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The Heavy Chain Diseases: Clinical and Pathologic Features Review Article [1] | January 15, 2014 | Oncology Journal [2], Hematologic Malignancies [3]By Giada Bianchi, MD [4], Kenneth C. Anderson, MD [5], Nancy Lee Harris, MD [6], and Aliyah R.Sohani, MD [7]

This review discusses the clinical presentation; epidemiology; laboratory, radiologic, and pathologicfeatures; and treatment options for each of the heavy chain diseases, emphasising the importance ofan accurate pathologic diagnosis and correct interpretation of immunologic studies in theiridentification.

Introduction

The heavy chain diseases are a group of three rare B-cell neoplasms that are clinically andmorphologically distinct from one another, but that have in common the production of an abnormalimmunoglobulin heavy chain incapable of binding light chains. The altered heavy chains containdeletions, insertions, and point mutations that are acquired during somatic hypermutation. Thesealterations typically result in loss of a large portion of the constant-1 (CH1) domain of theimmunoglobulin heavy chain molecule responsible for light chain binding, with variable effects onthe variable (V), diversity (D), and joining (J) regions (Figure 1).[1-3]

In the absence of an associated light chain, the CH1 domain of the normal heavy chain binds toheat-shock protein 78 (hsp78) and undergoes degradation in the proteasome compartment of cells;normal heavy chains unassociated with light chains are therefore never detected in serum or urine.In the heavy chain diseases, the altered structure of the CH1 domain prevents the heavy chain frombinding both the light chain and hsp78, thereby allowing it to bypass degradation by the proteasomeand be secreted into the serum or urine.[4] In addition, recent work suggests that the altered heavychain, which forms part of the transmembrane B-cell receptor, may facilitate antigen-independentaggregation and downstream signaling by the receptor, thereby conferring a growth advantage toneoplastic cells.[5]This common feature gives rise to three different diseases dependent on the heavy chain class thatis produced—each with a unique clinical presentation and characteristic findings on immunologiclaboratory evaluation and in biopsy specimens of involved tissues. The heavy chain diseases eachappear to represent an unusual variant of a type of lymphoma and are not true plasma cellneoplasms.[6] In this review, we describe the clinical and pathologic features of these diseases, withemphasis on clinical presentation and course, and histopathologic and laboratory findings, with asummary of what is known regarding treatment (Table).

Alpha Heavy Chain Disease

Epidemiology and pathogenesis

Alpha (or α) heavy chain disease is the most common of the three heavy chain diseases, with morethan 400 cases described in the literature since its initial description in 1968.[7] It has a strikingepidemiology, affecting primarily individuals of Mediterranean, Northern African, and Middle Easterndescent, particularly those of low socioeconomic background, suggesting an environmental, possiblyinfectious, pathogenetic mechanism.[8] Alpha heavy chain disease is most prevalent during thesecond and third decades of life, with a slight male predominance.

Clinical presentation

Alpha heavy chain disease typically affects the gastrointestinal system; rare cases of respiratory andlymphomatous forms have been reported. The digestive form of alpha heavy chain disease presentsas a malabsorption syndrome with weight loss, diarrhea, and abdominal discomfort. Nausea andemesis can also be present. Depending on the degree and duration of the malabsorption, patientscan manifest frank growth retardation, amenorrhea, and alopecia. Generalized lymphadenopathyand hepatosplenomegaly are uncommon in the digestive form but are hallmarks of the

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lymphomatous form, recognized as a distinct entity in 1989.[9] Physical examination in patients withdigestive alpha heavy chain disease often reveals ascites and anasarca. Nail clubbing and tetany canalso be seen.[10]Patients with the respiratory form of alpha heavy chain disease can present with dyspnea, mildhypoxemia, and diffuse pulmonary infiltrates, with a restrictive pattern on pulmonary function tests.Hilar lymphadenopathy, lymphomatous involvement of the pharyngeal mucosa, skin rash, andeosinophilia have been reported.[11]

