CLL is the most common of the non-Hodgkin lymphomas. The median age at diagnosis is 70 years with a slight male predominance of 1.7:1. The neoplastic cells in CLL are mature B cells. CLL is an indolent disease with a highly variable life expectancy. Transformation to aggressive disease occurs in 5% to 10% of cases at any time during the course of the illness, and is usually a terminal event.
CLL is the most common of the non-Hodgkin lymphomas. CLL is an indolent disease with a highly variable life expectancy.
Morphology—The lymphocytes in CLL are usually small and well differentiated. They are sometimes difficult to distinguish from normal lymphocytes, but they can be identified by their somewhat larger size, coarsely clumped chromatin, and tendency to break apart on peripheral blood smears, forming “smudge cells.” CLL can transform into a high-grade B-cell lymphoma known as Richter syndrome in approximately 3% of B-cell CLL cases. Another type of transformation is to the prolymphocytoid form, where patients can have a very high white count of characteristic prolymphocytes with prominent nucleoli.
Immunophenotyping—The CLL tumor cells express low levels of monoclonal surface IgM and IgD in the majority of cases, surface IgM only in approximately 25% of the cases, and surface IgD, other immunoglobulin isotypes, or no surface immunoglobulin in a small percentage of cases. A characteristic finding in CLL is expression of CD5, which is normally a pan-T-cell antigen, but is expressed on a minor normal subset of B cells. CLL cells also express the B-cell antigens CD19, CD20 (low level), and CD23. Immunophenotyping can also be used for prognosis: high-level expression of CD38 and ZAP-70 is associated with worse prognosis.
Cytogenetics—Chromosomal abnormalities in CLL have prognostic significance. Deletions of 11q and 17p are associated with significantly shorter survival. Deletion of 13q is associated with better prognosis.
Molecular genetics—As with all B-cell lymphomas, the cells of CLL have clonally rearranged immunoglobulin genes. CLL with hypermutated immunoglobulin gene regions (compared with the baseline unmutated sequences) has a better prognosis. Unmutated immunoglobulin genes are associated with worse prognosis.
Hairy cell leukemia is an uncommon form of non-Hodgkin lymphoma. This disease generally occurs in men with a median age at diagnosis of 50 years. The male to female ratio is approximately 4:1. The clinical manifestations are primarily the result of infiltration of the tumor cells into the bone marrow, liver, and spleen. A significant clinical finding on physical examination is the often massive splenomegaly. The liver is also enlarged, but to a much lesser degree than the spleen. Marrow failure is common in this disease, resulting in pancytopenia and its associated complications. Patients generally present with splenomegaly, leukopenia with a relative decrease in monocytes, and an inaspirable bone marrow.
Morphology— The diagnosis of hairy cell leukemia is supported by the identification of lymphocytes with bean-shaped nuclei and fairly abundant gray cytoplasm, giving the cells a somewhat monocytic appearance. Fine cytoplasmic projections that have a hair-like appearance on Wright–Giemsa-stained smears give this entity its name.
Cytochemistry—The cells in hairy cell leukemia stain positively for acid phosphatase that is partially or completely resistant to removal on the addition of tartrate. This is known as TRAP, for tartrate-resistant acid phosphatase. TRAP-positive lymphocytes with fine cytoplasmic projections are highly consistent with a diagnosis of hairy cell leukemia.
Immunophenotyping—The hairy cells have a B-cell phenotype, with monoclonal surface immunoglobulin, CD19 (increased), and CD20 (increased). Antigens that are relatively specific for hairy cell leukemia include the interleukin 2 receptor alpha, CD25, as well as surface CD11c and CD103. Immunohistochemistry performed on bone marrow biopsies or spleen can be used to detect DBA44, which is relatively selective, although not specific, for hairy cell leukemia. These results are all consistent with the identification of hairy cell leukemia as a B-cell disorder.
Molecular genetics—The neoplastic B cells of hairy cell leukemia have clonally rearranged immunoglobulin genes. Recently most hairy cell leukemias were found to have a mutation of the BRAF gene (V600E) that was previously found in melanoma. This mutation is relatively specific for hairy cell leukemia and does not appear to affect disease prognosis.
