Pathology > Basic Hematology > White Cell Disorders > Immunosecretory Disorders: Other PCD

Immunosecretory Disorders: Other PCD

"Nonsecretory" myeloma in which immunoglobulin is not synthesized (true nonsecretory) or secreted but not excreted, is rare (<5%). Cases have been reported in which there is production of J chain but no heavy or light chain.

Clinical, hematologic, and radiologic findings are similar to those of standard myeloma. Some have reported fewer problems with infection and less renal damage (no increase in circulating monoclonal immunoglobulin) but survival appears no better than the average myeloma patient.

Plasmacytoma (<1% of monoclonal gammopathies) is a solitary clonal mass of plasma cells - either bone or soft tissue. About 25% of cases are associated with an M spike. Bone lesions usually progress to multiple myeloma. Extraosseous lesions rarely spread and can be surgically excised.

 

Immunosecretory Disorders: MGUS

Plasma cell leukemia (plasma cells >2.0x109/L) can be either a primary or a terminal finding in myeloma. Treatment is with aggressive chemotherapy.

 

Monoclonal gammopathy of unknown significance (MGUS) is an asymptomatic disorder in which a monoclonal immunoglobulin is secreted by a fairly stable clone of plasma cells. MGUS is sometimes referred to as dysproteinemia without associated disease. The incidence of MGUS increases with age (1% at age 50 years; 5% at age 70 years; 10% at age 80 years). Approximately 10% of patients with MGUS will develop myeloma within 5 years. Almost 20% will develop a malignant PCD (myeloma, WM, amyloidosis, and ML) within 10 years.

The M protein of MGUS is < 30 g/L, usually IgG, but occassionally IgA or IgM, and without a Bence-Jones protein.

Bone marrow biopsy and aspirate show a mild increase in plasma cells, but no mass lesion.

 

Immunosecretory Disorders: Waldenstrom's

Waldenstrom's macroglobulinemia (WM) or primary macroglobulinemia (7% of monoclonal gammopathies) is a malignant proliferation of plasmacytoid lymphocytes corresponding to activated B lymphocytes.

The lymphocytes, plasmacytoid lymphocytes, and plasma cells diffusely infiltrate the bone marrow, lymph nodes, spleen, and liver (but not forming tumor masses, nor lytic lesions as does myeloma). WM is associated with ML, small lymphocytic type. "Flame" cells and Dutcher bodies are more likely to be encountered in WM than in other plasma cell disorders. Mast cells,

while accompaning many lymphoproliferative disorders are especially numerous and characteristic of Waldenstrom's.

The malignant cells secrete a monoclonal IgM protein which causes a macroglobulinemia. The large size of the IgM complexes or paraproteins

increases blood viscosity. Hyperviscosity results in neurologic, visual, and bleeding complications. Cryoglobulins can be seen in WM giving rise to Raynaud's phenomemon.

Waldenstrom's is a slowly progressive disorder, with survival of 2-5 years and longer, that most commonly presents in the sixth and seventh decades. Vague symptoms of weakness, weight loss and a mild bleeding tendency, often many years before diagnosis, are usually the first evidence of disease. Later lymphadenopathy and hepatosplenomegaly become prominent. In general, the clinical course is similar to that of chronic lymphocytic leukemia.

Although not curable, chemotherapy (alkalating agents ie. melphahan) can stay the disease. Plasmapheresis is also useful to quickly remove IgM from the plasma, lowering viscosity and improving blood flow.

 

Immunosecretory Disorders: Cryoglobulins

Cryoglobulinemia results from abnormal proteins that precipitate at reduced temperatures. It is associated with PCDs and chronic inflammation. Cryoglobulins can be 1) monoclonal immunoglobulins (Type I) as in myeloma or Waldenstrom's, 2) monoclonal proteins (usually IgM k) complexed to IgG (Type II), or 3) polyclonal immune complexes with no monoclonal component (Type III). Types II and III are associated with connective tissue and autoimmune disorders. Through the formation of protein gels at reduced body temperatures, precipitated cryoglobulins can occlude small vessels giving rise to Raynaud's phenomemon, vascular purpura (cold urticaria) and arthralgia.

Therapy is based on the treatment of the underlying disease and/or plasmapheresis and, of course, avoidance of cold.

Note that cold agglutinins which are RBC antibodies are different from cyroglobulins.

 

Immunosecretory Disorders: Heavy Chain Disease

Heavy chain disease (HCD) is a group of very rare PCDs producing excessive amounts of a monoclonal heavy chain, but no light chain. Monoclonal production of each of the major immunoglobulin heavy chain classes results in a different clinical presentation.

