Physicians are highly aware of the clinical manifestations and laboratory abnormalities associated with the diagnoses of multiple myeloma, amyloidosis, and lymphoplasmacytic lymphoma. This awareness includes the ability to interpret serum and urine electrophoresis results and/or elevation of serum or urine monoclonal light chains, as well as a knowledge of common symptoms. On the other hand, most are less aware of clinical presentations of the various heavy chain diseases (HCDs). This is due in great part to the low incidence of HCDs and their highly variable clinical course. HCDs are rare lymphoproliferative B-cell disorders whose hallmark is the accumulation and secretion of truncated constant heavy chains without the associated light chains. They are categorized both by the presence of three main classes of immunoglobulins (Igs)—namely alpha (α)-, gamma (γ)-, and mu (μ)- chains—and by variable disease prognosis and treatments.[2,3]
The excellent review by Drs. Bianchi, Anderson, Harris, and Sohani in this issue of ONCOLOGY provides a current, much-needed perspective on the diagnosis and management of HCDs.
As Dr. Bianchi and colleagues note, the most common of these unusual diseases are α-HCDs, which were first described in 1968. Because of their predominant involvement of the gastrointestinal tract, α-HCDs have been widely referred to as immunoproliferative small intestinal disease (IPSID, also known as Mediterranean lymphoma/Seligmann disease). To date, only a little over 400 cases (mostly in North Africa and the Middle East) have been described.[5,6] The disease affects younger individuals (median age, 20 to 30 years) who present with gastrointestinal symptoms such as profound diarrhea and malabsorption syndrome. In α-HCD, the antibody molecules, which are commonly of the α1-isotype, lack the VH and CH1 portion of the protein, and thus a disulfide linkage between the constant heavy and light chains cannot be established. α-HCD is now generally considered a variant of extranodal marginal zone lymphoma of mucosa-associated lymph node tissue (MALT lymphoma), defined by the World Health Organization (WHO) as a population of B cells and plasma cells that infiltrate the lamina propria.
Traditionally, three stages have been defined in α-HCD that affect the treatment strategy. Stage A is characterized by a diffuse and heavy infiltration of the lamina propria by generally benign-appearing lymphoplasmacytic cells. Stage A may progress into stage B, which is defined by the presence of gross tumor (immunoblastic) with or without ulcerations. Stage B is associated with enlarged mesenteric lymph nodes and the immunoblastic cells are commonly found in association with plasma cells, which can result in villous atrophy. In stage C, a heavy monomorphic proliferation of malignant cells involving the entire intestinal wall can be seen in association with the mesenteric and extra-abdominal lymph nodes.[9,10]
The driving signal for α-HCD is unknown. One potential mechanism of pathogenesis may be the chronic and intensive antigenic stimulation by infectious agents such as Campylobacter jejuni, similar to that of Helicobacter pylori in gastric MALT lymphomas. This infectious association and its higher prevalence in lower socioeconomic groups have resulted in the postulation that poor hygiene and sanitation are the primary drivers of the disease. However, the limited geographical distribution of α-HCD suggests that environmental/genetic as well as infectious etiologies may play a role. An interesting observation in a small group of 21 Middle Eastern patients with IPSID, who had a higher frequency of HLA-AW19 and HLA-B12 class I major histocompatibility complex (MHC) antigens compared with the general population, supports the notion that an inherent immunogenetic mechanism may be a contributing factor. Another pathologic mechanism for the development of HCDs was elegantly proposed over a decade ago based on empiric observation. Experiments showed that VH gene deletions/insertions, in addition to somatic hypermutations, can result in oncogenic genetic translocations and transformation of normal B cells into malignant lymphomas as well as HCDs.
