Editors: Hillman, Robert S.; Ault, Kenneth A.; Rinder, Henry M.Title: Hematology in Clinical Practice, 4th EditionCopyright 2005 McGraw-Hill> Table of Contents > Part II - White Blood Cell Disorders > Chapter 22 - Non-Hodgkin's Lymphomas

Chapter 22

Non-Hodgkin's LymphomasThe non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of disorders characterized by malignant proliferation of B or T lymphocytes. From a clinical standpoint, lymphomas generally present as solid tumors of the lymphoid systemthe lymph nodes, Waldeyer's ring, spleen, blood, and marrow. Because of the functional heterogeneity of lymphocytes and because lymphocytes by their nature have access to nearly every anatomic site, these diseases may involve any organ and are very heterogeneous. Despite multiple attempts to improve the classification of NHL, it remains difficult to predict the course of the disease in an individual patient based on prognostic factors. Perhaps more than any other malignant disease, the treatment of the patient must be individualized based on the behavior of the patient's own disease.The importance of accurate diagnosis and effective management of lymphomas has been heightened by their increasing incidence, the association of lymphomas with immune deficiency states, and improvements in therapy. The incidence in Western countries has more than doubled in the last 20 years and should increase even further because of the association of B-cell lymphomas with AIDS. The rising incidence may also reflect greater exposure to chemical agents in the environment.NHL in general is very responsive to therapy, and in most cases the physician can offer the patient with NHL both improved survival and improved quality of life. It is an unusual fact that the NHL patient with the most aggressive form of the disease can be offered the possibility of a cure, whereas the patient with indolent lymphoma may never be cured despite a relatively long survival.Because lymphoma cells tend to be very mobile, silently involving not only lymphoid organs but nearly every part of the body, concepts of staging, remission, and relapse are less useful and less important than in other malignancies. With increasingly sensitive means of detecting lymphoma cells, it is frequently possible to demonstrate their presence throughout the body in patients previously thought to have localized disease. Similarly, it is frequently possible to detect lymphoma cells in patients who appear by usual criteria to be in complete remission. Patients with lymphoma will sometimes undergo prolonged periods of quiescent disease punctuated by periods of increased disease activity. In general these patients must be followed up carefully, with a constant suspicion that minor symptoms may indicate progression or relapse.

DIAGNOSISUltimately, a diagnosis of lymphoma depends on finding abnormal numbers of lymphocytes that are destroying the normal architecture of the lymphoid tissues or invading nonlymphoid tissues or both. Detection of lymphoma in its early stages can be more of a challenge. It is difficult, probably impossible, to recognize a single malignant lymphocyte based on morphology alone, because lymphocytes are capable of dedifferentiation, proliferation, and differentiation in the course of a normal immune response. A reactive lymph node contains activated lymphocytes that look as malignant as any lymphoma cell.Thus, in order for one to accurately diagnose lymphoma, an adequate tissue biopsy is absolutely required. Lymphoma can be suspected on the basis of cytologic examination of blood, marrow, effusions, and aspirates, but the physician should always make every attempt to obtain a good surgical biopsy of involved lymphoid or nonlymphoid tissue in order to be certain of the diagnosis. When multiple sites are available for biopsy, one should avoid those sites where normal reactive nodes are frequently found, such as the groin and the axilla.With the availability of immunologic and genetic tests for clonality, one can make a strong presumptive diagnosis of lymphoma on the basis of the finding of clonal lymphocytes involving multiple sites, such as marrow and blood, but the finding of clonality does not absolutely prove malignancy, and clonality tells us nothing about prognosis. Therefore, a diagnosis based solely on these criteria should be viewed with caution.

CLASSIFICATIONOver the years, several different classifications of lymphomas have been popularized: the Rappaport classification, the Lukes-Collins classification, the International Working Formulation, the Revised European American Classification (REAL), and most recently a consensus classification sponsored by the World Health Organization (WHO), which closely follows the REAL system. The Working Formulation and WHO/REAL classifications are compared in Table 22-1. The Working Formulation and previous systems were based almost entirely on morphologic criteria. The Working Formulation was an advance because it emphasized the clinical behavior of the various lymphomas, grouping them into low-, intermediate-, and high-grade based on their aggressiveness. The REAL system, for the first time, incorporated immunologic and genetic criteria in classifying the lymphomas, and this has been extended in the WHO system.

Table 22-1. Lymphoma classification.

Revised European American (REAL) and WHO Consensus Classification

Working FormulationB-Cell NeoplasmsT-Cell Neoplasms

Low-Grade

Small lymphocyticB-cell CLL/SLLMarginal zone, mucosa associated (MALT)Mantle cellT-cell CLLLarge granular lymphocyticAdult T-cell lymphoma/leukemia

PlasmacytoidLymphoplasmacyticMarginal zone (MALT)

Follicular, small-cell, and mixed-cellFollicular, grades I and IIMantle cellMarginal zone (MALT)

Intermediate-Grade

Follicular, large-cellFollicular, grade III

Diffuse, small-cellMantle cellFollicular center, diffuse small-cellMarginal zone (MALT)T-cell CLLLarge granular lymphocyticAdult T-cell lymphoma/leukemiaAngioimmunoblasticAngiocentric

Diffuse, mixed-cellLarge B-cell lymphomaFollicular center, diffuse small-cellLymphoplasmacytoidMarginal zone (MALT)Mantle cellPeripheral T-cell lymphomaAdult T-cell lymphoma/leukemiaAngioimmunoblasticAngiocentricIntestinal T-cell lymphoma

Diffuse, large-cellDiffuse large B-cell lymphomaPeripheral T-cell lymphomaAdult T-cell lymphoma/leukemiaAngioimmunoblasticAngiocentricIntestinal T-cell lymphoma

High-Grade

Large-cell immunoblasticDiffuse large B-cell lymphomaPeripheral T-cell lymphomaAdult T-cell lymphoma/leukemiaAngioimmunoblasticAngiocentricIntestinal T-cell lymphomaAnaplastic large cell

LymphoblasticPrecursor B-cell lymphoblasticPrecursor T-cell lymphoblastic

Burkitt lymphomaBurkitt lymphomaPeripheral T-cell lymphoma

The WHO/REAL classification should hold promise in the design of future therapies. However, as can be seen in Table 22-1, it is difficult to correlate the WHO/REAL system with the Working Formulation. As long as the concept of tumor aggressiveness is preserved in the classification, there is extensive overlap and duplication. For example, the B-cell, marginal zone (MALT) lymphomas can present as follicular or diffuse small- or mixed-cell tumors with low to intermediate growth potential. It is likely that with more experience, the clinical classification and the immunogenetic classification will converge, and the situation will become clearer.The frequencies with which the more common forms of lymphoma will be encountered in practice are indicated in Table 22-2. When a patient presents with lymphoma it is important to obtain as much prognostic information as possible on the basis of whatever can be measured. This can be divided into histologic features, cytologic features, immunologic features, cytogenetics, and stage or extent of disease.

Histologic FeaturesThe normal architecture of a lymph node and the phenotypic and cytologic features of the lymphocytes found in various regions are illustrated in Figure 22-1. The histologic description of lymphoma focuses on the overall architecture of a lymphoid or nonlymphoid tissue. Perhaps the most useful histologic finding is whether there is nodular (or follicular) versus diffuse morphology (see Color Plates 54,55,56). Those lymphomas showing the formation of nodules, reminiscent of normal lymphoid follicles, tend to be more indolent and have a better prognosis than those showing diffuse infiltration. This distinction is true regardless of the details of the individual cells and regardless of the immunologic type of the lymphoma. Therefore, the first question the clinician should ask of NHL is whether it is nodular (follicular) or diffuse in histology. This distinction can only be made on the basis of an adequate biopsy.