Alpha chain disease, also known as Mediterranean lymphoma is the most common of the HCDs. It is most often seen in young adults from the Mediterranean area. The lamina propria of the intestinal mucosa and abdominal lymph nodes are infiltrated by lymphocytes, plasmacytoid lymphocytes, and plasma cells producing a chain proteins. The lymphoid infiltrate of the lamina propria of the intestinal mucosa results in villous atrophy, malabsorption, steatorrhea, diarrhea, and hypocalcemia. An abdominal mass of lymphoid tissue is often present. Serum a chains must be demonstrated for the diagnosis.

Presenting symptoms are most often abdominal pain, diarrhea, and malabsorption. In time a HCD may progress to a large cell B - immunoblastic lymphoma. Survival is variable from a few months to several years.

Gamma chain disease (g HCD) most commonly presents as lymphadenopathy, hepatosplenomegaly, anemia and fever. Although reported as most common in elderly patients g HCD can occur in patients < 20 years of age. No lytic bone lesions are present but plasmacytoid lymphocytes, plasma cells, eosinophils and histiocytes diffusely infiltrate the marrow and lymph nodes.

As many as one third of g HCD patients have an associated autoimmune disease including AIHA, Sjogren's syndrome, rheumatoid arthritis, SLE, thyroiditis, etc.

As with a HCD, survival in g HCD varies greatly from months to years. Death is most often secondary to infection.

Mu chain disease (m HCD) is the least common form of HCD. It is often associated with chronic lymphocytic leukemia (CLL) or with a disease similar to CLL in which there are large numbers of circulating lymphocytes. Marrow plasma cells are characteristically vacuolated. Hepatosplenomegaly is common as a presenting symptom, but without accompaning lymphadenopathy. Excess m chains are present in the peripheral blood and k light chains sometimes found in the urine.

Chemotherapy is similar to that used for CLL.

Chronic lymphocytic leukemia is occassionally (<10% of CLL) accompanied by a monoclonal protein (<2% of monoclonal gammopathies).

 

Immunosecretory Disorders: Amyloidosis

Amyloidosis is a syndrome in which proteins with a b pleated sheet secondary structure accumulate in tissues. Amyloid stains lightly eosinophilic with H&E, metachromatic with crystal violet. The b pleated sheet structure causes a green birefringence when Congo red stained material is polarized. Amyloid fibrils containing a part of the variable region of the light chain are labeled AL. Amyloid fibrils containing amyloid A, a protein derived from an acute phase reactant are called protein AA.

Amyloid fibrils consist of two paired filaments,creating a parallel array. This imposes a regular parallel order to the molecules of Congo red dye,causing polarization of light and the birefringentproperties characteristic of amyloid.

Primary amyloidosis (AL) is associated with PCDs (M proteins) and idiopathic causes, where as secondary amyloidosis (protein AA) is associated with chronic inflammation and arthritis and while there may be proteinuria, no monoclonal protein is seen.

Amyloid infiltrates cause organ damage resulting in failure as in the nephrotic renal syndrome. Heart failure can be seen secondary to amyloid deposition in the cardiac conduction system. GI tract infiltration can cause macroglossia, hemorrhage, malabsorption, diarrhea, and obstruction. Vascular damage results in amyloid purpura of the face (eyelids & periorbital tissue), neck and chest. Soft tissue accumulation may lead to the carpal tunnel syndrome and to shoulder "pads" virtually diagnostic of amyloidosis.

 

Immunosecretory Disorders: Summary

In summary, plasma cell disorders are malignant proliferations of

B lymphocyte origin. Although the terminally differentiated cell is the cell we observe, immunologic and molecular genetic studies indicate that the disorders arise in genetic events at an early stage in B cell development.

The infiltrating cells are lymphocytes, plasmacytoid lymphocytes, and plasma cells producing monoclonal immunoglobulin proteins. The effects of both the mass of cells and the excess immunoglobulin protein determine the nature of the individual diseases. Thus the disease course can range from an asymptomatic disease to a rapidly progressive fatal illnesses.

Despite advances in chemotherapy the plasma cell disorders remain incurable.

Historical Information

  • Thomas Dutcher (19 - ) is a pathologist in California.
  • Sir Fredrick W Mott (b1853) was an English neurologist.
  • Maurice Raynaud (1834-1881) a Paris physician
  • William Russell (1852-1940) was an Edinburgh physician.
  • Johan H Waldenstrom (b1877) was an orthopedic surgeon in Stockholm, Sweden.

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