). The patient was treated with 4 courses of CVP, 4 courses of CHOP, chlorambucil and prednisone, melphalan and prednisone, and, later, fludarabine. The patient died of pneumonia 2 years after the diagnosis of γ-heavy chain disease. Autopsy revealed plasma cell infiltrates involving the trachea, hilar and abdominal lymph nodes, spleen, kidneys, urinary bladder, and bone marrow.
A 53-year-old woman presented in 1992 with fatigue and inguinal lymphadenopathy of 5 months’ duration. A CT scan revealed enlarged retroperitoneal and pelvic lymph nodes. The bone marrow evaluation was not diagnostic. Results of CD20 and CD45RO staining showed scattered positive cells. Lymph node biopsy findings showed malignant lymphoma, which was diffuse, small cell lymphocytic type with plasmacytoid differentiation. Flow cytometric analysis of the inguinal lymph node revealed a population of B cells that were positive for HLA-DR, CD19, and CD20. SPEP showed a β-spike of 1.30 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.09 g of protein with a β-spike of 0.04 g (γ-heavy chain). The patient was treated with chlorambucil for 5 months with no response and then with 6 courses of CHOP, resulting in a marked decrease in lymphadenopathy. At 9-year follow-up, there was no evidence of clinical disease.
In 1997, γ-heavy chain disease was diagnosed in a 78-year-old woman who had had a known monoclonal IgM-λ in her serum since 1990. She was asymptomatic, and physical examination findings were normal. SPEP revealed a β-spike of 2.95 g/dL. γ-Heavy chain and IgM-λ (471 mg/dL) were present in the serum. On urine immunoelectrophoresis, no γ-heavy chain could be documented, but an IgM-λ fragment was present. A year later, SPEP revealed a β-spike of 3.06 g/dL (γ-heavy chain and IgM-λ [319 mg/dL]). A 24-hour urine specimen contained 0.32 g of protein with a β-spike of 0.31 g. At that time, γ-heavy chain was documented in the urine. Bone marrow examination showed 10%-20% atypical plasma cells and also morphologic evidence of an IgM chronic lymphoproliferative disease with plasmacytoid differentiation. An abdominal fat aspirate was negative for amyloid. Findings of a metastatic bone survey were negative. The patient was not treated. She was alive with Alzheimer disease 4 years after the diagnosis of γ-heavy chain disease.
A 78-year-old woman presented to Mayo Clinic in 1976 with a 10-year history of a diffuse mixed lymphocytic-histiocytic lymphoma (extranodal [infrascapular mass] and nodal) that was treated with nitrogen mustard, radiation therapy, cyclophosphamide, MOPP, and vinblastine. At that time, she was asymptomatic and had no evidence of lymphoma on physical examination. Results of bone marrow examination were negative. SPEP showed a β-spike of 0.89 g/dL (γ-heavy chain). The urine was not tested for γ-heavy chain. In 1977, she returned with fever and anorexia. Bone marrow findings of 50% lymphocytes and nests of large histiocytic cells were suggestive of mixed lymphocytic-histiocytic lymphoma. SPEP showed a β-spike of 0.94 g/dL (γ-heavy chain). A 24-hour urine specimen contained 0.27 g of protein with a β-spike of 0.11 g (γ-heavy chain). The patient was treated with vincristine and prednisone. She died of sepsis 14 months after the diagnosis of γ-heavy chain disease. (This patient was previously reported as Case 3 by Kyle et al .)
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