Pathophysiology
Summary
Plasma cell neoplasms arise when a mature B-cell undergoes a mutation, leading it to differentiate into monoclonal plasma cell clones. Consequently, these plasma cells release antibodies from the bone marrow, often secreting a monoclonal immunoglobulin, commonly referred to as the M protein.
Multiple myeloma (MM) is the most common plasma cell neoplasm and is primarily diagnosed in the elderly (~70 yrs). MM is marked by the infiltration of clonal plasma cells into various skeletal regions. A notable feature of MM is its production of large quantities of monoclonal immunoglobulin known as M proteins, which are most commonly IgG. Diagnosis is established using serum protein electrophoresis (SPEP) the M proteins appears as an ‘M spike’ in the gamma-globulin zone. Additionally, MM plasma cells can generate free light chains that are excreted in the urine, known as Bence Jones proteins.
Clinically, MM commonly exhibits lytic bone lesions, especially within the vertebral column. These lesions can result in back pain, a decrease in height, and fractures in various bones. The formation of these lytic bone lesions is attributed to increased osteoclast activity and reduced osteoblast activity, which is likely influenced by RANKL expression on osteoblasts. This imbalance favors bone resorption over formation and can cause hypercalcemia. MM can also cause normochromic normocytic anemia, as tumor cells displace bone marrow. This displacement can hinder regular antibody production, increasing susceptibility to recurrent infections, notably from pathogens such as Staph aureus, Strep pneumoniae, and E. coli.
Another worrisome feature of MM is its association with renal insufficiency, attributed to a combination of factors: Bence Jones proteins, direct light chain toxicity, amyloidosis, and metastatic calcification. Bence Jones proteins can bind uromodulin in urine, leading to dense cast formation and renal tubular obstruction. Light chain toxicity can result in a generalized reabsorptive defect in the PCT known as ‘Fanconi syndrome’, a type II RTA. AL amyloidosis results in amyloid light chain deposition in the tissue and damages the kidney. Metastatic calcification can also occur in MM, resulting in calcium deposition in the kidneys.
Bone marrow biopsy is an essential in diagnosing MM, showing an increase in plasma cells (> 10% of bone marrow cells). These cells, while resembling normal plasma cells, have a unique basophilic cytoplasm due to a protein-rich endoplasmic reticulum. Their cytoplasm features a distinct pale spot, representing the golgi apparatus, and their nuclei display a ‘wagon wheel’ chromatin pattern. MM (along with LPL/WM) is marked by the rouleaux formation in blood smears, a result of high serum protein.
Treatment of MM involves proteasome inhibitors like bortezomib. The high protein synthesis rate of plasma cells in MM makes it especially sensitive to this type of therapy.
Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a small M protein spike in the absence of the symptomatic spectrum seen in multiple myeloma. Notably, only a minority of MGUS cases evolve into MM, amyloidosis, or Waldenstrom's macroglobulinemia (WM). A bone marrow biopsy in MGUS patients reveals < 10% monoclonal plasma cells.
Solitary plasmacytoma is a localized plasma cell neoplasm that often manifests as a bone lesion that causes localized pain or pathologic fractures at the affected site. Notably, solitary plasmacytomas carry a risk of progression to multiple myeloma.
Lymphoplasmacytic lymphoma (LPL) arises from clonal mature B-cells, with a subset differentiating into monoclonal plasma cells that secrete IgM. LPL is marked by an M-spike on SPEP and a bone marrow biopsy displaying > 10% neoplastic cells. The neoplastic cells in LPL are a combination of plasma cells and a other lymphoid cells.
Clinically, the massive secretion of IgM pentamers in LPL gives rise to hyperviscosity syndrome, known as Waldenstrom's Macroglobulinemia (WM). Patients with WM can experience a plethora of symptoms due hyperviscosity: headaches, dizziness, auditory complications, confusion, visual impairments, and peripheral neuropathy. Excessive IgM in WM can interfere with clotting processes causing bleeding issues, and the precipitation of IgM pentamers at low temperatures (cryoglobulinemia) can cause symptoms like Raynaud's phenomenon, urticaria, and tissue necrosis.LPL also manifests as lymphadenopathy and hepatosplenomegaly from neoplastic infiltration of these regions, as well as anemia due to bone marrow displacement by tumor cells. Plasmapheresis is used to treat cases of severe hyperviscosity as it can alleviate symptoms by decreasing the levels of circulating IgM.
Lesson Outline
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FAQs
Plasma cell neoplasms arise when a mature B-cell undergoes a mutation, leading it to differentiate into monoclonal plasma cell clones. These clones then release their antibodies from the bone marrow. Specifically, these monoclonal plasma cells produce a unique type of immunoglobulin known as the M protein.
Multiple myeloma (MM) is the most common plasma cell neoplasm and typically occurs in the elderly, around the age of 70. MM is marked by clonal plasma cells that infiltrate various skeletal sites, producing large quantities of the monoclonal immunoglobulin ‘M’ protein. Clinically, MM often presents with lytic bone lesions, especially in the vertebral column. These lesions can lead to vertebral compression fractures, resulting in back pain and a reduction in height. Other manifestations include hypercalcemia, anemia, recurrent infections, and renal complications.
Diagnosing multiple myeloma involves a combination of tests and clinical observations. X-rays can reveal characteristic ‘punched-out’ lesions in the bones. Serum protein electrophoresis (SPEP) is used to detect the M protein, which creates a single narrow peak in the gamma-globulin region known as the M spike. Bone marrow biopsy shows an increased number of plasma cells. Additionally, the presence of Bence Jones proteins in the urine and recurrent infections can further support the diagnosis.
Multiple myeloma can lead to renal insufficiency through several mechanisms. Bence Jones proteins in urine can bind to uromodulin, forming dense casts that obstruct renal tubules. Additionally, direct toxicity from light chains can affect the proximal tubule, resulting in Fanconi syndrome. Amyloidosis, characterized by extracellular fibril deposits in tissues, can cause tissue damage. Additionally, elevated serum calcium levels, known as ‘metastatic calcification,’ can deposit in the kidneys, leading to injury.
While all these conditions are plasma cell disorders, they vary in presentation and progression. Multiple myeloma is marked by widespread bone lesions, anemia, hypercalcemia, and kidney issues. In contrast, MGUS is often asymptomatic, showing a minor M protein spike and fewer than 10% monoclonal cells in a bone marrow biopsy. Solitary plasmacytoma is localized, typically causing pain or fractures at the affected site. Lymphoplasmacytic lymphoma produces significant amounts of IgM pentamers, leading to symptoms associated with hyperviscosity syndrome such peripheral neuropathy, bleeding diathesis, and other symptoms collectively known as Waldenstrom macroglobulinemia (WM).