Cytologic FeaturesThe cytologic classification of a lymphoma depends on the appearance of the individual cells. Cells may be described as well versus poorly differentiated (Rappaport classification) or as large versus small, with folded or cleaved nuclei (Luke-Collins classification and International Formulation). In general, small, well-differentiated cells are seen with more indolent lymphomas, whereas large, poorly differentiated cells are typical of high-grade, aggressive lymphomas. However, this classification is weakened by the frequent presence of cells of many descriptions scattered throughout the lesion. Overall, the cytologic description of the cells is not as strongly associated with prognosis as is the histologic description (nodular versus diffuse).

Immunologic FeaturesThe immunologic classification of the lymphomas requires use of immunologic markers, genetic analysis, or both (see Chapters 19 and 21) to determine whether the cells are of B- or T-cell origin and to indicate clonality. Most (approximately 80%) NHLs are of B-cell origin. Clonality in a B-cell lymphoma can be indicated by uniform expression of a single light chain class of surface immunoglobulin ( or ) or by the presence of a single immunoglobulin gene rearrangement pattern. Clonality of the T-cell lymphomas is suggested by the expression of a single functional class marker (CD4 or CD8) or by a characteristic pattern of expression and deletion of other T-cell markers, but it is best demonstrated by genetic analysis for T-cellreceptor gene rearrangement.

Table 22-2. Frequencies of non-Hodgkin's lymphomas.

DiagnosisFrequency (%)

Diffuse large B-cell lymphoma31

Follicular lymphoma22

Small lymphocytic lymphoma6

Mantle cell lymphoma6

Peripheral T-cell lymphoma6

Marginal zone B-cell lymphoma, MALT type5

Mediastinal large B-cell lymphoma2

Anaplastic T-cell lymphoma2

Lymphoblastic lymphoma2

Burkitt-like lymphoma2

Marginal zone B-cell lymphoma1

Lymphoplasmacytic lymphoma1

Burkitt lymphoma< 1

Figure 22-1. The normal architecture, histology, and phenotype of a lymph node. The major lymphocyte subsets are distributed through the lymph node in characteristic regions. Follicular centers contain predominantly large proliferating B cells, whereas the mantle zones of the follicles contain smaller B cells in the resting state. Interfollicular regions and the paracortex contain predominantly T cells. Macrophages are located in the follicular centers and in the medulla of the node. Antigen, and circulating T cells, enter via the cortical afferent lymphatics. Antigen-stimulated T cells reenter the circulation via the efferent lymphatics. Disruption of the normal lymph node architecture is one of the major causes of immunodeficiency in lymphoma.

Immunologic analysis of lymphomas is particularly useful in distinguishing between a reactive process and a lymphoma. It is not uncommon for a lymph node biopsy to show a lymphocyte proliferation that could be a normal reactive process rather than a lymphoma. Since the reactive process is characterized by a heterogeneous collection of T and B cells arising from multiple clones of different progenitor cells, it is easy to distinguish immunologically from a lymphoma, where most cells are of one phenotype and belong to one clone.

Cytogenetic FeaturesSpecific NHL subtypes can also be classified based on nonrandom chromosomal translocations (Tables 22-3 and 22-4). Most share one common feature in that they involve the genes responsible for the coding of the immunologic receptors for antigen on the lymphocytes. For the B cells these are located on chromosome 14 (the immunoglobulin heavy chains) and on chromosomes 2 ( immunoglobulin light chain) and 22 ( immunoglobulin light chain). For the T cells, the T-cellreceptor genes are usually involved. Most of these mutations result in the juxtaposition of an immunologic receptor gene and its controlling elements next to a protooncogene, resulting in overexpression of the oncogene product. The best examples are the t(14;18) (q32;q21) translocation, which brings the immunoglobulin heavy chain locus next to the BCL-2 protooncogene, and the translocations that bring the c-myc oncogene next to immunoglobulin genes on chromosomes 14, 2, or 22. The BCL-2 abnormality occurs in at least 80% of nodular lymphomas, and the c-myc translocation is characteristic of Burkitt lymphoma. BCL-2 is a gene associated with the inhibition of programmed cell death (apoptosis). Thus, its over expression in lymphomas leads to prolongation of the lifespan of the cells and their accumulation to the detriment of the patient. The expression of bcl-2 has also been associated with poor overall survival. Deregulation of BCL-6 in large B-cell lymphomas and c-myc in Burkitt lymphoma is associated with uncontrolled cell proliferation. In a study of the expression of CD10, bcl-6, and MUM1 by immunohistochemistry, diffuse large cell lymphomas could be subclassified as germinal-center cell and nongerminal center cell derived disease, with the latter showing a significantly poorer survival.Table 22-3. Immunologic and cytogenetic features in the REAL classification of B-cell neoplasms.

DiseaseMorphologyImmunophenotypeGenotype

Small lymphocytic, CLLSmall, round lymphocytesDim sIgM, sIgDCD19, 20, 5, 23+CD10-Ig rearrangementsTrisomy 12 (3040%)Deletion 13q14 (50%)

LymphoplasmacytoidSmall lymphocytes with plasmacytoid featurescIg+,CD19, 20+CD5, 10-Ig rearrangementst(9;14) (50%)

Mantle cellSmall to medium irregular lymphocytessIgM, sIgD+CD19, 20, 5+CD10, CD23-Ig rearrangementst(11;14) (70%)involves BCL-1

Follicular center cellSmall, medium, or large, irregular, cleaved cellssIgM, sIgD+CD19, 20+CD10, 23CD5+Ig rearrangementst(14;18) (7095%)involves BCL-2

Marginal zone (MALT)Small or large, monocytoid lymphocytessIgM, sIgD+CD19, 20+CD5, 10, 23-Ig rearrangementsTrisomy 3t(11;18)

Hairy-cellSmall lymphocytes with cytoplasmic projectionssIgM, sIgD+CD19, 20, 11b, 103+FMC7+, CD5, 10, 23-Ig rearrangements

Diffuse large B-cellLarge, irregular lymphocytessIgM, sIgDCD19, 20+CD5, 10Ig rearrangementsRearrangements of 3q27 (BCL-6) (30%)

Burkitt lymphomaMedium round cells with abundant cytoplasmsIgM+CD19, 20, 10+CD5, 23-t(8;14), t(2;8), ort(8;22) involves c-myc

Table 22-4. Significance of some chromosomal translocations associated with B-cell neoplasms.

DiseaseTranslocationsFrequencyImmunoglobulin Gene(s)ProtooncogeneMechanism

Lymphoplasmacytoidt(9;14)50%IgHPAX-5 (9q13)A transcription factor controlling B-cell proliferation and differentiation

Mantle cellt(11;14)95%IgHBCL-1 (11q13)The gene for cyclin D1 that regulates the cell cycle

Follicular cellt(14;18)t(2;18)t(18;22)80%IgH or IgLBCL-2 (18q21)A gene that inhibits apoptosis

Diffuse large-cellt(3;14)510%IgH or IgLBCL-6 (3q27)A gene that appears to control some aspect of germinal center formation

Burkitt lymphomat(8;10)t(2;8)t(8;22)100%IgH or IgLc-myc (8q24)A transcription factor controlling proliferation, differentiation, and apoptosis

MALT lymphomat(11;18)30%IgHAPI2, MLTGenes involved in inhibition of apoptosis

Since immunoglobulin and T-cellreceptor genes are always rearranged as a part of the normal differentiation process of B and T lymphocytes (see Chapter 19), it is reasonable to conclude that the defect in lymphoma is often owing to abnormal rearrangement. This is confirmed by the observation that most of the translocations in B-cell lymphomas involve the J and S sequences of the immunoglobulin genes that are the sites of normal rearrangements. Most of the common genetic alterations seen in lymphomas can be detected by polymerase chain reaction (PCR) techniques or by fluorescence in-situ hybridization.Gene-expression profiling using microarray technology is now being explored as an even more sophisticated way of understanding lymphoid tumorogenesis and classifying the non-Hodgkin's lymphomas. For example, it has been reported that small cell lymphocytic lymphoma, marginal zone B-cell lymphoma, and mantle cell lymphoma can be reliably distinguished using a 44 gene microarray more than 95% of the time, a considerable improvement over traditional histopathology. Large B-cell lymphomas can also be divided into good and bad prognostic groups using a cDNA microarray analysis. In one series, the measurement of six genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL-2) was reported to reliably identify patients with very poor 5-year survivals (< 27%).

