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Heavy chain diseases

Written2020-06Diego Conde Royo, Luis Miguel Juárez Salcedo, Samir Dalia
Principe de Asturias University Hospital, Madrid, Spain (DCR), Gregorio Maran University Hospital, Madrid, Spain (LMJS), Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA (SD).

Abstract Review on the heavy chain diseases, difference and similarities among them with data on clinics and genes involved.

Keywords B-cell neoplasms; heavy chain diseases; gamma heavy chain disease; alpha heavy chain disease; mu heavy chain disease.

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ICD-Topo C420,C421,C424
ICD-Morpho 9762/3 Heavy chain diseases; Gamma heavy chain disease; Mu heavy chain disease; Alpha heavy chain disease
Atlas_Id 1723
Other namesImmunoproliferative small intestinal disease
Mediterranean lymphoma
Seligmann disease
Franklin disease.

Clinics and Pathology

Disease The heavy chain diseases (HCD) are three infrequent B-cell neoplasms defined by the generation of monoclonal immunoglobulin heavy chains in the absence of light chains (LC). Depending on the class of the heavy chain produced, three different entities must be distinguished: alpha HCD (IgA), gamma HCD (IgG), and mu HCD (IgM). All of them present different clinical, morphological, and prognostic features; however they could have similar characteristics to other well-defined histological entities. The clinical spectrum varies from asymptomatic forms to localized or systemic involvement (lymph nodes, bone marrow, liver/spleen, or gastrointestinal tract). Their prognosis varies ranging from indolent or slow-progressive disease to rapidly evolution and fatal events without treatment. Demonstration of free heavy chains by protein immunofixation or electrophoresis is needed to establish a diagnosis. Other studies such as histological samples, imaging, or endoscopic approaches will be helpful for better disease characterization. No standardized treatment is available for HCD except alpha subtype, thus management needs to be individualized: watch&wait strategy, antibiotics, surgery, or chemotherapy are the most frequent treatment tools in HCD.
Etiology An immunoglobulin is conformed by two heavy chains and two LCs, being the domain 1 of the heavy chain constant region (CH1) responsible for the light chain binding. If there is no LC for that junction, the heat shock protein 78 (CLPB (HSP78)) leads to proteasomal degradation of the heavy chain by its connection to CH1. This process is the reason why, in normal situations, free heavy chains are not detected in serum (Ria R et al., 2018). In HCD the CH1 domain presents an abnormal structure that avoids the attachment of LC or HSP78, as a result, free heavy chain may be detected in serum or urine (less frequent) (Munshi NC, et al. 2008). It has been proposed a growth advantage in the B malignant cells of HCD. The heavy chain is a component of the B-cell receptor and in HCD the mutant heavy chain facilitates antigen-independent proliferation leading to cell expansion (Corcos D, et al. 2011). In alpha HCD cases more studies had hypothesized different theories about its pathogenesis. In a context of impaired cellular and humoral immunity, Campylobacter Jejuni small bowel infection could produce chronic antigenic stimulation, which finally leads to a plasma cell proliferation (Hassane DC et al., 2003).
Epidemiology Alpha HCD is the most common of these entities. In the past 50 years around 500 cases were reported (Bianchi G, Sohani AR, 2018). There is no difference in incidence rate by gender, affecting young patients in their second and third decades (Cook JR, et al., 2017). It is related to low socio-economics status in Northern African, Mediterranean and Middle East areas (Wahner-Roedler DL, Kyle RA, 2005). In fact, alpha HCD is recognized also as Mediterranean lymphoma or Seligmann disease.
Gamma HCD, also known as Franklin disease, is less frequent than alpha HCD being around 150 cases described. It presents a slightly female predominance with a median age of diagnosis between 51-68 years (Wahner-Roedler DL, et al., 2003) (Bieliauskas S, et al., 2012).
Finally, mu HCD is the most rare of the three entities, with less than 50 cases reported in the literature. It is more prevalent in Caucasian race, almost equally distributed among males and females with a median age of 60 years at diagnosis (Wahner-Roedler DL, Kyle RA, 2005).
