The three groups of HCDs (alpha-HCD, gamma-HCD, and mu-HCD) are regarded as variants of non-Hodgkin lymphoma; all have abnormal heavy chains, usually with parts of the constant region deleted, but otherwise have diverse features [1]. The abnormal heavy chains, which have lost the ability to bind light chains or chaperone molecules, are also parts of the B cell receptor, and therefore, possibly through spontaneous aggregation of the receptors, may be responsible for the uncontrolled division of the neoplastic B cells [2].

Alpha-HCD has the least diversified presentation and the highest prevalence within the HCDs [1], though still a rare disease. It typically affects young people of Mediterranean origin [3]. This disease most often damages the gastrointestinal system and causes a malabsorption syndrome with weight loss, diarrhea, nausea and other digestive symptoms. Rarely, a respiratory form is also encountered.

The presentation of gamma-HCDs, which affect middle-aged and older people, is very heterogeneous [4]. The majority (two-thirds) of the patients have disseminated disease, whereas about a quarter have the disease localized to the bone marrow or other locations, most frequently the skin. About ten percent of the patients show only gammopathy. Gamma-HCD is associated with autoimmune diseases in about a quarter of the patients.

People suffering from the disseminated form of the disease present with the general symptoms of lymphoproliferative conditions, such as fever, weight loss, mild anemia and other general complaints. Lymphadenopathy and splenomegaly are common; hepatomegaly is less frequent [5]. Lymphadenopathy may eventually lead to edema of the soft palate.

Mu-HCD occurs mainly in late middle-aged adults. In the early examples of Mu-HCD, a strong association with chronic lymphocytic leukemia was suspected, but by now the two diseases seem more distinct [6], with only about a third of mu-HCD patients also diagnosed with chronic lymphocytic leukemia. The presentation of Mu-HCD is variable, as is its association with other conditions such as multiple myelomas, plasmacytoma, and other diseases, such as amyloidosis [7]. Splenomegaly is observed in almost all cases, and hepatomegaly is frequent. Lymphadenopathy is present in almost half the cases. Bone lesions and fractures are also fairly common and may be ascribed to lymphocytic infiltration of the bone [8].

• Anemia

  Some of these are general, such as mild anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hypocalcemia, hypokalemia, and hypomagnesemia. [symptoma.com]

  CBC may show anemia, leukopenia, thrombocytopenia, eosinophilia, and circulating atypical lymphocytes or plasma cells. [merckmanuals.com]

  He had direct Coombs' test positive auto-immune hemolytic anemia associted with subacute bacterial endocarditis (SBE). [ncbi.nlm.nih.gov]

  Up to one third of patients with γ-HCD have an associated autoimmune disorder (eg, rheumatoid arthritis, Sjogren syndrome, lupus erythematosus, and autoimmune hemolytic anemia ). [5, 6] Watchful observation is warranted in asymptomatic patients who have [emedicine.com]

• Asymptomatic

  Up to one third of patients with γ-HCD have an associated autoimmune disorder (eg, rheumatoid arthritis, Sjogren syndrome, lupus erythematosus, and autoimmune hemolytic anemia ). [5, 6] Watchful observation is warranted in asymptomatic patients who have [emedicine.com]

  The clinical course of gamma heavy chain disease varies from an asymptomatic state to a rapidly progressive malignancy. [ncbi.nlm.nih.gov]

  However, in patients with benign monoclonal gammopathy, patients are asymptomatic and there is no evidence of impairment of antibody response or bone marrow function. [patient.info]

• Swelling

  If heavy chains deposit in the kidneys, people might notice swelling in the legs and the rest of the body. [unckidneycenter.org]

  Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. [ncbi.nlm.nih.gov]

  Author: Lucien Courtois; Pierre Sujobert Category: Lymphoma: Mature B-cell and Plasma cell Neoplasms > Plasma Cell Neoplasm Published Date: 08/21/2017 A 64-year-old patient presented with lymph node swelling and altered performance status. [imagebank.hematology.org]

  Depending on the plasma cell disorder and which organs are affected, the person may have a variety of symptoms, such as: Bone aches Weakness, fatigue Numbness, weakness or tingling of the arms and legs Swelling of ankles and legs Shortness of breath, [labtestsonline.org]

  Symptoms include pain, swelling, loose teeth, exposed bone, drainage, and infection. This occurs in somewhere between 1 % and 5% of people who have been on the drugs for many years. [cancer.ucsf.edu]

• Pathologist

  According to the pathologist, the histological sections showed a lymph node with an unstructured architecture due to the proliferation of medium to large-sized lymphocytes with vesicular chromatin and nucleoli (centroblasts) and some other smaller cells [biochemia-medica.com]

  This core will be processed in the laboratory, calcium will be removed and the specimen will be sliced and reviewed on a slide by the pathologist. This process takes over 24 hours to complete. [cancer.ucsf.edu]