Other mechanisms of uncontrolled proliferation may be at work as well. An interesting observation has been made that some α-HCDs, especially those at higher stages (immunoblastic and lymphomatous types), have a paucity of secreted heavy chain proteins. These “nonsecretory” variants can produce a membrane-bound form of the α-chain which may provide a survival advantage by not only evading idiotypic negative selection but also participating in activating signals for B-cell proliferation via intracellular signaling.[14-16] Evidence for the latter stems from accumulating data that show that deletions of ligand-binding domains of the cell surface Ig family of receptors, such as those seen in diffuse large B cell lymphoma (DLBCL)-activated B-cell type or conformationally active mutant epidermal growth factor (EGF) receptors, can produce proteins capable of dimerization and subsequent intracellular proliferative signaling in the absence of a cognate ligand. This has been suggested to be a driving signal in pathogenesis of HCDs. No consistent cytogenetic abnormality has been found in α-HCD, although the number of patients studied has been few, with significant gaps in time between investigations. As Dr. Bianchi and colleagues describe, serum protein electrophoresis does not typically show a distinct gammopathy, but 50% of patients show an abnormal band co-migrating in the α2-/β-globulin region due to the presence of polymers of various lengths. Urinary excretion of a paraprotein is low, but intestinal secretions can be analyzed for secreted heavy chains.
The authors present a comprehensive overview of treatment, which is notable for the lack of one specific approach. In a prospective study of 23 patients with IPSID, 7 with stage A disease received antibiotics (tetracycline) for a median duration of 7 months initially. Those with stage B/C disease (16 patients) were given combination chemotherapy with COPP (cyclophosphamide, vincristine, procarbazine, and prednisolone); patients who achieved a complete response (CR) after the COPP regimen received antibiotics (tetracycline) for 6 more months. After a median follow-up of 68 months, 71% of stage A patients had a CR with tetracycline alone. Nearly 70% of stage B and C patients had a CR. The 5-year overall survival (OS) in the combined group was 70%. Three of the seven stage C patients with immunoblastic-type disease had a significantly shorter OS (7 months). A prospective randomized trial published in an abstract form compared abdominal irradiation plus chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) vs C-MOPP (cyclophosphamide, vincristine, procarbazine, and prednisone) and showed improved results with the doxorubicin-containing regimen.
As mentioned in the review by Bianchi et al, a prospective study of 21 North African patients with α-HCD treated with antibiotics alone for stage A disease and CHVP chemotherapy (cyclophosphamide, doxorubicin, teniposide, prednisone) at times alternating with bleomycin and doxorubicin plus vinblastine for stage B and C disease also provided good clinical results. In this study, six stage A patients were first treated with antibiotics alone, with two CRs. Among those with stage B and C disease, 9 of 13 patients achieved a CR, with one early relapse in a patient who received salvage chemotherapy. With all stages combined, 80% to 90% of patients had 2-year OS, and 45% to 65% had 3-year OS. In a case study, treatment of a 28-year-old patient with CEOP-IMVP-dexa (cyclophosphamide, epidoxorubicin, vincristine, prednisolone, ifosfamide, methotrexate, VP-16, dexamethasone) resulted in a CR 3 years after completion of treatment.
As mentioned by Bianchi and colleagues, surgical resection should be performed in cases of localized disease or visceral complications such as perforation. Bone marrow transplantation has been suggested for younger patients with refractory disease.
As Bianchi et al note, fewer than 150 cases of γ-HCD have been described in the literature. A recent report of 13 patients found a predominance in women and an association with a heterogeneous group of conditions, including nodal and extranodal MALT, splenic marginal zone, and splenic B-cell lymphomas; and autoimmune diseases. The most common autoimmune presentations, which account for 33% of all γ-HCD patients, include rheumatoid arthritis, Sjögren syndrome, immune thrombocytopenia purpura, autoimmune hemolytic anemia, and systemic lupus erythematosus. Although no pathognomonic pathologic features have been identified, histologically, pleomorphic plasmacytoid and plasma cells, expressing pan-B-cell markers, have been described. The cells produce structurally truncated gamma-immunoglobulin heavy chains that can be found intracytoplasmically without the associated light chains. In the largest single-institution analysis of 23 γ-HCD patients between 1976 and 1998, a total of 44% had disseminated disease (chronic lymphocytic leukemia [CLL], lymphoplasma cell proliferative disorder, angioimmunoblastic T-cell lymphoma, DLBCL, and Hodgkin lymphoma) while 26% presented with localized lymphoproliferative disease (thyroid, parotid, skin, oropharyngeal cavity). Those with localized disease can have a plasmacytoma-like feature as their presenting pathology. In this