CLINICAL FEATURESThe clinical manifestations of lymphoma can be considered under several general categories, which are discussed further under Laboratory Studies. The first category is those effects caused by enlargement of lymphoid tissues; second is the immunologic sequelae of the lymphoma; third is those effects caused by invasion of nonlymphoid tissues, particularly marrow; and last, the metabolic and humoral effects of the lymphoma.Enlargement of Lymphoid TissuesMost patients with lymphoma present with painless enlargement of lymph nodes or spleen or both. The effects of node enlargement vary from the cosmetic to such complications as obstruction of airway or major vessels, compression of the stomach, or obstruction of the intestines. In general the node enlargement is gradual and painless. Lymphomatous infiltration seldom results in an inflammatory response, and thus symptoms such as fever, weight loss, and night sweats are less common than in Hodgkin's disease.A common clinical situation is the patient who presents with one or more enlarged nodes and a history compatible with a recent viral infection. Although the only way to confidently rule out lymphoma is to take a biopsy of the node, one is usually reluctant to do this immediately. If the node enlargement has been sudden or painful (tender), then a reactive process is more likely than a lymphoma. If the node is very hard to palpate or fixed to underlying tissues, suspect carcinoma rather than lymphoma. In general a reactive process will subside over a few weeks. A node that persists longer than this, and is painless, firm, or grows in size, must undergo biopsy. Lymphomatous nodes can undergo fluctuating enlargement. A history of recurrent enlargement of a node is as compatible with lymphoma as is persistent enlargement. It is also possible to obtain a history of previous node biopsies that were read as reactive followed by a biopsy read as lymphoma. Thus a previous benign biopsy should not weigh against taking a biopsy of a suspicious node.

Multifocal versus Localized DiseaseNodal involvement in NHL is usually multifocal, with involved nodes separated by groups of normal nodes, and early dissemination throughout the body. Thus the concept of metastasis with orderly progression of disease from one node group to another, although useful in Hodgkin's disease, has little use in NHL.However, a few patients do present with localized disease, often in unusual locations. High-grade B-cell lymphomas can present in one node area or present as solitary brain tumors or osteolytic bone tumors. Gastrointestinal lymphomas can be localized and, if disseminated, tend to preferentially involve gut-associated lymphoid tissue.Interestingly, low- and intermediate-grade lymphomas are almost always disseminated at the time of presentation. Although the tumor masses associated with B-cell lymphomas tend to follow the anatomic distribution of the lymph nodes and lymphatics, T-cell malignancies are more likely to show a wider tissue distribution. T-cell malignancies resulting from clonal expansion of CD4-positive T cells generally involve the skin, sometimes with their major manifestation being skin infiltrations (mycosis fungoides). This situation reflects the natural propensity of T cells to migrate through the subepidermal layers of the skin. Both T- and B-cell lymphomas can have a blood (leukemic) component. The T-cell lymphomas and B-cell chronic lymphocytic leukemia (CLL) (see Chapter 21) are the most likely to result in high circulating lymphocyte counts, whereas other lymphomas usually have a minor circulating component that may not be reflected in the absolute lymphocyte count.

Other Clinical FeaturesA detailed history and a physical examination are very important in evaluating the NHL patient. Exposure to toxic chemicals, chemotherapeutic or immunosuppressive agents, or ionizing radiation can have epidemiologic importance, especially in the younger patient. HIV infection is a clear risk factor. A careful physical examination to look for other enlarged lymph nodes is essential for any patient presenting with a suspicious node. In addition to the common sites, involvement of retroclavicular nodes, Waldeyer's ring, and thoracic and retroperitoneal nodes should be sought by physical examination, x-ray, and CT scan. Renal and hepatic function tests should be done; however, in the absence of obstruction, involvement of these organs with lymphoma is frequently not reflected by chemistries.

Laboratory StudiesAs mentioned in the preceding section, Other Clinical Features, a detailed history and physical examination are important in identifying many manifestations of NHL. Renal and hepatic function tests should also be done. The evaluation of patients suspected of having lymphoma should include examination of blood and marrow for the presence of lymphoma cells as judged by morphology, cell surface markers, and genetic analysis. Sixty percent to 80 percent of lymphoma patients have involvement of blood, marrow, or both when sensitive techniques are used. This is true even when the complete blood count is perfectly normal

A. BLOOD AND MARROW TESTS FOR IMMUNOLOGIC EFFECTSMost patients with NHL do not develop profound marrow dysfunction even when the marrow is partially infiltrated with malignant cells. Immunologic testing of blood and marrow is best performed after the disease has been diagnosed by biopsy so that specific immunologic characteristics of the lymphoma are known. For example, if the lymphoma is of B-cell origin and is expressing immunoglobulin light chains, this information can be used to increase the sensitivity of the tests in blood and marrow.Most patients with lymphoma have or soon develop an immune deficiency that is characterized by diffuse hypogammaglobulinemia or by a poor response to new antigens and to infections (or both). However, a significant number of these patients, particularly those with T-cell lymphomas, may have diffuse or specific hypergammaglobulinemia, and a minority (about 5%) have a monoclonal serum immunoglobulin (M protein). Increased susceptibility to viral infection, and reactivation of viruses such as herpes zoster, may occur even prior to the onset of overt symptoms of lymphoma. This situation is owing to depression of cell-mediated immunity. Some lymphomas, particularly low-grade B-cell and CLL, may demonstrate autoantibodies directed against red blood cells or platelets, resulting in hemolytic anemia or immune thrombocytopenia.

B. TESTS FOR LYMPHOMATOUS INFILTRATION OF NONLYMPHOID ORGANSThe possibility of lymphomatous infiltration of nonlymphoid organs should always be suspected. Because lymphoma seldom elicits an inflammatory response as it invades, the involvement can be extensive before the patient becomes symptomatic. The most common involvement is seen in skin (especially T-cell lymphomas), lung, the gastrointestinal (GI) tract, the liver, bone and marrow, the kidney, and the central nervous system (CNS). Attention should be paid to all of these sites in evaluating a patient with lymphoma, and any otherwise unexplained findings should be fully evaluated by chemical and radiologic techniques. Liver involvement, for example, may be revealed by CT scan despite normal liver chemistries. Because the patient with lymphoma is subject to unusual and opportunistic infections, one is often faced with a difficult clinical distinction between infection and lymphomatous infiltration, for example, in the lung. These distinctions may require biopsy to resolve. Positron emission tomography (PET scanning) is being increasingly used in the initial staging and followup of lymphoma patients. Because it detects regions of increased metabolic activity it is sometimes more sensitive than CT or MRI in locating sites of lymphoma and in distinguishing between active tumor and residual scarring following treatment.