Clinics The localization of alpha HCD involves gastrointestinal tract, the duodenum is the most common location (63%) followed by jejunum (17%) and ileum (8%) (Pervez S et al., 2011). Different locations as bone marrow or other organs are infrequent, however thyroid or respiratory tract involvement has been reported (Cook JR, et al. 2017). Indeed, alpha HCD is also known as immunoproliferative small intestinal disease. Symptoms and laboratory tests results are consistent with malabsorption syndrome. Abdominal pain, nausea, diarrhea or steatorrhea are common; and in chronic cases: alopecia, weight loss, amenorrhea or bowel obstruction. Laboratory findings include: hypochromic anemia, hypocalcemia, hypomagnesemia, hypokalemia, hypoalbuminemia and incrased alkaline phosphatase (Bianchi G, Sohani AR, 2018). Usually, serum protein electrophoresis is normal; nevertheless, a monoclonal band could be observed in α2 or β region. Identification of altered alpha heavy chain by immunofixation is mandatory to confirm the diagnosis. This identification is performed on serum or jejunal/gastric fluid, whereas is commonly absent in urine (Ria R et al., 2018). Endoscopic studies are also helpful in the diagnostic approach. Five patterns have been proposed as diagnostic tool: ulcerated, mucosal fold thickening, mosaic, nodular and infiltrative. Being the last two the most characteristic of alpha HCD (Al-Saleem T, Al-Mondhiry H, 2005). Imaging studies may show stricture or dilatations of small bowel as well as mucosal disturbances such as hypertrophic or pseudopolypoid changes, including coarse folds (Bianchi G, et al., 2014).
In gamma HCD the vast majority of patients present systemic symptoms as a consequence of its systemic involvement. Fever, anorexia, weight loss and asthenia are frequent; while organ involvement encompass lymph nodes, liver, spleen, gastrointestinal tract, bone marrow or peripheral blood (Cook JR, et al. 2017). Autoinmune manifestations are reported in one-third of cases, being rheumatoid arthritis and systemic lupus erythematosus the most common along with autoimmune cytopenias, vasculitis, thyroidits or Sjögren syndrome. Indeed autoimmune disorders could antecede the lymphoma diagnosis (Wahner-Roedler DL, et al., 2003) (Bieliauskas S, et al., 2012). Three different patterns are defined: disseminated lymphoma, localized medullary disease and localized extramedullary disease (skin, thyroid or parathyroid gland or gastrointestinal tract) (Ria R et al., 2018). Laboratory findings are in consonance with the diagnostic of autoimmune disorders or organ involvement: anemia, hemolytic pattern, thrombocytopenia or circulating plasma cells/lymphocytes. The diagnosis of gamma HCD requires the demonstration of IgG without LC by immunofixation; however a monoclonal band in the β region could be observed on the electrophoresis. Urine studies could shown an abnormal gamma heavy chain as well as free LCs (Wahner-Roedler DL, Kyle RA, 2005).
Mu HCD cases are defined by a slowly progressive hematological neoplasm similar to chronic lymphocytic leukemia (CLL). The peripheral blood, liver, spleen and bone marrow are usually involved although lymph nodes may be preserved. Thus the main different between mu HCD and CLL is the location of the tumor, with the involvement of the liver and spleen meanwhile lymph nodes are not affected (Cook JR, et al. 2017). Is necessary a positive immunofixation against IgM to confirm the diagnosis. The serum protein electrophoresis is normal; nevertheless Bence Jones proteinuria is observed in 50% of cases since the neoplastic cells could produce LCs. However, the latter ones are not able to assemble with the heavy mu chain (Maisnar V, et al., 2008).
Pathology Microscopic features of alpha HCD are similar to those of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT); indeed is considered by the World Health Organization as a variant of it. The infiltrate is observed among the lamina propia of the bowel. It is composed of plasma cells and small lymphocytes being accompanied in some cases with marginal zone B cells and the development of lymphoepithelial lesions. Furthermore, the infiltrate could separate the crypts and be responsible for the formation of villous atrophy (Pervez S et al., 2011). In cases of progression to diffuse large B cell lymphoma, solid destructive aggregates of large plasmocytoid cells and immunoblasts that could produce ulceration are reported (Cook JR, et al. 2017).
Histological findings in gamma HCD are varied, becoming the microscopic diagnostic a real challenge; indeed some cases mimic other specific entities as MALT lymphoma or splenic marginal zone lymphoma. Gamma HCD lymph nodes usually present a heterogeneous proliferation of lymphocytes, plasma cells, and plasmacytoid lymphocytes (Wahner-Roedler DL, Kyle RA, 2005) (Bianchi G, et al., 2014). Similar to classic Hodgkin lymphoma or angioimmunoblastic T-cell lymphoma, in gamma HCD cases, an infiltrate of immunoblasts, histiocytes, and eosinophils could be observed as well as atypical Reed-Sternberg-like cells (Ria R et al., 2018). Bone marrow findings encompass lymphoplasmocytic aggregates or a slight peak in plasma cells with gamma heavy chain expression. On the other hand, the peripheral blood may resemble CLL/ lymphoplasmacytic lymphoma with lymphocytosis accompanied by plasmocytoid lymphocytes in some patients (Cook JR, et al. 2017).
The bone marrow findings of mu HCD consist of an infiltrate of vacuolated plasma cells with small and round lymphocytes resembling CLL cells (Ria R et al., 2018).
