Plasma Cell Neoplasia
cells are the basis for our humoral immunity--the arm of the immune system that uses secreted and circulating antibodies to neutralize abnormal or intrusive substances. As fully mature B-lymphocytes, plasma cells have acquired the complex skill of producing immunoglobulin molecules, better known as antibodies.
Malignant plasma cells
The name of this section thus has an oxymoronic cast: how can terminally differentiated plasma cells be malignant? Have you ever heard of cancers composed of mature nerve cells or skeletal muscle? The clue to this mystery is that malignant plasma cells have matured from a malignant, less terminally differentiated precursor that is their proliferating and circulating source. There are several types of neoplastic plasma cell proliferations:
Multiple myeloma (MM)
MM (images) is the best known and most common form of plasma cell malignancy, accounting for about 10% of lymphohematopoietic malignancies.
In the U.S.A. its incidence is 4 per 100,000 per year. Only 3% of the patients are less than 40 years old, and the occurence of the disease in anyone less than 30 years old must be very carefully evaluated. Radiation may play a role in some instances, since the incidence is increased in atom bomb survivors and workers at some nuclear reactors.
As the name implies, malignant plasma cells collect in multiple foci in the bone marrow, producing lytic bone lesions detectable in skeletal surveys. These plasma cells may be morphologically identical to their benign, mature counterparts or they may have various immature or blastic features such as large nuclei, prominent nucleoli or fine chromatin (see marrow aspirate smears). The immunophenotype of the malignant plasma cells includes the following features:
1) Non-reactive for antigens such as CD19 and CD20 that are present on most B-cells and for pan-leukocyte marker LCA. Benign plasma cells are often positive for CD19.
2) Reactive for CD38, plama cell antigen-1, and usually EMA, a pattern shared with benign plasma cells.
3) Reactive for CD56, a neural adhesion molecule, unlike benign plasma cells.
Most MMs are aneuploid by flow cytometry and show an average of 11 abnormalities per karyotype. Recurrent abnormal findings are less frequent than they are in other B-cell malignancies, but translocations involving the immunoglobulin heavy chain gene locus at 14q32 are present in 20%-40% of cases. Often the translocation partner is the cyclin D1 gene at 11q13. An important negative prognostic finding is partial or complete deletion of chromosome 13, as detected by FISH using the RB1 gene probe. Trisomies of chromosomes 6, 9, and 17 convey a better progrnosis. An additional, non-cytogenetic prognostic factor is the level of serum beta-2-microglobulin, with high levels indicating increased rates of plasma cell turnover.
The secreted products of plasma cell play a large role in both the diagnosis and pathogenesis of MM. They include:
Chief among the many baneful effects of MM are:
- Both intact clonal immunoglobulin and free clonal light chains. Because of their imbalanced production, both kinds of protein may be seen in the same patient. When one of these proteins is detectable in the blood or concentrated urine, it is called an "M-component" or "M-protein". A normal kidney will retain whole immunogloblulins, so an immunoglobulin M-component is usually not found in the urine until glomerular function has begun to fail. Conversely, light chains are freely filtered by the glomerulus, and when the resorption threshold of the renal tubular cells is exceeded, they appear in the urine.
For each case of MM, the M-protein has exclusively either kappa or lambda light chains; and the intact immunoglobulin is most frequently IgG, less often IgA, and rarely another isotype. Only rare MMs fail to secrete detectable amounts of immunoprotein.
Serum protein electrophoresis|
The clonality or homogeneity of the M-component allows it to be detected by special studies such as serum protein electrophoresis, immunoelectrophoresis, and immunofixation (images). The latter 2 modalities are more difficult and expensive, but their increased sensitivity may be necessary to detect a small M-component.
Free light chains in the urine are called "Bence-Jones proteins", which occur in 80% of patients. They not usually detected by routine dipstick protein assays, which are somewhat specific for albumin. After a 24-hour urine sample has been concentrated, clonal Bence-Jones protein can be demonstrated by immunoelectrophoresis and immunofixation. In some cases light chains may not appear in the urine because of proximal tubule resorption. For this reason, a serum light chain assay may be a more sensitive method of detecting light chain disease.