C. SERUM ASSAY TESTS FOR METABOLIC AND HUMORAL EFFECTSSome patients with lymphoma develop profound marrow dysfunction even when the marrow cannot be shown to be heavily involved with lymphoma. However, more common is the presence of significant numbers of lymphoma cells in the marrow with relatively normal blood counts. Anemia and thrombocytopenia are more often seen as side effects of therapy than as presenting features. Because lymphocytes produce a variety of cytokines with diverse effects on other cells, patients with lymphoma can display generalized metabolic and systemic symptoms. Most common are unexplained fever, weight loss, night sweats, and chills; less common are hypercalcemia and hypoglycemia. The availability of serum assays for lymphocyte-produced cytokines and their receptors may be useful in evaluating patients for these effects.

CHARACTERISTICS OF INDIVIDUAL LYMPHOMASSome types of lymphoma have relatively specific profiles of clinical presentation, histology, cell phenotype, and cytogenetic abnormalities. The following descriptions highlight the more important disease states as classified in the Working Formulation or REAL classification. Tables 22-3 and 22-5 summarize the features of many of these lymphoma types.

Low-Grade LymphomasThe nodular, or follicular, lymphomas dominate this class. In fact, they make up one-third or more of all cases of NHL. Follicular lymphomas typically occur in middle-aged or elderly adults. They usually present as a slow-growing, non tender enlargement of lymph nodes, taking months to years to appear and evolve. More than 75% of patients have disseminated disease at presentation, and 50% or more have marrow involvement. They tend to be resistant to curative chemotherapy, but even so, have a median survival of 7 years as compared with survival of 1- 2 years for the intermediate- and high-grade lymphomas that fail to respond to curative chemotherapy or transplantation. With time, the follicular lymphomas can exhibit a change in histology and behavior to a more high-grade tumor class with a concomitant reduction in survival.Once a diagnosis is made from a node or tumor mass biopsy, a search for evidence of disseminated disease should be undertaken, using studies of blood and marrow for cell morphology, immunologic markers, and gene rearrangements. These studies will usually be positive. More complex staging (staging laparotomy or organ biopsy) is unnecessary unless it appears that the disease may in fact be localized.These tumors are usually of B-cell origin, and their nodular pattern of growth is reminiscent of their origin in the germinal center. The presence of larger cells and mixtures of diffuse as well as nodular architecture suggests a more aggressive variant of the disease. The characteristic cell phenotypes are summarized in Figure 22-2. These cells correspond to the phenotype of maturing lymphocytes of both T- and B-cell type (see Chapter 19). The presence or absence of CD5 is important because it is characteristic of B-cell CLL and its presence suggests a less aggressive variant. In addition, there is a rough positive correlation between the intensity of expression of surface immunoglobulin and the aggressiveness of the disease.

Table 22-5. Immunologic and cytogenetic features in the REAL classification of T-cell neoplasms.

DiseaseMorphologyImmunophenotypeGenotype

T-cell CLLSmall lymphocytes or prolymphocytesTdT-CD2, 3, 5, 7+CD4+8- > CD8+4+ > CD4-8+CD25-TCR rearrangementsInv14 (q11;q32) (75%)

Cutaneous T-cellSmall and large cells with cerebriform nucleiTdT-CD2, 3, 5+, 7CD4+8-, CD25TCR rearrangement

Large granular lymphocyteLymphocytes with abundant cytoplasm and azurophilic granulesTdT-CD2, 3+, 5CD8, 16, 57+CD4, 56, 25-TCR rearrangement

Peripheral T-cellSmall to medium-sized irregular lymphocytesTdT-CD2, 3, 5, 7CD4 and/or 8+TCR rearrangement

Adult T-cellHighly variableTdT-CD2, 3, 5, 25+CD7-, CD4+8-TCR rearrangementIntegrated HTLV-1

Anaplastic large-cellLarge blastic pleomorphic cellsTdT-CD2, 3, 5, 7CD25, CD30+TCR rearrangementt(2;5) (ALK)

Precursor T lymphoblasticMedium-sized blastic cellsTdT+CD7+CD2, 3, 5CD4, 8+ or CD4, 8-Variable TCR and IgG rearrangement

The cells display the characteristic immunoglobulin gene rearrangements seen in B cells. In addition, most will display a t(14:18) chromosomal translocation, which places the BCL-2 protooncogene under the influence of the immunoglobulin heavy chain gene locus. The use of PCR technology to detect immunoglobulin gene rearrangements and the BCL-2 translocation permits the detection of very small numbers of malignant cells in clinical specimens.

A. TISSUE-BASED VARIANT OF B-CELL CLLAnother low-grade lymphoma is characterized by a diffuse infiltration of small, noncleaved lymphocytes. The tissue-based variant of B-cell CLL is almost always associated with a leukemic phase of varying degree. The presence of the CD5 marker and low levels of surface immunoglobulin are characteristic. Its presentation and response to therapy are identical to that of CLL. In many cases it evolves over time to a more aggressive variant of lymphoma.

B. LYMPHO-PLASMA-CYTOID VARIANTThe lymphoplasmacytoid variant is frequently associated with an IgM component that leads to its being considered along with multiple myeloma as a plasma cell neoplasm (see Chapter 25). However, the biology and clinical behavior of this disease more closely resemble that of the low-grade lymphomas.

C. MARGINAL ZONE LYMPHOMASAn additional variant of low- to intermediate-grade lymphomas has been brought to the fore front by the REAL classification the marginal zone lymphomas. Three clinical presentations have now been described, including nodal marginal zone, splenic marginal zone, and extranodal with masses in the respiratory or GI system, involving subepithelial, mucosa-associated lymphoid tissue (MALT tumors). Patients with MALT tumors generally have a history of autoimmune disease or chronic antigenic stimulation. Sites of presentation include the GI tract, especially the stomach, salivary glands, skin, lung, thyroid, and orbit. Gastric MALT lymphoma (see Color Plate 58) commonly presents with symptoms of dyspepsia, anorexia, epigastric pain, and GI bleeding. Its pathogenesis is related to Helicobacter pylori infection, and some 70% of cases will show regression of the tumor with antibiotic therapy alone. This has led to the use of antibiotic and acid blockade as first line therapy. Sustained responses are seen reliably in patients with stage I diseases (endoscopic appearance of gastritis), whereas chemotherapy and gastrectomy may be needed in patients who present with more advanced disease.

Splenic marginal zone lymphoma appears to be another distinct entity, although much less common. It is distinguished by variable lymphocytosis (10,000 - 40,000/L) with the appearance of villous lymphocytes in both blood and marrow, moderate to marked splenomegaly, and the presence of a small M component (either IgG or IgM) of less than 30 g/L. B symptoms are rare and the lactic dehydrogenase (LDH) level tends to be normal at presentation. Spleen histology shows giant follicles with some red pulp infiltration but not to the degree seen in hairy-cell leukemia. By immunophenotype, the tumor cells are usually positive for sIg and CD22, 24, and 25 (unlike hairy cells, which are CD24 and 25 negative), and negative for CD5, 23, and 76b. No consistent or unique chromosomal abnormalities have been reported.Intermediate-Grade LymphomasThe intermediate-grade lymphomas share characteristics of the low- and high-grade tumors. Patterns of disease histology include nodular large-cell lymphoma; a small cell or mixed small and large-cell tumor with diffuse histology; and a diffuse large-cell lymphoma. The latter may be classified as high-grade if the cells are poorly differentiated. The classification of lymphomas as intermediate-grade is done more on the basis of what the tumor is not, rather than on specific characteristics. Thus, when a lymphoma does not fit the profile of either a low- or high-grade lymphoma it is assigned to the intermediate-grade class.Most of the intermediate-grade lymphomas are of B-cell origin. There are no unique characteristics to the clinical presentation or course other than an intermediate level of aggressiveness of the tumor growth. The physician must observe the patient to determine the pattern and course of the disease over time in order to derive the prognosis for the individual patient. For treatment purposes, intermediate-grade lymphomas are generally considered in the same category as high-grade lymphomas.Another class of B-cell lymphomas, which has been emphasized by the REAL classification, is mantle cell lymphoma (see Color Plate 55). This lymphoma variant is characterized immunophenotypically by the presence of CD5 (like CLL), but, unlike CLL, it does not express CD23. Most mantle cell lymphomas have a t(11;14) translocation that involves the BCL-1 protooncogene (see Table 22-3). Patients with this lymphoma respond poorly to therapy and relapse early. Therefore, these lymphomas are clinically very distinct from the low-grade lymphomas, which they otherwise resemble.