In alpha HCD expression of pan B antigens (CD19, CD20, CD79a and PAX 5) is observed in lymphocytes; CD 138 and CD 79a is also expressed by plasma cell that lack the CD20 antigen. Both, plasma cells and lymphocytes, shows monoclonal alpha heavy chain in their cytoplasm without LC. Marginal zone cells have CD5 and CD10 in their surface, lacking CD20 (Al-Saleem T, Al-Mondhiry H, 2005) (Cook JR, et al. 2017).
Gamma HCD cells express CD79a and cytoplasmic gamma heavy chain with no expression of LC in the majority of cases; meanwhile are negative for CD5 and CD10. Furthermore, CD20 and CD138 are also observed on lymphocytes and plasma cells, respectively (Wahner-Roedler DL, Kyle RA, 2005) (Bieliauskas S, et al., 2012).
The expression of monoclonal cytoplasmic mu heavy chain is going to define mu HCD cells, and may be accompanied by monotypic LC. As well, the expression of B cell antigens is frequent and similar to previous cases CD5 and CD10 are commonly negative (Cook JR, et al. 2017).
Cytogenetics Rearrangements in immunoglobulin genes (IGHA, IGHG, and IGHM) and high levels of somatic hypermutations are frequent. Deletions on those genes imply the production of a truncated heavy chain protein responsible for the failure to form a complete immunoglobulin molecule. The deletions take part in IGHV and variable regions of the CH1 domain (Wahner-Roedler DL, Kyle RA, 2005).
The t(11;18)(q21;q21) ( BIRC3 / MALT1) reported in pulmonary and gastric MALT lymphoma have not been associated with alpha HCD (Ye H, et al., 2003). Isolated cytogenetic abnormalities have been described in rare cases with an uncertain role in the pathogenesis of the disease.
Abnormal karyotype has been described in half gamma HCD patients, however, no characteristic genetic aberration was recognized (Cook JR, et al. 2017).
Treatment The treatment approach in alpha HCD is defined by disease stage. Antimicrobial treatment should be implemented if an infection is documented or in early-stage. Ampicillin, tetracycline, or metronidazole are recommended, alone or in combination. Despite early regression or dramatic improvement of symptoms are commonly reported, an empiric 6-month antibiotic course is suggested since relapses have been described with shorter treatment duration. Remission rates with this regimen are around 33-71% (Ria R et al., 2018). However, disease relapses are usual. In these cases, or if the patient did not achieve remission after 1 year of antibiotic treatment or in intermediate/advanced stage, anthracycline-based regimens are the treatment choice. Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is the most frequent scheme and along with other alternatives as cyclophosphamide, doxorubicin, and prednisone (CVP), could achieve 5-year overall survival rates of 67%, with a complete remission rate of 64%. In relapsed/refractory cases, high dose chemotherapy followed by stem cell transplantation remains as a potential line in individualized cases (Bianchi G, Sohani AR, 2018).
Similar to the previous, start of treatment depends on the disease stage in gamma HCD patients. A wide range of approaches includes watch&wait strategy in asymptomatic cases, immunosuppressive therapy when autoimmune entities are diagnosed, radiotherapy, or surgery in localized extranodal disease and chemotherapy in systemic disease. A variety of chemotherapy schemes have been reported with no standardized treatment: melphalan, chlorambucil, bortezomib, CHOP, fludarabine or rituximab, alone or in combination (Inoue D, et al., 2012) (Ria R et al., 2018).
Similar to previous cases, there is no standardized treatment for mu HCD patients. Also, the lower incidence of this disease implies an increased difficulty to establish a common approach. Watch&wait strategy is reserved for asymptomatic patients while schemes like CHOP, CVP, cyclophosphamide, or fludarabine in monotherapy are administrated in symptomatic cases (Yanai M, et al., 2004) (Wahner-Roedler DL, Kyle RA, 2005).
Prognosis Some authors considered alpha HCD as a pre-lymphomatous condition with fluctuating prognosis depending on the stage. The natural history consists of subsequent remissions and relapses periods until lymphoma development. Three different disease phases have been postulated: an early one which bowel wall infiltration without distinguishable mass is the main characteristic, an intermediate stage when the tumor is disrupting the wall of the small bowel with or without lymphoid involvement and an advanced phase defined by the presence of bulky mass (Bianchi G, Sohani AR, 2018).
The natural course of gamma HCD is associated with systemic expression of lymphoma, being its prognosis indolent or poor depending on the aggressive behavior or not of that lymphoma. The Mayo Clinic series reported a median overall survival of 7.4 years with most of the mortality non-related to the lymphoma (Wahner-Roedler DL, et al., 2003).


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This paper should be referenced as such :
Conde Royo D, Juárez Salcedo LM, Dalia S
Heavy chain diseases;
Atlas Genet Cytogenet Oncol Haematol. in press
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