Laboratory features and diagnostic evaluation

Common laboratory abnormalities in patients with alpha heavy chain disease includemild-to-moderate anemia, typically hypochromic; hypoalbuminemia; hypocalcemia; hypokalemia;and hypomagnesemia. Deficiency of lipophilic and hydrophilic vitamins and minerals is frequent. Thelevel of alkaline phosphatase is typically elevated, occasionally to a moderate to severe grade, dueto an increase in the gastrointestinal isoform of the enzyme.[10]Because of defective heavy chain assembly and consequent diversity of immunoglobulin A (IgA)molecular forms, serum protein electrophoresis may appear normal or showhypogammaglobulinemia. When a monoclonal band is identified, it is usually broad and migrates inthe α2 or β region of the electrophoretogram, requiring anti-IgA antiserum for its identification byimmunofixation.[12] The abnormal alpha heavy chain may be found in jejunal or gastric fluids, but isusually present in only small amounts in urine, and Bence Jones proteinuria has not beendescribed.[12,13]Microbiologic evaluation for the presence of intestinal bacteria and parasites should be conducted onstool or biopsy specimens. Radiologic studies of the upper gastrointestinal tract can show dilationsand strictures of the small bowel loops, hypertrophic or pseudopolypoid mucosa, or coarse mucosalfolds. Upper endoscopy is the diagnostic study of choice, since alpha heavy chain disease typicallyaffects the proximal small bowel at the level of the duodenum or jejunum. In a Tunisian-French studyconducted in patients with suspected alpha heavy chain disease, five patterns of endoscopicmucosal abnormality were reported. The infiltrative and nodular patterns were the most sensitiveand specific for the diagnosis of alpha heavy chain disease; in contrast, ulcerations, mosaic pattern,and isolated mucosal fold thickening alone were nondiagnostic.[14]

Histologic and immunophenotypic characteristics

The lymphoma associated with alpha heavy chain disease typically involves the small intestine andhas characteristic features of extranodal marginal zone lymphoma of mucosa-associated lymphoidtissue (MALT lymphoma); in this clinicopathologic setting, it has been termed immunoproliferativesmall intestinal disease (IPSID). The lamina propria of the bowel is heavily infiltrated by alymphoplasmacytic infiltrate rich in plasma cells, admixed with small lymphocytes resemblingmarginal zone B cells; lymphoepithelial lesions may also be present (Figure 2).[15-17] The infiltrateseparates the crypts, and villous atrophy may be seen.[15,17] The plasma cells and marginal zonecells express monoclonal cytoplasmic alpha chain without light chains. The marginal zone cellsexpress pan-B-cell antigens and are negative for CD5 and CD10, while the plasma cells are positivefor CD138 and negative for CD20.[15,17] An association between IPSID and Campylobacter jejuniinfection has been identified in some cases, suggesting a causative role for this organism in IPSIDpathogenesis, analogous to that of Helicobacter pylori in gastric MALT lymphoma.[17] However, Cjejuni has also been detected in other lymphomas of the small intestine, and to date no laboratorystudies of the effects of C jejuni on lymphoma cells or in an animal model have beenreported.[18,19]

Treatment and prognosis

Given that alpha heavy chain disease has a higher incidence in individuals of lower socioeconomicstatus, a primary-prevention strategy to improve sanitation would likely have a profound impact onits incidence. Its natural history without treatment is local progression initially, followed by systemicspread. Enlargement of lymphomatous masses typically leads to local complications, including smallbowel obstruction, perforation, and intussusception, which can be fatal. Profound malnutrition andcachexia or infectious complications are other causes of death in this population.[20]Any documented bacterial or parasitic gastrointestinal infection should be eradicated withappropriate antimicrobial therapy. A trial of empiric antibiotic therapy with metronidazole, ampicillin,or tetracycline should be administered, even in the absence of a documented infection, to improve