High-Grade LymphomasSeveral diseases with unique profiles fall into the high-grade lymphoma category. It is also common to see tumors of both B- and T-cell origin within this grouping. Four of the more important node-based high-grade lymphomas are diffuse large-cell lymphoma, formerly referred to as diffuse histiocytic lymphoma; large-cell immunoblastic lymphoma; lymphoblastic lymphoma; and a very aggressive small-cell tumor called Burkitt lymphoma. In general, these are all very rapidly growing tumors with a poor prognosis when left untreated.

A. DIFFUSE LARGE-CELL LYMPHOMAThe large-cell lymphoma patient frequently presents with one or more rapidly developing tumor masses involving nodal or extranodal sites. As is typical of most lymphomas, the mass is not tender and does not cause inflammation or interfere with organ function except by compression. Retroperitoneal disease can obstruct venous drainage of the legs, resulting in edema and thrombophlebitis.Staging studies should involve a large-volume biopsy of the tumor for histology and cell phenotype studies. Marrow and blood studies for morphology, immunophenotype, chromosomal analysis, and T- and B-cell gene rearrangements should be obtained to prove disseminated disease. Cerebrospinal fluid examination and imaging of the CNS are indicated in patients with neurologic findings. Patients can present with localized involvement of the brain or widely disseminated lymphoma involving the CNS. Ten percent to 20 percent of the large cell lymphomas may be limited to a single node or extranodal site such as bone, Waldeyer's ring, thyroid, lachrymal glands, or the gastrointestinal tract.The typical large-cell tumor mass shows complete effacement of normal lymphoid architecture with a monotonous infiltrate of large lymphocytes (see Color Plates 56 and 57). These cells are usually of B-cell origin with a phenotype not distinctly different from that of other lymphomas except for an increased expression of surface immunoglobulin in many cases. Many of these lymphomas have chromosomal rearrangements that involve BCL-6, either alone or in combination with involvement of BCL-2 and, in some cases, c-myc (see Tables 22-3 and 22-4). In addition, mutations of the p53 tumor-suppressor gene are seen. This complex genetic background may explain the clinical heterogeneity that characterizes this disease.

B. LARGE-CELL IMMUNOBLASTIC LYMPHOMASome of the diffuse large-cell lymphomas are composed of so-called immunoblasts, that is, cells with abundant basophilic cytoplasm and nuclei with a large central nucleolus. Some of these cells resemble plasma cells or plasma blasts. This form is referred to as immunoblastic lymphoma and may be of either T- or B-cell origin. It is most commonly seen in older patients, often with pre-existing immunologic disease such as Sjgren syndrome, thyroiditis, or celiac sprue or a previous lymphoproliferative disease such as CLL, myeloma, or angioimmunoblastic lymphadenopathy. In those patients with a T-cell angioimmunoblastic lymphoma, leukopenia and polyclonal hypergammaglobulinemia are often seen. Angioimmunoblastic lymphoma has an extremely poor prognosis, especially in older patients.

C. LYMPHOBLASTIC LYMPHOMAPrecursor lymphoblastic lymphoma represents another high-grade malignancy with diffuse histology. This condition is a disease of younger individuals and children. It often presents with a bulky, rapidly growing mediastinal mass. The marrow and CNS are frequently involved. On biopsy, the mass consists of a diffuse infiltrate of cells with convoluted nuclei and little cytoplasm. The phenotype of the cells is most often that of a preB or T cell. This tumor shares characteristics with acute lymphocytic leukemia (ALL) and is treated with a similar regimen. Patients presenting with lymphoblastic lymphoma frequently have a leukemic component to their disease and may rapidly progress to overt ALL.

D. BURKITT LYMPHOMABurkitt lymphoma, another disease in the high-grade category, is a very aggressive tumor of immature B-cell origin. The characteristic histology is that of a diffuse infiltrate of small noncleaved lymphocytes interspersed with large cells imparting a starry sky appearance under low-power magnification (see Color Plate 60). The vacuoles in these cells responsible for the starry sky appearance stain positively for fat using the oil red O stain (see Color Plate 61). The tumor is associated with a unique chromosomal rearrangement involving the c-myc protooncogene on chromosome 8 moving to one of the immunoglobulin gene loci, the most common being t(8;14) (see Tables 22-3 and 22-4).A form of Burkitt lymphoma occurs endemically in children in Africa. It usually presents as a tumor mass localized to the jaw or retroperitoneum with involvement of bone, kidney, ovaries, and CNS. This endemic form is strongly associated with Epstein-Barr virus infection. In Western countries, Burkitt lymphoma is a nonendemic disease of children and young adults with no clear connection to the Epstein-Barr virus. It most often presents as a rapidly growing tumor of abdominal lymph nodes, although marrow involvement is generally present at the time of diagnosis.

E. B-CELL LYMPHOMA IN AIDS PATIENTSAn increasing incidence of B-cell lymphomas is being seen in AIDS patients. They are strongly associated with Epstein-Barr virus and may also show rearrangements involving c-myc and mutation of p53. Many of these involve the brain. Clinical staging is important in planning treatment and should be carried out without delay. Patients with a single tumor mass and low LDH indicating a small tumor mass have the best prognosis. Bulky tumor in the abdomen imparts a worse prognosis, and involvement of either marrow or the CNS together with a high LDH predict a high failure rate even with multidrug chemotherapy. The incidence of AIDS-related lymphoma has not changed with the introduction of highly active antiretroviral therapy. This is in contrast to the marked reduction in the incidence of Kaposi sarcoma.

F. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERSPost-transplant B-cell lymphomas are seen in organ transplant patients receiving chronic immunosuppressive therapy. They generally arise in extranodal sites and are extremely aggressive. Early onset lymphomas are usually related to Epstein-Barr virus infection and are polyclonal or oligoclonal, whereas late-onset lymphomas are true monoclonal malignancies of the diffuse large B cell and Burkitt-like type. Most of the monoclonal B-cell lymphomas derive from germinal center B cells.