The diagnosis of hairy cell leukemia is supported by the identification of lymphocytes with bean-shaped nuclei and fairly abundant gray cytoplasm, giving the cells a somewhat monocytic appearance. Fine cytoplasmic projections that have a hair-like appearance on Wright–Giemsa-stained smears give this entity its name.
The plasma cell dyscrasias are disorders in which there is an expansion of a single clone of immunoglobulin-secreting cells. This results in the appearance of high levels of complete or incomplete immunoglobulin molecules in the serum or urine. The monoclonal immunoglobulin in the serum is known as an M-component because it is found in the prototype disorder in this group of diseases, multiple myeloma. Incomplete immunoglobulins containing only light chains or only heavy chains may be produced in certain plasma cell dyscrasias. The free light chains, which are known as Bence-Jones proteins, may be excreted into the urine. The 5 disorders included in this grouping of plasma cell dyscrasias are plasma cell myeloma, Waldenström macroglobulinemia, heavy chain disease, primary amyloidosis, and monoclonal gammopathy of unknown significance (MGUS). Amyloidosis is discussed in Chapter 3, and the other entities are described as follows.
Plasma cell myeloma, also known as multiple myeloma, is a disorder resulting from proliferation of a single plasma cell clone that produces a monoclonal immunoglobulin. The median age for presentation is 62 years. The most frequent presenting symptom is bone pain resulting from osteolytic lesions produced by clusters of plasma cells infiltrating the bone. The bones most often affected are the skull, the ribs, the vertebrae, and the long bones of the extremities. Because patients with multiple myeloma are often anemic, fatigue and weakness are common presenting symptoms. Patients may also experience recurrent bacterial infections as a result of the leukopenia that occurs later in the disease. In addition, the passage of free light chains into the urine may result in “myeloma kidney” and lead to renal failure. The diagnosis of myeloma depends on the presence of a monoclonal protein in the serum or urine, and then the type of myeloma is further classified based on the severity of the disease (Table 13–2). A skeletal survey is included in the initial workup of myeloma to assess the extent of bone involvement.
The diagnosis of myeloma depends on the presence of a monoclonal protein in the serum or urine, and then the type of myeloma is further classified based on the severity of the disease.
Table 13–2Diagnostic Criteria for Plasma Cell Myeloma
Morphology—The diagnosis of plasma cell neoplasm is made when increased numbers of plasma cells are observed in a bone marrow or tissue biopsy. In the bone marrow, plasma cell numbers will be increased, and they form small clusters to extensive sheets in bone marrow biopsies. Solitary tissue lesions, often involving bone, may also show sheets of abnormal plasma cells and are classified as plasmacytomas. Abnormal plasma cells are rarely seen in the peripheral blood, and “plasma cell leukemia” is considered an end-stage presentation of this disorder.
Immunophenotyping—Abnormal plasma cells can be detected by flow cytometry based on abnormal loss of CD19 and CD45, expression of CD38 and CD138, and monoclonal immunoglobulin light chain in the cytoplasm. The abnormal cells may express CD56, which is absent on normal plasma cells. In tissue sections, the abnormal plasma cells are recognized by expression of CD138 and monoclonal cytoplasmic immunoglobulin light chain expression.
Cytogenetics—Chromosomal abnormalities in myeloma have prognostic significance. Most commonly FISH is used to identify specific abnormalities. For FISH, fluorescent DNA probes for the genes of interest are used to localize these genes in chromosome preparations or in cell nuclei. These probes can determine if 2 separate genes are brought together in a translocation or if a gene is broken apart by a translocation. It is helpful to use some kind of enrichment technique, such as magnetic beads coated with antibodies that plasma cells express (eg, CD138), to obtain enough plasma cells to study. Favorable risk cytogenetic abnormalities include hyperdiploidy, t(11;14) or t(6;14). Poor risk cytogenetic abnormalities include deletion of chromosome 13, t(4;14), t(14;16), t(14;20), deletion of 17p13, and hypodiploidy.