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malabsorption symptoms and assess for disease responsiveness. A 6-month course of antimicrobialtherapy is the shortest duration shown to be effective treatment, although regression of symptoms istypically observed early in antibiotic-sensitive disease. In patients with early-stage disease, aresponse rate to antimicrobial treatment between 33% and 71% has been reported associated withdocumented clinical, laboratory, and histological remission; however, disease recurrence isfrequent.[21] Patients should therefore be closely monitored to assess for disease progression whilereceiving antibiotics. Refractory disease is treated with either total abdominal radiation or, morecommonly, combination chemotherapy. There is no standardized regimen for the treatment of alphaheavy chain disease, but doxorubicin-containing combination chemotherapy such as CHOP(cyclophosphamide, doxorubicin, vincristine, and prednisone), CHVP (cyclophosphamide,doxorubicin, teniposide, and prednisone), or ABV (doxorubicin, bleomycin, and vinblastine) appearsto be superior to doxorubicin-free regimens such as COPP (cyclophosphamide, vincristine,procarbazine, and prednisolone); however, the latter may be better tolerated in severelymalnourished patients.[22-24] The complete remission rate after treatment with multidrugchemotherapy is 64%, and 5-year overall survival is 67%.[21] Surgical debulking of the tumor masscan be pursued, followed by systemic chemotherapy.[25] For patients with refractory or relapsingdisease, high-dose therapy with autologous hematopoietic stem cell transplantation should beconsidered.

Gamma Heavy Chain Disease

Epidemiology and pathogenesis

Gamma (or γ) heavy chain disease is also called Franklin disease, after the physician who firstdescribed it in 1964.[26] It is uncommon, with approximately 130 cases reported in the literature. Inrecent series, the median age at diagnosis is 51 to 68 years, and there is a clear femalepredominance.[27,28]While the pathogenesis of gamma heavy chain disease is unknown, an autoimmune disease ispresent in about 25% of patients. Rheumatoid arthritis is the most common autoimmune conditionassociated with gamma heavy chain disease; Sjögren syndrome, systemic lupus erythematosus,vasculitis, and myasthenia gravis, as well as autoimmune cytopenias, including idiopathicthrombocytopenic purpura, have also been reported.[29] Manifestations of autoimmune diseaseoften precede gamma heavy chain disease by many years. Most patients with gamma heavy chaindisease (83% to 91%) have an underlying systemic or localized lymphoplasmacytic neoplasm.

Clinical presentation

Gamma heavy chain disease has a heterogeneous clinical and pathologic presentation. Overall,three patterns of disease can be identified, based on the presence or absence of an associatedlymphoma. Disseminated lymphoma is seen in 57% to 66% of patients,[8] who typically present withconstitutional symptoms, including fever, malaise, and weight loss, which are associated in 50% ofcases with generalized lymphadenopathy; splenomegaly; and, less commonly, hepatomegaly.[27]Approximately one-quarter of patients present with lymphoma limited to the bone marrow (referredto in the literature as localized medullary disease) or with localized extranodal disease (referred to inthe literature as localized extramedullary disease). The most commonly reported extranodal site ofdisease is the skin; involvement of the thyroid or parotid gland, the oropharyngeal cavity, and thegastrointestinal tract have been reported.[27,29] Finally, 9% to 17% of patients have no evidentlymphoplasmacytic neoplasm at diagnosis; the majority of these patients have a pre-existingautoimmune disease. Clinical manifestations are mainly those of the autoimmune disease, includingrheumatoid nodules, rashes, synovitis, and joint deformities.