T-CELL LYMPHOMA CLASSIFICATIONAs techniques for diagnosing clonal lymphoid malignancies have improved, especially the ability to detect rearrangements of the B- and T-cell antigen receptor genes, an increasing number of tumors of T-cell origin have been identified. Clinical clues to the presence of a T-cell malignancy include the presence of B symptoms, leukopenia or aplastic anemia (or both), disseminated disease with marrow involvement, hepatosplenomegaly, and lung and skin involvement. Several subtypes of T-cell disease have been identified. These are defined largely by their clinical profiles; however, the ultimate diagnosis of a T-cell lymphoma requires study of cell surface markers and an analysis for T-cellreceptor gene rearrangement. The latter is the only certain way of proving a clonal origin for T cells. The array of surface markers can be helpful in that frequently T-cell lymphomas will express some, but not all, of the characteristic T-cell markers. The unexpected absence of a T-cell marker on a population of T cells can be a clue to their malignant nature. In addition, the presence of CD4, CD8, or both provides some help in predicting the signs and symptoms related to lymphomas of T-helper (CD4+) or T-cytotoxic/ suppressor (CD8+) subtypes.Histologic subclassifications of T-cell lymphoma distinguish between peripheral T-cell lymphoma, several angiocentric forms, and a Hodgkin's diseaselike form (see Table 22-5). Many T-cell lymphomas are characterized by a pleomorphic cell population, often including large numbers of macrophages. This diverse cell population is probably recruited to the site of the tumor by production of cytokines by the malignant T cells. In addition, production of these cytokines explains the common occurrence of inflammatory signs and symptoms.Peripheral T-Cell LymphomaMost patients present with peripheral T-cell lymphoma, which is a diffuse small- or large-cell lymphoma with the phenotype of mature T cells. More than one-half of these patients have B symptoms (fever, chills, weight loss) suggesting active cytokine production by the malignant cells. Widespread lymphadenopathy is the rule, and many patients have involvement of extranodal sites, marrow, blood, liver, spleen, lung, and skin.Large Granular Lymphocyte DiseaseLarge granular lymphocyte (LGL) disease is a distinct disorder arising from a clonal proliferation of a granular lymphocyte, derived from a CD3+, CD8+ T cell. Although sometimes confused with an NK cell, these are true T cells. The disease presents clinically as a low-grade lymphoproliferative disorder with splenomegaly but little or no lymphadenopathy, pancytopenia complicated by recurrent bacterial infections, and, in a quarter of cases, an autoimmune disorder such as rheumatoid arthritis. LGL disease in patients with rheumatoid arthritis can be indistinguishable from Felty syndrome. Proliferation of LGL cells has also been reported in association with other hematologic malignancies (monoclonal gammopathy of undetermined significance, multiple myeloma, and myelodysplasia) and with both marrow and organ transplantation.The diagnosis of LGL leukemia can usually be made from the appearance of large numbers of granular lymphocytes (GL) in the peripheral blood and bone marrow. Most patients demonstrate GL levels greater than 2000/L, although when the other clinical features are present, a GL count greater than 500/L is acceptable (normal GL count 223 - 699/L). True NK-cell disease is very uncommon and often presents as a leukemia with a very aggressive course.Lymphomatoid Granulomatosis & Polymorphic ReticulosisLess common, angiocentric types of T cell lymphoma include two entities: lymphomatoid granulomatosis and polymorphic reticulosis (lethal midline granuloma) of the upper respiratory tract. The latter is characterized by destructive lesions of the nose, sinuses, and nasopharynx. Patients with lymphomatoid granulomatosis complain of fever, weight loss, shortness of breath, cough, and hemoptysis. They have single or multiple lung nodules or masses on chest x-ray. Recently lymphomatoid granulomatosis has been reclassified as a mixed B- and T-cell lymphoma in which the B cells are EBV positive.Angioimmunoblastic LymphadenopathyAngioimmunoblastic lymphadenopathy is a disease of the elderly that presents with generalized lymphadenopathy, hepatosplenomegaly, B symptoms, polyclonal expansion of B cells with hypergammaglobulinemia, and, in some cases, autoantibodies resulting in hemolytic anemia or thrombocytopenia. It is an aggressive disease that progresses to either overt T- or B-cell lymphoma.

HISTIOCYTIC MEDULLARY RETICULOSIS & LENNERT LYMPHOMAHistiocytic medullary reticulosis HMR is primarily a disease of the marrow that results in profound pancytopenia with infiltration of phagocytic cells that characteristically ingest erythrocytes. As with other T-cell lymphomas, it is usually accompanied by fever, weight loss, lymphadenopathy, and hepatosplenomegaly. Lennert lymphoma is characterized by the appearance of large numbers of epithelioid cells mixed with lymphoid cells, often forming granulomas.Hodgkin's Disease like T-Cell LymphomaHodgkin's disease like T-cell lymphoma, as implied by its name, mimics the presentation and histology of Hodgkin's disease. However, the T-cell infiltrate of the involved nodes is clonal. It is important to distinguish this variant since its prognosis is significantly poorer than that of Hodgkin's disease.Other PresentationsT-cell malignancies can also present as CLL (see Chapter 21), ALL (see Chapter 24), or as skin disease (cutaneous T-cell lymphoma/mycosis fungoides/Saezary syndrome; see Color Plates 52 and 59). The presenting skin lesions of mycosis fungoides vary from an eczematous or psoriatic-appearing lesion to plaques with sharply demarcated margins. With time these cutaneous lesions develop into painless nodules that can ulcerate and become infected. Severe itching is the rule, and many patients will develop generalized erythroderma progressing to exfoliation. Survival can range from a few months to several decades, depending on extent of blood, nodal, and visceral disease. When disease is limited to the skin, median survival is in excess of 10 years. However, most patients will in time progress to stage IV with involvement of lymph nodes and visceral organs. Blood and marrow involvement is characterized by the appearance in the circulation of small or large lymphocytes with highly convoluted (cerebriform) nuclei. These cells are acid phosphatase positive and CD4 positive. Their presence signifies progression from mycosis fungoides to Saezary cell leukemia.On skin biopsy the CD4 T-helper cell lymphomas typically show a lymphocytic or mixed cell infiltrate immediately under the epidermis. In some patients the epidermis is actually invaded by clusters of lymphocytes producing unique lesions called Pautrier microabscesses (see Color Plate 59). This pattern is quite different from that seen with B-cell lymphomas, where the cells tend to congregate in the lower dermis, leaving a clear subepidermal zone. T-cell receptor gene rearrangement analysis can be used to identify the clonal T-cell nature of the infiltrate in unclear cases.Table 22-6. WHO classification of cutaneous lymphomas.

Mycosis fungoides/Szary syndromeAnaplastic large cell lymphoma, primary cutaneous typePeripheral T-cell lymphomaNK/T-cell lymphomaSubcutaneous pannicilitis-like T-cell lymphomaExtranodal marginal zone lymphoma of MALT typeFollicular lymphomaDiffuse large B-cell lymphomaExtramedullary plasmacytoma

Lymphomas of the skin are not all T-cell malignancies; B-cell lymphomas and Hodgkin's disease can also initially present with cutaneous involvement. As a reflection of this, classification schemes for the cutaneous lymphomas have been proposed by the WHO and the EORTC (European Organization for Research and Treatment of Cancer). The newer WHO classification is summarized in Table 22-6.

THERAPY & CLINICAL COURSEThe success rate in treating lymphoma is of course related to grade of disease as well as many other prognostic factors. For both high-grade and low-grade lymphomas the most important prognostic indicators are summarized in Table 22-7, and the outcomes associated with combinations of these factors are shown in Table 22-8. Patients with low-grade lymphomas often have a good prognosis in terms of their long-term survival but are very rarely cured, ultimately dying of their disease. Conversely, patients with high-grade lymphomas, who have a very poor prognosis when untreated, and a much shorter average survival, can often be cured by aggressive therapy (Figure 22-3). Thus, NHL therapy must be tailored to the disease and to the patient. In many institutions these patients will be treated according to research protocols. This permits continuous improvement in therapy as new regimens for radiotherapy, multidrug chemotherapy, and marrow transplantation are introduced. Successful treatment of the lymphoma also requires a high-quality blood transfusion service to provide red blood cell and platelet support and an aggressive approach to the control of infection in these immunocompromised patients.Table 22-7. Prognostic indices in high- and low-grade lymphomas.

Adverse Factors for High-Grade LymphomaAdverse Factors for Low-Grade Lymphoma

Age > 60 yrAge > 60 yr

Serum LDH elevatedSerum LDH elevated

Performance status 2 - 4B symptoms or ESR > 30

Stage III or IVMale sex

Extranodal involvementExtranodal involvement

Table 22-8. Survival according to prognostic indices.