Molecular genetics—Plasma cell neoplasms have clonal rearrangements of their immunoglobulin genes.
Protein electrophoresis—The evaluation of a patient for multiple myeloma begins with protein electrophoresis of serum and urine to identify any monoclonal proteins (see Chapter 2 for protein electrophoresis and immunofixation). An M-component on an electrophoretic gel is a dense band of protein that is not usually present. It most often migrates in the gamma region of the gel, but occasionally appears in the beta or alpha-2 region. To increase the likelihood of M-component detection in the urine, the samples evaluated for M-components must be concentrated prior to electrophoresis. Confirmation that a band identified on serum or urine protein electrophoresis represents an M-component involves further analysis by immunofixation electrophoresis (see Chapter 2) or, much less frequently now, by immunoelectrophoresis. Both of these tests permit identification of the specific heavy chain and light chain of the M-component, if both are present. It is also necessary to quantify serum immunoglobulins to determine if the concentration of the M-component is greater than 35 g/L.
Other chemistry tests—Beta-2 microglobulin is the light chain of a class 1 major histocompatibility complex protein, and is present on the surface of all nucleated cells. Increased levels of the unbound beta-2 microglobulin in the plasma are found in multiple myeloma and are considered a reflection of tumor burden. Other tests used to evaluate myeloma include measurement of serum calcium and evaluation of renal function.
Waldenström macroglobulinemia is the clinical syndrome associated with lymphoplasmacytic lymphoma in the WHO classification. There is a diffuse infiltration of the bone marrow by small lymphocytes and plasma cells that synthesize an IgM immunoglobulin, which is referred to as a macroglobulin. It is similar to plasma cell myeloma in that both have an M-component. However, the M-component in Waldenström macroglobulinemia is always an IgM molecule, and unlike the relatively rare IgM myeloma patient, individuals with Waldenström macroglobulinemia do not have lytic bone lesions. The mean age for presentation is 63 years, with a slight male predominance. Patients frequently present with fatigue, weight loss, weakness, and bleeding from anemia and thrombocytopenia. When present in sufficient concentration, the large circulating IgM protein produces a hyperviscosity syndrome in the plasma and tissue deposition of IgM. Most patients with Waldenström macroglobulinemia have an elevated serum viscosity, but only 15% to 20% are symptomatic. The most common symptoms associated with slow blood flow from hyperviscosity are blurred vision, mucosal bleeding, dizziness, and, on funduscopic examination of the eye, papilledema, hemorrhage, and distention of the retinal veins.
The M-component in Waldenström macroglobulinemia is always an IgM molecule, and unlike the relatively rare IgM myeloma patient, individuals with Waldenström macroglobulinemia do not have lytic bone lesions.
Morphology—The pathological correlate of Waldenström macroglobulinemia is lymphoplasmacytic lymphoma. The abnormal cells are small mature-appearing lymphocytes, some of which may resemble small plasma cells. The cells can be present in tissue biopsies, peripheral blood, or bone marrow.
Immunophenotyping—The abnormal cells express the B cell markers CD19 and CD20 without coexpression of CD5 or CD10. The cells will have surface expression of monoclonal immunoglobulin. The abnormal cells may express plasma cell antigens such as CD38 or CD138.
Protein electrophoresis—The diagnosis of Waldenström macroglobulinemia requires demonstration of an IgM serum protein concentration greater than 30 g/L. As with multiple myeloma, Waldenström macroglobulinemia must be differentiated from an IgM MGUS.
Molecular genetics—Recently a mutation in the MYD88 gene (L265P) has been found to be specifically associated with Waldenström macroglobulinemia.