Amyloid seen in some cases of MM is an altered form of the light chain M-component that deposits in various locations, stiffening, displacing, and harming the normal tissue. It may be present in other, non-neoplastic diseases too.
Osteoclast Activating Factor is the functional name for several cytokines, mainly IL-1 and tumor necrosis factor-beta, secreted by MM cells. These cytokines cause much of the bone resorption and the resultant hypercalcemia associated with the disease.
- Infections due mainly to decreased antibodies (the most frequent cause of death).
- Kidney disease (the second most common cause of death). Its etiology in myeloma is manifold:
- So-called "myeloma kidney", caused by waxy casts of precipitated, nephrotoxic, monoclonal light chains blocking the tubules. Lambda light-chains are more perilous than kappa ones.
- Hypercalcemia (initially present in 25% of patients) or hyperuricemia.
- Amyloidosis affecting the kidney.
- Renal infections.
- Deposits of light chains as glomerular nodules, more often seen with kappa light chains.
- Anemia with weakness and fatigue (very common presenting findings).
- Bone disease, with pain aggravated by movement and less at rest, sometimes with an associated loss of height from vertebral collapse.
- Abnormal bleeding.
- Serum hyperviscosity.
"Asymptomatic" or "smouldering" myeloma refers to a form of disease with a serum M-protein >= 3 g/dl and/or >= 10% clonal plasma cells in the bone marrow (so MGUS is no longer a possible diagnosis), but without the related organ or tissue impairment that characterizes full-blown (symptomatic) myeloma. Although these patients should not be treated, they most be followed closely because progression is likely.
MM is usually an incurable disease. Despite therapy, most patients die within 3 years. Indications for therapy include an increasing M protein, anemia, hypercalcemia, renal problems, lytic bone lesions, or extramedullary disease. Patients may enter a protocol study or may be offered standard treatment of either melphalan plus prednisone or a combination of alkylating agents. High-dose therapy with autologous hematopoietic stem cell support is also used. Few patients are eligible for allogeneic bone marrow transplantation, and even these face a transplantation-related mortality of up to 40%. More recent drugs include thalidomide and its analogues (revlimid), bortezomib (velcade), and arsenic trioxide.
These are the unifocal counterparts of MM. Because the volume of plasma cells is small, M-components are unusual. Some plasmacytomas occur in the marrow, where they commonly progress after years to MM. Others are extra-medullary. Especially in the upper respiratory tract, extra-medullary plasmacytomas have an excellent prognosis: after excision and local radiotherapy, most of them are cured.
Monoclonal gammopathy of uncertain significance (MGUS)
MGUS is identified by a small serum M-component produced by a minor clone of plasma cells that may not be detectable by bone marrow biopsy. The most important characteristic is a serum M-component < 3 g/dl that doesn't increase with time. Additional features include:
< 10% plasma cells in the marrow.
absence of end-organ or tissue impairment in the form of lytic bone lesions, renal insufficiency, anemia, hypercalcemia, hyperviscosity, amyloidosis, or recurrent bacterial infections.
urine with little or no Bence Jones protein.
MGUS is a phenomenon of the elderly and is increasingly frequent with age, seen in about 3% of people older than 70 years. The qualifier "uncertain significance" betrays our ignorance about the condition's malignant potential in individual patients. In one large study 241 patients with MGUS were followed for a median of 22 years:
Status After Average 22 Years
|No progression of M-component||19%|
|Developed malignant immunoproliferative disease; MM in 16%
|Died of unrelated causes
|M-component became > 3 g/dl but no chemotherapy needed
Depending on the level of the MGUS M-component, guidelines exist for appropriate follow-up. If the M-component is < 2 g/dl, it is measured by an SPEP again in 6 mos and, if stable, annually thereafter. Bone marrow exam and imaging studies are called for only in the event of additional abnormalities.
Sometimes it is hard to say whether a patient has a MGUS on the one hand or, on the other,
MM or Waldenstrom's macroglobulinemia. With some exceptions the following features are suggestive of malignancy:
- M-protein > 3 g/dl
- Plasma cells > 10% of marrow cellularity
- An elevated plasma cell labeling index
(a measure of the cells' proliferative tendency)
- Monoclonal light chains accompanying the M-protein.
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