High-Grade Lymphoma Low-Grade Lymphoma

2-yr Survival5-yr Survival5-yr Survival10-yr Survival

Low risk: 0 - 1 factor84%73%89%70%

Intermediate risk: 2 - 3 factors60%47%71%49%

High risk: > 3 factors34%26%47%8%

Radiation TherapyRadiation therapy is very effective in destroying sites of bulky disease. Relatively low doses (2000 cGy) will result in spectacular regression of a tumor mass. However, since most patients have widely disseminated disease at presentation, the role of radiotherapy is only palliative, and limited to the treatment of a restricted site of symptomatic disease. The only situation in which radiotherapy may be undertaken with curative intent is in localized (stage I or II) disease, where cures have been reported in high-, low-, and intermediate-grade lymphomas. However, radiotherapy alone can only be recommended after an exhaustive search using radiologic, immunologic, and molecular techniques has failed to find any evidence of dissemination of the lymphoma. Even when there is no evidence for blood, marrow, or other organ involvement, up to 50% of apparent stage I lymphomas will relapse at a distant site and need multidrug chemotherapy with or without transplantation.

Treatment of Low-Grade LymphomasLow-grade lymphomas are frequently extremely indolent, with long periods of regression or stable disease interrupted by periods of increased disease activity. No evidence exists that aggressive chemotherapy can cure these patients. Thus a conservative therapeutic approach is indicated, ranging from no therapy at all during quiescent periods to the use of minimal chemotherapy or radiotherapy designed to control flare-ups and eliminate symptoms. Some of these patients will survive for 5 - 10 years, requiring only brief periods of treatment or none at all. The usual treatment for these patients is local radiotherapy to bulky symptomatic disease and a mild regimen of chemotherapy such as oral chlorambucil or cyclophosphamide or a cyclophosphamide-vincristine-prednisone regimen (Table 22-9). Chemotherapy should be continued until the disease has regressed and appears quiescent, and then should be stopped and the patient closely observed. Such patients may gradually become more resistant to treatment with shorter periods of remission, or they may convert to a higher grade of lymphoma with a more rapid growth pattern.Recently there have been reports of a high level of responsiveness in patients with low-grade lymphoma to the newer agents such as fludarabine and 2-chlordeoxyadenosine (2-CdA). These agents, which are proving very effective in the treatment of the CLLs (see Chapter 21), now have roles in the therapy of other low-grade lymphomas. These agents are highly immunosuppressive, especially in combination with corticosteroids, and their use increases the risk of opportunistic infections.Some patients with low- or intermediate-grade lymphoma will show a pattern of continual slow growth of the disease despite therapy (unresponsive disease) or will have brief responses followed by rapid resumption of growth. These patients have a markedly poorer prognosis. In this case more aggressive chemotherapy protocols are justified in an attempt to achieve longer remissions. Such protocols include chemotherapy capable of crossing into the CNS, such as high-dose methotrexate with leucovorin rescue, cytosine arabinoside, or both. Such multidrug protocols involve a high level of treatment-related morbidity and mortality (up to 5 - 10%) but do result in prolonged disease-free survival in up to 50% of patients. Because of a tendency to see late relapses it is unclear what proportion of these may be considered cures.Immunotherapy has shown considerable promise in the treatment of the low-grade lymphomas. Several different approaches are being studied. Monoclonal antibodies against B cell epitopes-for example, CD19 or CD20 together or alone, coupled with toxins or radioisotopes have been produced. Rituximab, a chimeric anti-CD20 monoclonal antibody with specificity for the late preB stage to plasma cell differentiation, is now being used in various combinations with chemotherapy and stem cell rescue strategies. Patients with follicular histology show the best response; 80% of patients who fail on chemotherapy alone respond to rituximab with minimal toxicity. Although the best use of this agent is still a matter of study, it is typically given in doses of 375 mg/m2 as a weekly infusion for up to 8 weeks. Its use as an up front part of combination chemotherapeutic regimens is also being studied. Another approach to immunotherapy involves coupling a radionuclide, such as 131I or 90Y, to an anti-CD20 antibody (131I tositumomab and 90Y ibritumomab). When given in myeloablative doses followed by stem cell rescue, this approach is well tolerated and can produce prolonged remissions in more than 50% of relapsed patients.

Table 22-9. Some typical chemotherapeutic regimens for lymphoma.

RegimenDrug Dosage and Schedule

Single agent

Cyclophosphamide or100 PO qd

Chlorambucil412 mg PO qd

Fludarabine25 mg/m2/IV days 15

CVP Repeated q3 weeks

Cyclophosphamide400 mg/m2 PO days 15

Vincristine1.4 mg/m2 IV day 1

Prednisone100 mg/m2 PO days 15

CHOP Repeated q3 weeks

Cyclophosphamide750 mg/m2 IV day 1

Adriamycin50 mg/m2 IV day 1

Vincristine1.4 mg/m2 IV day 1

Prednisone100 mg PO days 15

R-CHOP Repeated q3 weeks

Rituximab375 mg/m2 IV day 1

CHOP (as above)Beginning day 3

Chemotherapy with autologous marrow support

BCNU112 mg/m2 IV days 14

Cyclophosphamide900 mg/m2 IV q12h days 14

Etoposide (VP-16)250 mg/m2 IV q12h days 14

Infusion of autologous marrow cellsAt least 2 106 CD34+ cells/kg IV day 7

Lymphoma vaccine therapy is another potentially useful approach. Typically the vaccine is custom-made using a sample of the patient's own tumor cells to derive an idiotype protein, which is unique to the patient's lymphoma. This tumor-derived protein is then combined with an imunnostimulant, such as keyhole limpet hemocyanin, and injected subcutaneously on a monthly schedule for up to 2 years. Simultaneous treatment with G-CSF may help magnify the immune response. Patients with the lowest tumor burden appear to do the best; therefore, candidate patients should be pretreated with combination chemotherapy.

Treatment of High-Grade LymphomasPatients with high-grade lymphomas have a poor prognosis when left untreated and should receive aggressive chemotherapy without waiting to see how the disease responds to milder therapy. A high-dose, multidrug protocol, such as cyclophosphamide-adriamycin-vincristine-prednisone (CHOP) should always be used in these patients. Even more aggressive chemotherapy with autologous stem cell transplantation offers a significantly better chance of survival in selected patients; long-term survivals approach 60%. An international index of prognostic factors has been applied to these patients and has demonstrated that age (greater than 60 years), elevated LDH, poor performance status, the presence of stage III or IV disease, and the presence of more than one site of extranodal involvement are the most significant factors. Patients with 0 to 1 risk factor show 5-year survivals of greater than 70%, whereas patients with four or more risk factors have survivals of 20 - 30%.There is also evidence that patients with intermediate-risk lymphomas achieve significantly better survivals when treated with high-dose therapy and stem cell transplantation, rather than conventional CHOP. However, the simple addition of rituximab to the CHOP regimen has now provided greatly improved results and has become the standard of care for these patients. To date, the rituximab-CHOP combination has not been randomly tested against transplantation. For patients with low-risk lymphomas, conventional and high-dose therapy with transplantation seems to offer equivalent results.Patients with high-grade lymphomas who relapse after conventional chemotherapy are routinely treated with very high-dose chemotherapy regimens, sometimes including total body irradiation, followed by peripheral stem cell transplantation. The success of this salvage therapy has been reported by several centers to range from 30% to 50% long-term disease-free survival. Radioimmunotherapy is another promising approach for relapsed high-grade lymphomas. Recently, the proteosome inhibitor bortezomib, which is active in myeloma, has shown some activity in non-Hodgkin's lymphomas as well. Thus, the addition of this new agent to existing regimens is now being studied.

