Chapter 136 - Plasma Cell Disorders Flashcards
Name the conditions that constitue the plasma cell disorders.
Multiple myeloma, Waldenström macroglobulinemia, primary amyloidosis and heavy chain diseases.
Name the synonyms for plasma cell disorders.
Monoclonal gammopathies, paraproteinemias, plasma cell dyscrasias and dysproteinemias.
What is the fundamental difference between a normal and a pathological plasma cell?
“Under normal circumstances, maturation to antibody-secreting plasma cells and their proliferation is stimulated by exposure to the antigen for which the surface immunoglobulin is specific; however, in the plasma cell disorders, the control over this process is lost.”
Which mechanisms explain the clinical manifestations due to plasma cell dyscrasia?
“The clinical manifestations of all the plasma cell disorders relate to ehe xpansion of the neoplastic cells, to the secretion of cell products (immunoglobulin molecules or subunits, lymphokines, and to some extent to the host’s response to the tumor.”
Explain the differences between isotypes, allotypes and idiotypes.
“There are three categories of structural variation among immunoglobulin molecules that form antigenic determinants, and these are used to classifiy immunoglobulins. Isotypes are those determinants that distinguish among the main classes of antibodies of a given species and are the same in all normal individuals of that species. Therefore, isotypic determinants are, by definition, recognized by antibodies from a distinct species (heterologous sera) but not by antibodes from a distinct species (homologous sera). There are five heavy chain isotypes (M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes are distinct determinants of the same species in the amino acid sequence of otherwise similar immunoglobulins. These differences are determined by allelic genes; by definition, they are detected by antibodies made in the same species. Idiotypes are the third category of antigenic determinants. They are unique to the molecules produced by a given clone of antibody-producing cells. Idiotypes are formed by the unique structure of the antigen-binding portion of the molecule.”
What is the value of normal light chain secretion per day?
Less than 10mg per day.
Electrophoretic analysis might identify an M component. Where would you expect to find such a component?
“Electrophoretic analysis permits separation of components of the serum proteins. The immunoglobulins move heterogeneously in an electric field and form a broad peak in the gamma region, which is usually increased in the sera of patients with plasma cell tumors. There is a sharp spike in this region called an M component (M for monoclonal). Less commonly, the M component may appear in the β2 or α2 globulin region.”
The monoclonal antibody mus be present at a concentration of at least 5g/L to be accurately quantitated by electrophoresis, corresponding to ~10 to the ninth cells producing this antibody.
True or False?
True.
What is the different use of electrophoresis versus immunoelectrophoresis?
Immunoelectrophoresis helps one determine the type of immunoglobulin and its monoclonal origin, hence giving a qualitative assessment, while electrophoresis gives one a quantitative assessment of plasma proteins.
The M component is not specific enough to be used as a screening test in asymptomatic patients.
True or False?
True.
“the amout of M component in the serum is a reliable measure of the tumor burden, making M component an excellent tumor marker to manage therapy, yet it is not specific enough to be used to screen asymptomatic patients.”
Name the conditions associated with the differential diagnosis of an M component.
“In addition to plasma cell disorder, M components may be detected in other lymphoid neoplasmas such as chronic lymphocytic leukemia and lymphomas of B- or T- cell origin; nonlymphoid neoplasms such as chronic myeloid leukemia, breast cancer, and colon cancer; a variety of nonneoplastic cponditions such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher’s disease, and pyoderma gangrenosum; and a number of autoimmune conditions, including rheymatoid arthritis, myasthenia gravis, and cold agglutinin disease. Monoclonal proteins are also observed in immunosupressed patients after organ transplant and, rarely, allogeneic transplant. At least two very are skin disease - lichen myxedematous (also knon as papular mucinosis) and necrobiotic xanthogranuloma - are associated with a monoclonal gammopathy.”
Explain the pathophysiollogy of two rare skin disorders associated with monoclona gammopathy.
“In papular mucinosis[/lichen myxedematous], highly cationic IgG is deposited in the dermis of the patients. This organ specificity may reflect the specificity of the antibody for some antigenic component of the dermis. Necrobiotic xanthogranuloma is a histiocytic infiltration of the skin, usually of the face, that produces red or yellow nodules that can enlarge to plaques. Approximately 10% progress to myeloma.”
What is the percentage of patients with sensory motor neuropathy with monoclonal paraprotein?
5%.
In approximately 1% of patients with myeloma, biclonal or triclonal gammopathy is observed.
True or False?
True.
What is the percetange of patients with extramedullary or solitatory bone plasmacytomas and no M component?
About one-third.
Compare the frequency of ligt and heavy chain myelomas.
“In ~20% of myleomas, only light chains are produced and, in most cases, are secreted in the urine as Bence Jones proteins. The frequency of myelomas of a particular heavy chain class is roughly proportional to the serum concentration, and therefore, IgG meylomas ar emore common than IgA and IgD myelomas.”
Define multiple myeloma.
“Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms, including bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting anormalities, neurologic symptoms, and manifestations of hyperviscosity.”
Name the main risk factors currently identified for myleoma.
“The cause of myeloma is not known. Myeloma ocurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency. Myleoma has been seen more commonly than expected among farmers, wood workers, leather workers, and those xposed to petroleum products.”
Which mutations have been assocaited with multiple myeloma? Is there a common pathway that explain its pathophysiology?
“A variety of chromossomal alterations have been found in patients with myeloma: hyperdiplidy, 13q14 deletions, translocations t(11;14)(q13;q32); t(4;14)(p16;q32), and t(14;16), and 17p13 deletions. Evidence is strong that errors in switch recombination - the genetic mechanism to change antibody heavy chain isotype - participate in the transformation process. However, no common molecular pathogenetic pathway has yet emerged. Genome sequencing studies have failed to identify any recurrent mutations with frequency >20%; N-ras, K-ras, and B-raf mutations are most common and combined occur in over 40% of patients.”