• Inflammation

  It may also be difficult to distinguish gamma-HCD from inflammation or infections. The disease is accompanied by general symptoms, such as anemia. The complete blood cell count often reveals eosinophilia and thrombocytopenia. [symptoma.com]

  However, if they become trapped in the tissues of the kidneys, lungs, skin, joints or blood vessels, the light chains can set off reactions leading to tissue or organ inflammation and damage. [lls.org]

• Nausea

  There could also be frothy or foamy urine, tiredness, a bad taste in the mouth, loss of appetite, itching, trouble concentrating or difficulty with memory, nausea, and vomiting. [unckidneycenter.org]

  This disease most often damages the gastrointestinal system and causes a malabsorption syndrome with weight loss, diarrhea, nausea and other digestive symptoms. Rarely, a respiratory form is also encountered. [symptoma.com]

• Vomiting

  There could also be frothy or foamy urine, tiredness, a bad taste in the mouth, loss of appetite, itching, trouble concentrating or difficulty with memory, nausea, and vomiting. [unckidneycenter.org]

Alpha-HCD is accompanied by some abnormal laboratory results. Some of these are general, such as mild anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hypocalcemia, hypokalemia, and hypomagnesemia. Plasma alkaline phosphatase levels are often high, owing to an increase in the intestinal isoform of the enzyme [3]. Serum electrophoresis can be normal, and the electrophoretic pattern is not revealing [9]. Thus, the diagnosis of the disease, that is the identification of the abnormal heavy chain, has to rely on immunological methods [9]. The mutated protein is also present in intestinal secretions, but absent, or only in very small concentrations, in urine. If otherwise undetected, the defective heavy chain has to be identified by an intestinal biopsy.

Alpha-HCD primarily affects the duodenum and jejunum, and these parts of the small bowel are heavily infiltrated by plasma cells mixed with small lymphocytes. Endoscopy of the upper part of the gastrointestinal tract has been used to identify mucosal abnormalities. Of the several types of anomaly identified, the patterns of infiltration are the most sensitive predictors of the disease [10]. The disease has been classified as the immunoproliferative small intestinal disease (IPSID); an association with Campylobacter jejuni infection has been proposed for this and other lymphomas of the small intestine.

Diagnosis of gamma-HCDs is challenging because this disease presents as a spectrum of disorders. The difficulty in differentiating the gamma-HCDs from other lymphoproliferative diseases is reflected by the fact that the 2008 World Health Organization classification places this condition as a separate disease within the heavy chain disease group, but then also discusses gamma-HCD as a variant of lymphoplasmacytic lymphoma [11]. It may also be difficult to distinguish gamma-HCD from inflammation or infections.

The disease is accompanied by general symptoms, such as anemia. The complete blood cell count often reveals eosinophilia and thrombocytopenia. Serum protein electrophoresis shows the monoclonal gamma heavy chain in about three-quarter of the patients. The defective gamma chain is often present in the urine. Diagnosis is by immunological detection of the abnormal heavy chain in the serum or urine, with no immunologically observable light chains. The sites affected are mainly the bone marrow, spleen, and lymph nodes, but extranodal sites are also involved [11]. The histology is variable. Hyperuricemia frequently occurs in advanced stages.

For diagnosing Mu-HCDs, exploration of the bone marrow is often necessary. The marrow contains multivacuolated plasma cells, observed in the majority (two-thirds) of the patients; thus, this is a characteristic but not universal feature of the disease. Almost half of the patients present with osteolytic lesions, necessitating the evaluation of the state of the skeleton.

Serum or urine protein electrophoresis and immunofixation are indispensable for diagnosis. The mu heavy chains are shown by these methods to be present in the form of heterogeneous polymers without associated light chains [12] [13]. However, light chains are produced, and being unbound to the heavy chains, are often excreted in the urine.

• Hyperglobulinemia

  1998 44 Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. ( 9482908 ) Goossens T....KA1ppers R. 1998 45 A case of mu heavy-chain disease associated with hyperglobulinemia [malacards.org]

  : A case of mu heavy-chain disease associated with hyperglobulinemia, anemia, and a positive Coombs test. Ann Hematol 1998, 77:231–234. PubMed CrossRef Google Scholar 21. [link.springer.com]

• Hyperglobulinemia

  1998 44 Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. ( 9482908 ) Goossens T....KA1ppers R. 1998 45 A case of mu heavy-chain disease associated with hyperglobulinemia [malacards.org]

  : A case of mu heavy-chain disease associated with hyperglobulinemia, anemia, and a positive Coombs test. Ann Hematol 1998, 77:231–234. PubMed CrossRef Google Scholar 21. [link.springer.com]

• Hyperuricemia

  Hyperuricemia frequently occurs in advanced stages. For diagnosing Mu-HCDs, exploration of the bone marrow is often necessary. [symptoma.com]