Marrow Transplantation/Peripheral Blood Stem Cell SupportAllogeneic transplantation has curative potential in the patient with a matched sibling. Success depends on the responsiveness of the tumor to chemotherapy and the patient's age and overall state of health. Compared to autologous transplantation (ABMTx), it is associated with higher transplantation related mortality, but a better chance of long-term disease-free survival, approaching 70 - 80% at 5 years. Unlike acute leukemia, the outcome does not appear to correlate with the antitumor effect of GVHD.Because many more patients are eligible, ABMTx has become a major treatment option for patients with high-grade lymphomas and relapsed Hodgkin's disease. The procedure has undergone a gradual transition so that it is now more correctly referred to as high-dose chemotherapy with peripheral blood stem cell (PBSC) support. Most transplant protocols now make use of autologous peripheral blood stem cells collected by apheresis, rather than bone marrow. The rate of recovery of the patient's blood counts, especially the platelet count, is more rapid with the peripheral stem cell method.In essence ABMTx/PBSC support is not a transplant in the usual sense of the word, but is really a strategy for overcoming the major dose-limiting toxicity of chemotherapy, marrow failure, by supporting the patients with infusions of marrow cells, blood progenitor cells, or both. The fundamental rationale is that it may be possible to achieve cures of some diseases by increasing the dose of chemotherapy to 5 - 10 times that which could be given without replacement of hematopoietic progenitor cells. This has proved to be the case for some diseases. It must be remembered, however, that the procedure cannot be successful if the disease is not responsive to very high-dose chemotherapy. ABMTx/PBSC support has the advantage that it can be used in patients who do not have an HLA-compatible family or unrelated donor, it can be applied to older patients with much greater safety than allogeneic transplantation, and it does not have the complication of graft-versus-host disease. Its major disadvantage is the risk of relapse due to small numbers of tumor cells in the autologous marrow or PBSC collection. There is increasing evidence that this is indeed a serious consideration that limits the success of this strategy.

A. PROCEDUREABMTx/PBSC protocols now involve the collection of PBSCs instead of marrow (Figure 22-4). PBSCs are collected from the patient by repeated leukapheresis, usually one to five times over as many days. The timing of these collections is critical since for them to be successful. In order to obtain adequate numbers of stem cells it is necessary to increase the proportion of circulating progenitor cells in the blood. This may be done either by collecting the cells during the period that the patient is recovering from conventional chemotherapy or when the granulocyte count is rising in response to either granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF). In either case it is preferable to begin collections when the count is rising sharply, either at the level of 1000 - 2000/L following chemotherapy or after 4 - 5 days of daily colony-stimulating factor injections. The leukocytes from these collections are frozen until needed by the patient. Usually between 1 and 10 1010 cells are collected. Enumeration of the CD34+ cells, which include all of the hematopoietic progenitor cells, has improved the ability to determine how many cells are required for successful engraftment. Between 2 and 5 106 CD34+ cells/kg are adequate, and in some patients this goal may be reached in a single apheresis session.

The patient is then admitted for high-dose chemotherapy, which may contain any of a number of different combinations of drugs according to specific protocols (see Table 22-9). Some ABMTx regimens include total body irradiation in addition to chemotherapy. The doses of drugs are chosen so as to result in total ablation of the marrow while avoiding lethal toxicity to other organs such as lung, liver, and heart. Within 1 - 4 days following chemotherapy, patients receive intravenous infusions of their PBSC and begin receiving daily injections of G-CSF or GM-CSF.Following reinfusion of the progenitor cells, there is a period of 5 - 10 days in which the patient is absolutely pancytopenic, with essentially no leukocytes, and dependent on platelet support. After this latent period, there is, under the influence of the myeloid growth factors, a rapid rise in the leukocyte count. Platelet recovery usually lags behind the white blood cells, and the patients may require platelet support for weeks to months, although the use of PBSC hastens platelet recovery.The management of these patients is essentially the same as that of any patient receiving high-dose, marrow-ablative chemotherapy. They are at high risk for severe infections and must receive intensive antibiotic coverage (see Chapter 17). In addition, the chemotherapy may result in reversible toxicity to other organs that would not be seen with lower doses.

B. OUTCOME AND PROGNOSISThe ultimate outcome of ABMTx/PBSC therapy depends on three factors. First, there is a significant treatment-related mortality, which is usually less than 5%. Second, and most likely, is the possibility that the patient's tumor could not be ablated completely by the chemotherapy and radiation. A fairly high percentage of patients relapse within the first 1 - 2 years. For most protocols in the treatment of high-grade non-Hodgkin's lymphomas, this is in the range of 30 - 50% of patients. Third, there is the possibility that the marrow and PBSC collections contain small numbers of tumor cells that will regrow. Since ABMTx/PBSC therapy involves the reinfusion of more than 1010 cells, and since even the most sensitive detection methods permit the identification of only about 1 tumor cell in 106 cells, it is possible that the patient can receive as many as 104 tumor cells even if they are undetectable. It has been shown in the case of non-Hodgkin's lymphoma that the risk of relapse is higher in patients who have such very small numbers of cells detectable in their stem cell collections.Strategies for depleting these tumor cells, which involve treating the marrow with monoclonal antibodies, in vitro chemotherapy, or immunotoxins (purging), have been evaluated but do not yet offer a consistently clear improvement in outcome. Recently, devices for purification of the CD34+ stem cells using immunoabsorptive columns based on the ability of monoclonal antibodies to bind to the CD34 antigen have become available. There is hope that this procedure will simultaneously enrich for the desired stem cells and deplete unwanted tumor cells. It is striking that successful engraftment can be achieved by infusion of as few as 1 to 2 106 purified CD34+ cells, with exactly the same engraftment kinetics as infusion of 10,000 times more unenriched marrow or blood cells.The prognosis for the patient with relapsed or refractory non-Hodgkin's lymphoma who undergoes a modern ABMTx protocol is 30 - 50% long-term disease-free survival. Although far from perfect, this represents a significant improvement over conventional chemotherapy for this patient group. Treatment with rituximab post-transplant may improve survival, although optimal dosing needs to be defined.

Treatment Regimens for T-Cell LymphomasEarly-stage mycosis fungoides with disease limited to the skin is best treated with topical therapy. Barely perceptible skin lesions (plaques, papules, or eczematous patches) will usually respond to topical steroids, alone. PUVA therapy (oral psoralen with UVA irradiation) or topical nitrogen mustard (mechlorethamine) applied as an aqueous solution or ointment will induce complete remission, lasting more than a year, in most patients with skin-limited disease. Hypersensitivity reactions are, however, seen in up to 50% of patients treated with mechlorethamine. If topical therapy does not work, total-skin electron-beam irradiation can be used, usually in combination with maintenance PUVA, interferon-, or oral methotrexate to prevent rapid relapse.Patients with cutaneous tumors and nodal involvement are treated with local-field electron beam and PUVA maintenance or, in the case of refractory or visceral disease, single-agent (methotrexate, 2-CdA, fludarabine, or pentostatin) or combination chemotherapy (EPOCH). Patients with generalized erythroderma should receive photophoresis, together with low-dose interferon- or methotrexate when the response is poor. Photophoresis involves collecting the patient's leukocytes by leukopheresis after the oral administration of methoxypsoralen and then exposing them to UV light. When the treated leukocytes are reinfused they somehow stimulate a host response to the tumor cells and significant improvement in the patient's erythroderma. Photophoresis has also been used as an adjuvant to chemotherapy in Szary cell leukemia patients.LGL disease in otherwise asymptomatic patients may best be simply observed. Survivals can exceed 10 years. The principal indications for treatment are recurrent infections secondary to severe neutropenia and B symptoms. Patients may respond to prednisone alone or in combination with Cytoxan, or to low-dose oral methotrexate. Combination chemotherapy (CHOP-like regimen) has been used in patients with aggressive disease with only limited success.

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