Laboratory features and diagnostic evaluation

Cytopenias, in particular a normochromic, normocytic anemia, is present at diagnosis due to eitheran autoimmune disease or bone marrow infiltration. Coombs-positive autoimmune hemolytic anemiaand autoimmune thrombocytopenia may be present. Occasionally, circulating monoclonalplasmacytoid lymphocytes or plasma cells are evident, and rarely, features of chronic lymphocyticleukemia or plasma cell leukemia may be present.[8]The diagnosis of gamma heavy chain disease requires the demonstration of abnormalimmunoglobulin protein consisting solely of gamma heavy chain, without associated light chains, byserum or urine immunofixation studies (Figure 3). The abnormal, truncated gamma heavy chain is

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often present in urine, due to its low molecular weight and existence as a dimer (rather than apolymer, as is the case for alpha and mu heavy chain disease proteins).[2] Persistent absence oflight chains on immunofixation after treatment of the serum with 2-mercapto-ethanol, a substancethat makes light chains more accessible to antisera by destroying immunoglobulin polymers, canhelp to substantiate the diagnosis. Supporting laboratory findings include elevation in serumimmunoglobulin G (IgG), without accompanying elevation in serum free light chains. Clinical andlaboratory distinction of gamma heavy chain disease from an infectious or inflammatory process issometimes difficult due to the protean clinical presentations, with constitutional symptoms and ahistory of autoimmune disease seen in a large proportion of patients overall; this complexity iscompounded by the tendency of the monoclonal band to migrate in the β region of theelectrophoretogram, where it may be obscured by other proteins.[4,27,29] Immunofixationelectrophoresis is used to characterize the monoclonal band. Rarely, biclonal gammopathy with anadditional intact monoclonal immunoglobulin may be present in the serum, or small amounts of freelight chain may be excreted in urine as Bence Jones protein.[27,30]

Histologic and immunophenotypic characteristics

The associated lymphoma typically involves bone marrow, spleen, and lymph nodes, but patientsmay also present with localized extranodal disease in sites often involved in MALT lymphoma, suchas skin, thyroid, salivary glands, gastrointestinal tract, and conjunctiva.[28,29] Examination ofinvolved tissues usually demonstrates a mixed population of lymphocytes, plasmacytoidlymphocytes, and plasma cells that is morphologically similar to lymphoplasmacytic lymphoma(Figure 4). The infiltrate is often more polymorphous, with variable numbers of immunoblasts,eosinophils, and histiocytes; rarely, atypical Reed-Sternberg–like cells suggest a morphologicdifferential diagnosis of Hodgkin lymphoma or certain types of peripheral T-cell lymphoma.[29] Othercases may demonstrate clinicopathologic features of other small B-cell neoplasms, including MALTlymphoma, splenic marginal zone lymphoma, or other splenic small B-cell neoplasms,[28] illustratingthe pathologic heterogeneity of gamma heavy chain disease relative to the alpha and mu subtypes.This histologic diversity, with many cases demonstrating features unlike lymphoplasmacyticlymphoma, suggests gamma heavy chain disease is pathogenetically distinct fromlymphoplasmacytic lymphoma; this is further supported by a study of 11 cases of gamma heavychain disease showing all were negative for MYD88 L265P, a recurrent somatic mutation found in themajority of lymphoplasmacytic lymphomas.[31,32]The lack of production of immunoglobulin light chains by IgG-positive B cells and plasma cells can beshown by immunohistochemical or in-situ hybridization studies on paraffin-embedded tissue or byflow cytometry (see Figure 4). Importantly, the plasmacytic differentiation will be missed if onlykappa and lambda light chain staining is done, as in the usual workup for lymphoma. The neoplasticcells express mature B-cell antigens (CD19, CD20), and lack CD5 and CD10; depending on the extentof plasmacytic differentiation, they may demonstrate partial or complete expression ofpost–germinal center B-cell and plasma cell markers, such as Mum1/IRF4, CD38, and CD138 (seeFigure 4).[4,28]

