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
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
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
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
As many as one third of g HCD patients have an associated autoimmune
disease including AIHA, Sjogren's syndrome, rheumatoid arthritis, SLE,
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
Immunosecretory Disorders: Summary
In summary, plasma cell disorders are malignant proliferations
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.
- 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,