Plasma Cell and Related Neoplasms
Diane C. Farhi
Plasma cell neoplasms comprise a wide spectrum of disease (Tables 25.1 and 25.2). The entities discussed below differ widely in clinical presentation, tumor burden, and clinical aggressiveness.
Certain B-cell neoplasms are discussed here, as their features are similar to plasma cell neoplasms.
Clonal immunoglobulin disorders are essentially by-products of clonal plasma cell disorders, in which the main signs and symptoms are caused by immunoglobulin deposition in a β-pleated sheet (amyloidosis) or in granules (deposition diseases) (Table 25.3).
Clinicopathologic syndromes occurring in plasma cell neoplasia are also included in this chapter (Table 25.4). Although the underlying disease is essentially a clonal plasma cell disorder, evidence of neoplastic plasma cells or clonal immunoglobulin production may be difficult to find.
PLASMA CELL AND RELATED B-CELL NEOPLASMS
Heavy Chain Disease
Heavy chain disease (HCD) is characterized by the presence of free clonal immunoglobulin heavy chains in the serum or urine or by the presence of clonal heavy chains (without detectable light chains) in plasma cell cytoplasm (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40). As a whole, HCD cases are rare.
α-HCD is typically characterized by low to absent serum and urine clonal immunoglobulin. The plasma cells contain abnormally truncated α heavy chains. The underlying disorder is usually intestinal lymphoma of mucosa-associated lymphoid tissue (immunoproliferative small intestinal disease), but other types of lymphoma, multiple myeloma (MM), and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) have also been reported. The etiologic agent has been identified as Campylobacter jejuni in many, if not all, cases, and antibacterial therapy may eliminate the lymphoid disease. Patients may present with malabsorption. The peripheral blood rarely shows leukemic dissemination. The bone marrow is involved only in the presence of a histologically high-grade component. Complications include clonal amyloidosis, intestinal diffuse large B-cell lymphoma, and intestinal T-cell lymphoma. The differential diagnosis includes other plasma cell disorders producing intact immunoglobulin molecules but giving false-negative test results for serum or urine light chains, with a resulting erroneous diagnosis of α-HCD.
γ-HCD may involve any of the γ-chain classes. The γ chain is typically truncated and’or dimerized. The underlying disorder may be Franklin disease, a syndrome characterized by fever, hepatosplenomegaly, autoimmunity, acquired immunodeficiency, and variable serum levels of free γ chains. Other associated disorders include acquired cutis laxa, rheumatoid arthritis, other autoimmune diseases, Hodgkin lymphoma, extranodal marginal zone lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, MM, amyloidosis, and clonal myeloid disease. Peripheral blood findings include pancytopenia, atypical lymphocytosis, and eosinophilia. The bone marrow usually fails to show a lymphoplasmacytic disorder; when present, the plasma cells are often vacuolated. Complications include γ-heavy-chain deposition disease and clonal amyloidosis. The differential diagnosis includes the detection of normal urine γ-chain fragments, which may lead to an erroneous diagnosis of γ-HCD.
δ-HCD occurs in immunoglobulin D (IgD)-λ MM owing to dissociation of immunoglobulin heavy and light chains; in such cases, λ light chains are also detected. δ-HCD has also been reported in IgM MM, possibly attributable to clonal heavy chain switching followed by dissociation of immunoglobulin heavy and light chains.
μ-HCD is characterized by low serum and urine levels of free μ chains, sometimes accompanied by intact IgM-κ, free κ chains, or κ-chain urinary casts. The μ chain is abnormally truncated. The underlying disorder may be chronic lymphocytic leukemia, monoclonal gammopathy of undetermined significance, MM, or systemic amyloidosis. Splenomegaly and extranodal tumors have been reported. In some cases, no definite morphologic diagnosis can be rendered. When involved, the bone marrow shows an infiltrate of lymphocytes and vacuolated plasma cells expressing IgM-κ (Fig. 25.1).
Light Chain Disease
Light chain disease is characterized by the presence of free clonal immunoglobulin light chains in the serum and’or urine (41, 42, 43, 44, 45, 46). Clonal light chain urinary excretion is termed
Bence Jones proteinuria. Disorders producing clonal light chain disease include B-cell chronic lymphocytic leukemia’small lymphocytic lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, large B-cell lymphoma, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, multiple myeloma, solitary plasmacytoma of bone, and light chain (AL) amyloidosis.
Bence Jones proteinuria. Disorders producing clonal light chain disease include B-cell chronic lymphocytic leukemia’small lymphocytic lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, large B-cell lymphoma, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, multiple myeloma, solitary plasmacytoma of bone, and light chain (AL) amyloidosis.
TABLE 25.1 WHO Classification of Plasma Cell Neoplasms | ||||
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Laboratory studies show the presence of serum and’or urine free immunoglobulin light chains. Immunofixation confirms clonality and identifies the light chain.
The peripheral blood and bone marrow show findings characteristic of the underlying disorder. In some cases, no evidence of a clonal B-cell or plasma cell infiltrate can be identified. Complications include AL amyloidosis and light chain deposition disease.