The heavy chain diseases are a group of lymphoproliferative disorders in which there is production of monoclonal immunoglobulins with only heavy chains. Each type of heavy chain disease is named for the abnormal heavy chain produced, resulting in:
Alpha chain disease—a high serum concentration of the heavy chain present in IgA
Gamma chain disease—a high serum concentration of the heavy chain present in IgG
Mu chain disease—a high serum concentration of the heavy chain present in IgM
All the heavy chain diseases are rare, with alpha chain disease having the highest incidence of the related disorders. In all 3 disorders, the monoclonal heavy chain is defective with internal deletions of most of the variable region of the protein and some portion of the first constant region domain. Common clinical findings in patients with heavy chain disease are splenomegaly, hepatomegaly, and lymphadenopathy. Almost all cases of mu chain disease have been associated with CLL. Gamma chain disease has been found in the presence of a variety of autoimmune disorders and in lymphoplasmacytic lymphoma. Alpha chain disease is associated with extranodal marginal zone lymphoma of the MALT type, which usually involves the gastrointestinal tract.
The diagnosis of heavy chain disease is made primarily by demonstration of a monoclonal heavy chain by protein electrophoresis of serum, concentrated urine, or both. The diagnosis of heavy chain disease should prompt an investigation into the presence of lymphoma if that diagnosis has not already been made.
Monoclonal Gammopathies of Unknown Significance
Patients with MGUS are asymptomatic but have a monoclonal protein in their serum and/or urine. There is an increasing incidence of MGUS with aging. Because the incidence of malignant monoclonal gammopathies also increases with age, it is essential to differentiate patients who have MGUS from those who have plasma cell myeloma or Waldenström macroglobulinemia. Most patients with MGUS remain clinically stable without therapy for many years. However, as many as 15% to 20% develop myeloma, macroglobulinemia, amyloidosis, or lymphoma. Indolent myeloma and smoldering myeloma, disorders with many features of multiple myeloma and Waldenström macroglobulinemia that do not meet the criteria for diagnosis, can be differentiated from MGUS because MGUS has a lower amount of immunoglobulin in the serum and a lower percentage of plasma cells in the bone marrow.
Because the incidence of malignant monoclonal gammopathies also increases with age, it is essential to differentiate patients who have MGUS from those who have plasma cell myeloma or Waldenström macroglobulinemia.
MGUS is diagnosed by the presence of a monoclonal serum or urine immunoglobulin at a concentration less than that required for a myeloma diagnosis, less than 10% abnormal plasma cells in the bone marrow, no lytic bone lesions, and no symptoms suggestive of multiple myeloma.
Description and Diagnosis
Hodgkin lymphoma is distinguished from non-Hodgkin lymphoma by the presence of a neoplastic giant cell known as a Reed–Sternberg cell in the lymph node. For many years the lineage of the Reed–Sternberg cell was controversial, but the best information now indicates that the Reed–Sternberg cell is an abnormal malignant B cell. Hodgkin disease is a common form of malignancy in young adults with a second peak incidence in older individuals. Unlike the multiple classification schemes for non-Hodgkin lymphomas, a classification of Hodgkin disease known as the Rye classification was accepted for decades. This classification system has now been incorporated with minor changes into the WHO classification system for hematologic malignancies. Hodgkin lymphoma is divided into 2 broad categories: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Classical Hodgkin lymphoma is characterized by infrequent Reed–Sternberg cells in a background of normal lymphocytes, plasma cells, eosinophils, and granulocytes. The Reed–Sternberg cells lack expression of the pan-hematopoietic marker CD45; they occasionally express the B-cell marker CD20, and they characteristically express CD30 and CD15. The different subtypes of classical Hodgkin lymphoma in the WHO classification are characterized primarily by differences in tissue architecture and the composition of the cellular background.
Hodgkin lymphoma is distinguished from non-Hodgkin lymphoma by the presence of a neoplastic giant cell known as a Reed–Sternberg cell in the lymph node.
Nodular lymphocyte-predominant Hodgkin lymphoma also shows scattered large abnormal cells, but these do not have the appearance of Reed–Sternberg cells. The abnormal cells in nodular lymphocyte-predominant Hodgkin lymphoma have convoluted nuclei, leading to the term “popcorn cells.” These abnormal cells express the pan-hematopoietic marker CD45 and the B-cell marker CD20; they variably express CD30 and do not express CD15. The abnormal cells are frequently ringed by normal T cells. Nodular lymphocyte-predominant Hodgkin lymphoma is best thought of as a low-grade B-cell lymphoma.