cohort, autoimmune disease with associative lymphoproliferative disorder (CLL and plasma cell disorders) was seen in 13%, and an equal percentage of patients had only autoimmune disease as their presenting pathology. Interestingly, none were diagnosed with HCD prior to the diagnosis of their lymphoid or autoimmune diseases, suggesting that the underlying disease is the possible driving force for heavy chain secretion. Approximately 60% to 80% of patients have an identifiable monoclonal gammopathy (immunoglobulin G1 [IgG1]), with the majority in the β-region of a gel immunoelectrophoresis. As Bianchi et al correctly recognize in their review, the absence of a definite monoclonal spike, as well as a lack of urinary paraprotein and light chains, makes the diagnosis difficult. Thus the absence of an underlying κ or λ light chain staining in the face of numerous plasmacytoid/plasmacytic cells should be followed by staining for Ig heavy chains as well as CD138, to rule out HCD.[28,29] As in α-HCD, conventional cytogenetics are not informative. The γ-HCD proteins are dimers of truncated heavy chains with variable lengths. In the majority of patients studied, the defective chains have normal starting VH-coding sequences interrupted by deletions of different lengths in the internal V chain sequences.[26,29] As in α-HCD cases, the CH1 domain is deleted, with a normal protein sequence beginning at the hinge region. The prognosis of γ-HCD is variable, depending on the nature of accompanying disease and whether it is localized or disseminated. Rituximab-based treatment (R-CHOP, R-fludarabine) for lymphoma-associated disease and melphalan/bortezomib-based treatment for plasmacytic forms have been implemented, although there is no established standard treatment. In general, asymptomatic patients can be observed.
Mu-HCD is the rarest of this unusual group of B-cell neoplasms (with 30 to 40 cases reported in the literature) . It was initially reported in 1970, in a CLL patient who presented with lytic bone lesions atypical of CLL, in addition to hepatosplenomegaly. Mu-HCD affects mainly Caucasian individuals with a median age of 57 years. In a study of 27 cases, 80% were associated with other underlying hematologic diseases, including monoclonal gammopathy of undetermined significance (MGUS), lymphoplasmacytic lymphoma (LPL), myeloma, and CLL. In contrast to α- and γ-HCDs, μ-type diseased cells are capable of producing light chains that are secreted in the urine as Bence Jones proteins but that do not have the common nephrotoxic consequences typical of myeloma, although case reports of cast nephropathy and amyloidosis have been reported.[31-33] The immunoglobulin heavy chains are characterized by monoclonal μ-chains lacking heavy chain variable region (VH) DNA, and some patients have variable loss of the CH1 region, with an inability to bind the light chains. The absence of a monoclonal immunoglobulin component (M-component) makes identification of this disease challenging. The histology appears to show increased numbers of lymphocytes, with scattered vacuolated plasma cells.
Therapy is based on the underlying associated disease. Because of the extreme rarity of the disease, no large patient cohorts can be studied. Detection of μ-HCD in an otherwise asymptomatic MGUS patient can be observed but needs to be evaluated for development of LPL or myeloma.
One of the first tenets of medicine is, “if you hear hoof beats, don’t look for zebras.” However, HCDs are the exception to this rule. In fact, clinicians should be aware of them, especially in patients with a common hematologic diagnosis such as CLL but with atypical features. Similarly, in patients with underlying autoimmune disease, associated hematologic abnormalities may be linked to an associated heavy chain disorder and not directly to the autoimmune disease. The rarity of the HCDs makes general treatment recommendations challenging. While basic therapies often follow the paradigms of lymphoma therapy, this too may evolve as newer agents are used in various lymphomas. For example, the use of lenalidomide in CLL, B-cell receptor inhibitors in mantle cell lymphoma, and phosphoinositide 3-kinase (PI3K) inhibitors in both diseases may provide strategies previously not tested.
One important consideration should be noted. Given that the prognosis of HCDs, especially those of γ- and μ-HCDs, is significantly variable and dependent upon the underlying associative disease, one should be mindful of whether a specific HCD diagnosis has a clinical implication per se. This is further complicated by the usefulness of the serum/tissue level of a particular heavy chain type as a marker of treatment response. For instance, it is not unusual to identify persistent disease in the face of γ and μ heavy chain proteins disappearing from the serum and to have a relapse of the underlying disease without the reappearance of the pathologic heavy chain protein.[3,28] An exception to this may be α-HCD, as early-stage detection may provide an opportunity to treat the disease with a simple antibiotic regimen alone prior to its dissemination to lymph nodes and development into an aggressive lymphoma.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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