Treatment and prognosis

Treatment of gamma heavy chain disease is typically tailored to the symptomatology and to thepresence of an accompanying autoimmune disease or overt lymphoma. Consequently, there is nostandardized treatment. For patients presenting with disseminated lymphoma or with symptomaticdisease limited to the bone marrow (localized medullary disease), chemotherapy is recommended.Regimens include chlorambucil; rituximab in CD20-positive disease; melphalan and prednisone, orbortezomib and prednisone, for plasma cell–predominant disease; and CHOP (with rituximab inCD20-positive cases) for aggressive, refractory disease. The combination of fludarabine andrituximab has recently been effective in controlling disease in patients with gamma heavy chaindisease and associated pancytopenia.[33] Successful treatment of localized extranodal disease withsurgical resection or radiation therapy has also been reported.[29] Patients with no overt lymphomaor who are asymptomatic can be followed expectantly without therapy. Autoimmune disease shouldbe treated according to usual guidelines. Adequate infectious disease prophylaxis and surveillanceare critical, particularly in patients receiving immunosuppressive treatments.In view of the heterogeneity of the disease and treatment, the prognosis is highly variable. Patientswith no overt lymphoma may have prolonged survival without treatment, even with occasionalspontaneous remissions.[29] Those with treated, localized lymphoma may achieve a sustainedcomplete clinical and immunologic remission. Those with systemic lymphoma may have either an

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aggressive, rapidly progressive course associated with poor prognosis or may have indolent disease.In the Mayo Clinic series, median survival was 7.4 years (range, 1 month to more than 2decades).[27] The serum level of monoclonal gamma heavy chain can be used to assess diseaseevolution and response to treatment.

Mu Heavy Chain Disease

Epidemiology and pathogenesis

In 1970, Dr. Forte, a hematology fellow at Mount Sinai School of Medicine, New York, and Dr. Ballardfrom the Hematology Department at the New York Veterans Administration Hospital, independentlyreported the first two cases of mu (or μ) heavy chain disease.[34,35] Both patients were men in theirlate fifties, presenting with unremitting joint pain or stiffness. Mu heavy chain disease is the rarest inthis family of conditions, with only 30 to 40 cases reported in the literature. The disease occurspredominantly in Caucasian men, with a median age of 58 years at diagnosis.[8] The cause of muheavy chain disease is not known, but most patients have a lymphoid neoplasm resembling chroniclymphocytic leukemia/small lymphocytic lymphoma.[1]

Clinical presentation

The symptoms and signs of mu heavy chain disease are related to the associated lymphoma.Splenomegaly is almost universally present, with hepatomegaly in three-quarters of patients.[8]Palpable, superficial lymphadenopathy is identified in 40% of patients. The literature contains singlecase reports of mu heavy chain disease associated with systemic lupus erythematosus, portalhypertension, recurrent pulmonary infections, splenomegaly, and pancytopenia, as well asmyelodysplastic syndrome and systemic amyloidosis, each with clinical features reflecting theaccompanying disorder.[36,37] In one case, diffuse large B-cell lymphoma of the breast wasdiagnosed 2 years after successful initial treatment with single-agent cyclophosphamide.[38]Inter-estingly, the original 1970 papers by Drs. Forte and Ballard each reported pathologic lytic bonelesions that were attributed to lymphocytic infiltration of bone marrow. Lytic bone lesions have beensubsequently reported in about 20% of patients. Carpal tunnel syndrome and amyloid deposition inthe rectal mucosa were also present in the first two patients with mu heavy chain disease.[39]

Laboratory features and diagnostic evaluation

The most common laboratory abnormality is anemia, typically hypoproliferative and related to bonemarrow infiltration by neoplastic cells. Thrombocytopenia is less common, and lymphocytosis maybe present. Routine serum protein electrophoresis is normal in more than half of cases.[1]Immunofixation reveals reactivity to anti-mu in polymers of diverse sizes, with no associated kappaor lambda light chain.[1,36,37,40,41] In a few cases, biclonal gammopathy with an additional intactmonoclonal immunoglobulin may be present.[1] Although mu heavy chain is only rarely found in theurine, the neoplastic cells also produce monoclonal light chains, usually of kappa type, that fail toassemble with the truncated heavy chain and are excreted in the urine as Bence Jonesprotein.[1,35,42] Bence Jones proteinuria, although frequently detected, rarely causes renalcomplications.[42]

