Chapter 106. Plasma Cell Disorders (Part 10) doc

IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain.. Mu Heavy

Chapter 106 Plasma Cell Disorders

(Part 10)

Heavy Chain Diseases

The heavy chain diseases are rare lymphoplasmacytic malignancies Their clinical manifestations vary with the heavy chain isotype Patients secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the

Fd region Gamma, alpha, and mu heavy chain diseases have been described, but

no reports of delta or epsilon heavy chain diseases have appeared Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted

Gamma Heavy Chain Disease (Franklin's Disease)

This disease affects individuals of widely different age groups and countries of origin It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness Its most distinctive symptom is palatal edema, resulting from involvement of nodes in Waldeyer's ring, and this

may progress to produce respiratory compromise The diagnosis depends on the demonstration of an anomalous serum M component [often <20 g/L (<2 g/dL)]

that reacts with anti-IgG but not anti-light chain reagents The M component is

typically present in both serum and urine Most of the paraproteins have been of

the gamma1 subclass, but other subclasses have been seen The patients may have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemotherapy

Alpha Heavy Chain Disease (Seligmann's Disease)

This is the most common of the heavy chain diseases It is closely related to

a malignancy known as Mediterranean lymphoma, a disease that affects young

persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead

of a sharp peak on electrophoretic profiles Despite the polymerization, hyperviscosity is not a common problem in alpha heavy chain disease Without J chain–facilitated dimerization, viscosity does not increase dramatically Light chains are absent from serum and urine The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and

paraaortic adenopathy Respiratory tract involvement occurs rarely Patients may vary widely in their clinical course Some may develop diffuse aggressive histologies of malignant lymphoma Chemotherapy may produce long-term remissions Rare patients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimulation, perhaps by some chronic intestinal infection Chemotherapy plus antibiotics may be more effective than chemotherapy alone Immunoproliferative small intestinal disease (IPSID) is recognized as an infectious pathogen–associated human lymphoma that has

association with Campylobacter jejuni It involves mainly the proximal small

intestine resulting in malabsorption, diarrhea, and abdominal pain IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain Early-stage IPSID responds to antibiotics (30–70% complete remission) Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma

Mu Heavy Chain Disease

The secretion of isolated mu heavy chains into the serum appears to occur

in a very rare subset of patients with chronic lymphocytic leukemia The only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine The diagnosis requires ultracentrifugation or gel filtration

to confirm the nonreactivity of the paraprotein with the light chain reagents, because some intact macroglobulins fail to interact with these serums The tumor cells seem to have a defect in the assembly of light and heavy chains, because they appear to contain both in their cytoplasm There is no evidence that such patients should be treated differently from other patients with chronic lymphocytic leukemia (Chap 105)

Further Readings

Ghobrial IM et al: Waldenström macroglobulinaemia Lancet Oncol 4:679,

2003 [PMID: 14602248]

Harousseau JL, Moreau P: Evolving role of stem cell transplantation in multiple myeloma Clin Lymphoma Myeloma 6:89, 2005 [PMID: 16231846]

Hideshima T et al: Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets Nature Rev Cancer 7:585, 2007 [PMID: 17646864]

The International Myeloma Working Group: Criteria for the classification

of monoclonal gammopathies, multiple myeloma and related disorders: A report

of the International Myeloma Working Group Br J Haematol 121:749, 2003

Kuehl WM, Bergsagel PL: Multiple myeloma: Evolving genetic events and host interactions Nature Rev Cancer 2:175, 2002 [PMID: 11990854]

Kyle RA, Rajkumar SV: Multiple myeloma N Engl J Med 351:1860, 2004 [PMID: 15509819]

——— et al: Prevalence of monoclonal gammopathy of undetermined significance N Engl J Med 354:1362, 2006

——— et al: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma J Clin Oncol 25:2464, 2007

Mitsiades CS et al: Focus on multiple myeloma Cancer Cell 6:439, 2005

Munshi NC, Anderson KC: Plasma cell neoplasm, in Principles and

Practice of Oncology, 7th ed, V DeVita, S Rosenberg, S Hellman (eds)

Philadelphia, Lippincott–Raven Publishers, 2005

Treon SP et al: Update on treatment recommendations from the Third International Workshop on Waldenström's macroglobulinemia Blood 107:3442,

2006 [PMID: 16410453]

Wahner-Roedler DL et al: Gamma-heavy chain disease: Review of 23 cases Medicine 82:236, 2003 [PMID: 12861101]

Bibliography

Attal M et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma N Engl J Med 335:91,

1996 [PMID: 8649495]

Attal M et al: InterGroupe Francophone du Myelome Single versus double autologous stem-cell transplantation for multiple myeloma N Engl J Med 349:2495, 2003 [PMID: 14695409]

Attal M et al: Maintenance therapy with thalidomide improves survival in multiple myeloma patients Blood 2006 Jul 27; [Epub ahead of print]

Berenson JR et al: Efficacy of pamidronate in reducing skeletal events in

patients with advanced multiple myeloma N Engl J Med 334:488, 1996 [PMID: 8559201]

Berenson JR et al: American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma J Clin Oncol 20:3719, 2002 [PMID: 12202673]

Berenson JR et al: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients Blood 99:3163, 2002 [PMID: 11964279]

Dispenzieri A et al: POEMS syndrome: Definitions and long-term outcome Blood 101:2496, 2003 [PMID: 12456500]

Gahrton G et al: Progress in allogeneic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: A comparison between transplants performed 1983–93 and 1994–8 at European Group for Blood and Marrow Transplantation centers Br J Haematol 113:209, 2001 [PMID: 11360893]

Greipp PR et al: International staging system for multiple myeloma J Clin Oncol 23:3412, 2005 [PMID: 15809451]

Hideshima T, Anderson KC: Novel therapeutic approaches for multiple myeloma Nature Rev Cancer 2:927, 2002 [PMID: 12459731]

Holland J et al: Plasmacytoma Treatment results and conversion to myeloma Cancer 69:1513, 1992 [PMID: 1540888]

Rajkumar SV et al: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance Blood 106:812, 2005 [PMID: 15855274]

Rajkumar SV et al: Phase III clinical trail thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group J Clin Oncol 24:431, 2006 [PMID: 16365178]

Richardson PG et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma N Engl J Med 352:2487, 2005 [PMID: 15958804]

Treon SP et al: Report of the Third International Workshop on Waldenström's macroglobulinemia Clin Lymphoma 5:215, 2005 [PMID:

15794850]