The differential diagnosis includes polyclonal gammopathy and urinary excretion of polyclonal light chains, which have been reported in acute myeloid leukemia and acute lymphoblastic leukemia.
Monoclonal Gammopathy of Undetermined Significance
Monoclonal gammopathy of undetermined significance (MGUS) is a common condition, occurring in 3% of individuals older than 70 years of age (47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93). It is usually characterized by a serum clonal immunoglobulin level of less than 30 g’L, minimal to absent urinary clonal immunoglobulin, less than 10% plasma cells in the bone marrow, and no evidence of systemic disease, such as lytic bone lesions, anemia, hypercalcemia, and renal insufficiency.
TABLE 25.2 Differential Features of Plasma Cell Neoplasms | |||||||||||||||||||||||||||||||||||||||||||||||||
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MGUS arises primarily as a de novo disease, and also possibly from chronic antigenic stimulation by Helicobacter pylori, hepatitis C virus, and’or human immunodeficiency virus type 1.
Laboratory studies demonstrate clonal serum and’or urine immunoglobulin, The heavy chain isotypes are approximately IgG in 70% to 75% of patients, IgA in 10% to 20%, IgM in 5% to 10%, and multiple clonal bands in 1% to 2%. Biclonal cases usually show a combination of IgG with IgA, IgM, or a second IgG.
Clonal immunoglobulin isotypes are related to clinical features. IgM MGUS is associated with cold aggulutinin disease, polyneuropathy, Waldenström macroglobulinemia, and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome. IgA MGUS may be associated with a higher risk of transformation to multiple myeloma (MM). IgD, IgE, and light chain MGUS are rare and have been reported to show minimal bone marrow disease and no evidence of progression. MGUS may be biclonal and, rarely, MGUS may produce two different light chains from a single clone.
The peripheral blood rarely shows morphologically identifiable clonal cells. A neutrophilic leukemoid reaction may be present, caused by clonal plasma cell production of granulocyte colony-stimulating factor. This finding may be mistaken for chronic neutrophilic leukemia.
Bone marrow aspirate smears show both clonal and reactive plasmacytosis in almost all cases, usually comprising no more than 10% of nucleated cells. Clonal plasma cells are often slightly larger than normal plasma cells and contain a nucleolus. However, the morphologic differences between clonal and nonclonal cells are not always clear.
Histologic sections of the bone marrow show scattered, minimally atypical plasma cells without discrete aggregates.
Other findings may include pure red cell aplasia, erythroid and megakaryocytic hyperplasia caused by immune-mediated cytopenias, immunoglobulin crystals, storage histiocytes, crystal-storing histiocytosis, and renal osteodystrophy.
TABLE 25.3 Differential Features of Clonal Immunoglobulin Disorders | ||||||||||||||||||||||||||||||||
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Immunophenotyping usually shows clonal populations in both the peripheral blood and bone marrow. Clonal plasma cells typically express CD38, CD56, and CD138, with little or no CD19 and CD45 expression. Compared to MM, MGUS cells more often coexpress B-cell and plasma cell antigens, including CD10, CD11,CD20, CD22, surface immunoglobulin light chain, and bcl-2. Reactive plasma cells are present in the bone marrow in almost all cases, and typically express CD19 and CD38, but not CD56.
Genetic studies show clonal anomalies of chromosomes 6, 9, 17, trisomy 8, monosomy 13, deletion 13q, and deletion 20q in approximately 75% of cases, with multiple clones in the majority. The most common translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32), both involving IGH@ (immunoglobulin heavy gene) on chromosome 14q32.
Transformation to a more aggressive lymphoplasmacytic disorder occurs in approximately 30% of cases within 30 years of diagnosis, and is heralded by progressive increase in the amount of serum monoclonal protein. MGUS usually converts to MM but may also progress to lymphoplasmacytic lymphoma, systemic clonal (AL) amyloidosis, immunoglobulin deposition disease, or other lymphoplasmacytic disorders. A higher percentage of bone marrow plasma cells (10% to 30% of nucleated cells) is associated with a greater risk of transformation.
MGUS has been reported with B-cell chronic lymphocytic leukemia, large B-cell lymphoma, Hodgkin lymphoma, T-cell large granular lymphocytic leukemia, Sézary syndrome, myeloproliferative neoplasms, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, histiocytic disorders, xanthomatosis, and acute myeloid leukemia. A common clonal origin of MGUS and other malignancies has been demonstrated in some cases.
TABLE 25.4 Clinicopathologic Syndromes in Plasma Cell Neoplasia | ||||||||||||
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The differential diagnosis consists primarily of lymphoplasmacytic lymphoma and MM, as well as transient carba-mazepine-induced monoclonal gammopathy.
Multiple Myeloma
Multiple myeloma (MM) is characterized by a serum clonal immunoglobulin level of more than 30 g’L, the presence of serum and’or urine clonal immunoglobulin, bone marrow plasmacytosis of more than 10%, and evidence of systemic disease, namely lytic bone lesions, anemia, hypercalcemia, and’or renal failure (Figs. 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 25.10, 25.11, 25.12, 25.13, 25.14, 25.15, 25.16, 25.17, 25.18, 25.19and 25.20) (94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203).
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