  Hypercalcemia and hyperuricemia can occur as a result of myeloma and can contribute to renal failure. In addition, the myeloma cells can directly infiltrate the kidneys resulting in dysfunction. [cancer.ucsf.edu]

• Hyperviscosity

  Hyperviscosity. Nephrotic syndrome, cardiac failure, malabsorption. Peripheral neuropathies, carpal tunnel syndrome. Incidental persistent elevated erythrocyte sedimentation rate (ESR). [patient.info]

• Immunoglobulin A Increased

  The heavy-chain fragment (molecular weight, 32,000 daltons) has disappeared from the serum and urine, while the previously low levels of normal immunoglobulins have increased. [ncbi.nlm.nih.gov]

Management of symptomatic disease focuses on palliative care, as disease treatment has been disappointing. (See Treatment, Medication, and Follow-up ) [emedicine.com]

This review focuses on current knowledge and novel insight regarding its pathogenesis, outcome, and treatment, with an emphasis on future directions. [ncbi.nlm.nih.gov]

Treatment usually includes chemotherapy drugs and corticosteroids. Length of survival and response to treatment vary widely. Generic Name Select Brand Names cyclophosphamide CYTOXAN (LYOPHILIZED) prednisone RAYOS NOTE: This is the Consumer Version. [merck.com]

[…] scp=0036616817&partnerID=8YFLogxK M3 - Article VL - 3 SP - 247 EP - 254 JO - Current Treatment Options in Oncology T2 - Current Treatment Options in Oncology JF - Current Treatment Options in Oncology SN - 1527-2729 IS - 3 ER - [mayoclinic.pure.elsevier.com]

Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics. [ncbi.nlm.nih.gov]

Prognosis The clinical course is variable, depending on subtype. Outcome is very good in patients without lymphoma, in whom prognosis is related to underlying autoimmune disease. [atlasgeneticsoncology.org]

Prognosis This will depend on the underlying cause. Prognosis is often poor. However, in patients with benign monoclonal gammopathy, patients are asymptomatic and there is no evidence of impairment of antibody response or bone marrow function. [patient.info]

Prognosis The course of mu-HCD is variable. [emedicine.medscape.com]

Etiology Deletions, insertions or point mutations in the constant 1 (CH1) domain of the IgH are acquired during the process of somatic hypermutation. [atlasgeneticsoncology.org]

Etiology, Epidemiology and Pathophysiology Etiology The cause or causes of myeloma are unknown, but there is some evidence to support a number of theories of its origin, including viral, genetic, and exposure to toxic chemicals, the most notable being [cancer.ucsf.edu]

Kyle Springer Science & Business Media, 31.07.2012 - 1431 Seiten Neoplastic Diseases of the Blood integrates the history, epidemiology, pathology, pathophysiology, and therapeutics of modern neoplastic hematopathology. [books.google.de]

The heavy chain thus bypasses degradation and is instead secreted into the serum, where it can be detected. [2, 5, 6] Epidemiology Frequency United States Mu-HCD is the least common of the HCDs. [emedicine.medscape.com]

October 01, 2015) Signs and Symptoms Fever (alpha & gamma) Hypocalcemia (alpha) Malabsorption (alpha) Wasting (alpha) Weakness (gamma) Weight loss (gamma) Diagnostic Exams Immunophenotyping Peripheral blood smear Progression and Transformation None Epidemiology [seer.cancer.gov]

Plasma cell disorders can be considered as a spectrum of conditions ranging from monoclonal gammopathy of undetermined significance (MGUS), through asymptomatic, to symptomatic myeloma. [ 1 ] Epidemiology The incidence of a paraprotein is 3.2% in people [patient.info]

Kyle Springer Science & Business Media, 31.07.2012 - 1431 Seiten Neoplastic Diseases of the Blood integrates the history, epidemiology, pathology, pathophysiology, and therapeutics of modern neoplastic hematopathology. [books.google.de]

Pathophysiology The pathogenesis of mu-HCD is not completely understood. [emedicine.medscape.com]

Pathophysiology of ECM Accumulation A striking feature of MIDD is the dramatic accumulation of ECM, whose pathogenesis is beginning to be understood. [cjasn.asnjournals.org]

Pathophysiology Malignant plasma cells develop from an immune cell called a B lymphocyte. [cancer.ucsf.edu]

Infiltration of the intestinal tract wall by cancerous plasma cells often prevents proper absorption of nutrients from food ( malabsorption ), resulting in severe diarrhea and weight loss. A rare form affects the respiratory tract. [merck.com]

Infiltration of the intestinal tract wall by cancerous plasma cells often prevents proper absorption of nutrients from food (malabsorption), resulting in severe diarrhea and weight loss. A rare form affects the respiratory tract. [msdmanuals.com]

It is possible that the production of large quantities of Ig as well as structural alterations may prevent appropriate processing. [doi.org]

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