What is the meaning of the following factors regarding multiple myeloma: (i) additional mutations over time; (ii) IL6; (iii) morphology of plasma cell.
(i) “There is also evidence of complex clusters of subclonal variants at diagnosis that acquire additional mutations over time, indicative of genomic evolution that may drive disease progression.”
(ii) “Interleukin (IL) 6 may play a role in driving myeloma cell proliferation.”
(iii) “It remains difficult to distniguish benign from malignant plasma cells based on morphologic criteria in all but a few cases.”
The neoplastic event in myeloma may involve cells earlier in B-cell differentiation than the plasma cell.
True or False?
True.
Summarize the epidemiology worldwide of multiple myeloma.
“An estimated 24 050 new cases of myeloma were diagnosed in 2014, and 11 090 people died from the disease in the United States. Myeloma increases in incidence with age. The median age at diagnosis is 70 years, it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. Myeloma accounts for 1,3 of all malignancies in whites and 2% in blacks, and 13% of all hematologic cancers in whites and 33% in blacks.”
“The incidence of myeloma is highest in African Americans and Pacific Islanders; intermediate in Europeans and North American whites; and lowest in people from developing countries including Asia. The higher incidence in more devloped countries may result from the combination of a longer life expectancy and more frequent medical surveillance. Incidence of multiple myeloma in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area. Chinese and Japanese populations have a lower incidence than whites.”
Immunoproliferative small-intestinal disease with alpha heavy chain disease is most prevalent in the Mediterranean area.
True or False?
True.
Name the different signaling pathways that lead to the progression of multiple myeloma: (i) growth; (ii) drug resistance; (iii) migration.
(i) Ras/Raf/MAPK
(ii) PI3K/Akt
(iii) Protein kinase C
Multiple myeloma cells do not need other cells for growth, drug resistance nor migration.
True or False?
False.
“Multiple myeloma (MM) cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu. These effects are due both to direct MM cell-BMSC binding and to induction of various cytokines, including IL-6, insulin-like growth factor type 1 (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell-derived growth factor (SDF)-1alpha.”
How frequent is bone pain in multiple myeloma?
Almost 70% of patients are affected.
What are the differences between bone pain due to multiple myeloma and metastatic carcinoma?
“Unlike pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipiated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture.”
Explain the pathophysiology of bone pain in multiple myeloma.
“The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The increased osteoclast activity is mediated by osteoclast activating factors (OAFs) made by the myeloma cells (….). The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning is less useful in diagnosis than is plain radiography.”
How can one measure osteoclast activating factor activity?
“OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NK-kB (RANK) ligand, macrophage inhibitory factor [MIP]-1alpha, and tumor necrosis factor [TNF]”
How does one explain hypercalcemia in multiple myeloma?
“The bone lysis resulsts in substancial mobilization of calcium from bone, and serious acute and chronic omplication of hypercalcemia may dominate the clinical picture.”
Where should one look for palpable bone lesions or their consequences in myeloma?
“Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull, clavicles, and sternum; and the collapse of vertebrae may lead to spinal cord compression.”
What is the second and third most common clinical problems in multiple myleoma?
First - bone pain (70%).
Second - bacterial infections.
Third - renal involvement (50%) or failure (25%).
Name the most common infection in multiple myeloma.
“The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptotoccus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract.”
How does one explain the increased susceptibility for infections in myeloma patients?
“First, patients with myeloma have diffuse hypogammaglobulinemia, if the M component is excluded. The hypogammaglobulinemia is realted to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component resulsts in fractional catabolic rates of 8-16% instead of the normal 2%. These patients have very poor antibody responses, especially to polyssacharide antigens such as those on bacterial cell walls .Most measures of T-cell function in myleoma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probabgly the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients. Some commonly used to therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to bacterial and fungal infections, and bortezomib predisposes to herpesvirus reactivation.”
How frequently is the kidney involved in multiple myeloma patients?
“Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in more than 50% of patients.”
Explain the pathophysiology of renal failure in myeloma.
“Many factors contribute to this. Hyeprcalcemia is the most common cause of renal failure. Glomerualr deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, biphosphonate use, and occasional infiltration of the kidney by myleoma cells all may contribute to renal dysfunction. However, tubular damage assocaited with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes.”
What is the earlist form of renal failure in myeloma?
Adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine.”
Proteinuria in myeloma is usually associated with hyperetnsion.
True or False?
False.
The anion gap is elevated in myeloma.
True or False?
False.
“Patients with myleoma also have a decrased anion gap [i.e., Na+ - (Cl- + HCO3-)] because the M component is cationic, resulting in retention of chloride.”
What might the explanation for hyponatremia in myeloma?
“[The decreased anion gap] is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water a result of the increased protein.”
Renal dysfunction due to light chain deposition disease, light chain cast nephopathy, and amyloidosis is partially reversible with effective therapy.
True or False?
True.
Dehydration might lead to acute renal failure most commonly in myeloma patients than in the normal population.
True or False?
True.
Name the type of anemia most frequently associated with myeloma.
“Normocytic and normochromic anemia occurs in ~80% of myeloma patients.”
Explain the pathophysiology of anemia in myeloma patients.
“[Anemia] is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoieses by factors made by the tumor, to reduceted production of erythropoietin by the kidney, and to the ffects of long-term therapy. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency.”
Granulocytopenia and thrombocytopenia are rare in myeloma except when therapy-induced.
True or False?
True.