Cytologic and immunophenotypic characteristics

Bone marrow aspirate smears and touch preparations contain characteristic plasma cells withprominent cytoplasmic vacuoles, which are typically admixed with small, round lymphocytesresembling those seen in chronic lymphocytic leukemia (Figure 5).[1,35,37] Results ofimmunophenotypic analysis have been reported in only a few cases: the neoplastic cells expresscytoplasmic immunoglobulin M (IgM) and lack light chain staining by immunohistochemistry; by flowcytometry, they express CD19, CD20, and CD38.[38,43] Weak expression for kappa light chain orCD5 has been reported rarely.[1,38]

Treatment and prognosis

Data regarding treatment and prognosis are limited because of the rarity of this disease. Detectablemonoclonal mu heavy chain in a patient who is otherwise asymptomatic requires only observationwithout therapy.[44] If and when an underlying malignancy develops, treatment regimens reportedin the literature include CHOP, CVP (cyclophosphamide, vincristine, and prednisone), single-agentfludarabine, and single-agent cyclophosphamide.[8,43] Median overall survival is approximately 2

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years, with a large range—from less than a month to over a decade. However, these statistics arelikely underestimates of overall survival, since the presence of monoclonal mu heavy chains isfrequently missed on serum protein electrophoresis, especially in the absence of an associated overtlymphoma. A spontaneous remission of mu heavy chain disease has been reported.[8]

Conclusion

Heavy chain diseases are a family of rare disorders characterized by alterations in theimmunoglobulin heavy chain resulting in the pathognomonic finding of free heavy chains withoutassociated light chains in the serum and/or urine. Diagnosis of these diseases remains challengingdue to their rarity; their nonspecific clinical presentations; and the skill required in interpretingimmunologic laboratory tests and tissue biopsies from affected patients, necessitating closecollaboration between clinicians and pathologists. In addition, it remains difficult to outline the besttreatment approaches for these uncommon conditions. The advent of molecular genetic techniquesin lymphoma diagnosis may pave the way for improved diagnostic techniques and treatmentapproaches, as well as a better understanding of the pathogenesis underlying this fascinating groupof diseases.Acknowledgments: The authors are grateful to Dr. Mandakolathur R. Murali for his critical review ofthe manuscript, and to Dr. Judith A. Ferry, Michelle Forrestall Lee, and Stephen Conley for theirassistance with figure composition.Financial Disclosure: Dr. Anderson serves on the advisory boards of Celgene, Gilead, Novartis,Onyx, and Sanofi-Aventis. The remaining authors have no significant financial interest or otherrelationship with the manufacturers of any products or providers of any service mentioned in thisarticle.

Figure 1: Immunoglobulin Molecule in HeavyChain Disease

Table: Characteristic Clinicopathologic Featuresof the Heavy Chain Di...

Figure 3: Serum Protein Electrophoresis (SPEP)and Urine Protein Elect...

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Figure 2: Pathology of Alpha Heavy ChainDisease

Figure 4: Pathology of Gamma Heavy ChainDisease

Figure 5: Pathology of Mu Heavy Chain Disease

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39. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated with systemicamyloidosis. Hematology. 2004;9:135-7.

40. Maisnar V, Tichy M, Stulik J, et al. Capillary immunotyping electrophoresis and high resolutiontwo-dimensional electrophoresis for the detection of mu-heavy chain disease. Clin Chim Acta.2008;389:171-3.

41. Tamura A, Yamashiro A, Mizutani F, et al. Immunochemical properties of free mu-chain protein ina patient with mu-heavy chain disease [Japanese]. Rinsho Byori. 2003;51:847-51.

42. Preud’homme JL, Bauwens M, Dumont G, et al. Cast nephropathy in mu heavy chain disease. ClinNephrol. 1997;48:118-21.

43. Yanai M, Maeda A, Watanabe N, et al. Successful treatment of mu-heavy chain disease withfludarabine monophosphate: a case report. Int J Hematol. 2004;79:174-7.

44. Witzig TE, Wahner-Roedler DL. Heavy chain disease. Curr Treat Options Oncol. 2002;3:247-54. Source URL:

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