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InternalMed_Harrison. FISH and PCR studies (to check for concordance of results), or more frequently if there are concerns about changes in BCR-ABL1 transcripts (e.g., every 3 months). Monitoring by molecular studies only is reasonable in patients who are in major molecular response. Cytogenetic relapse on imatinib is an indication of treatment failure and need to change TKI therapy. Mutational analysis in this instance helps in the selection of the next TKI and identifies mutations in 30–50% of patients. Mutational studies in patients in complete cytogenetic response (in whom there may be concerns of increasing BCR-ABL1 transcripts) identify mutations in ≤5% and are therefore not indicated. Earlier response has been identified as a prognostic factor for long-term outcome, including achievement of partial cytogenetic response (BCR-ABL1 transcripts ≤10%) by 3–6 months of therapy. Failure to achieve such a response on imatinib therapy has been associated with significantly worse survival in some studies


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InternalMed_Harrison. cytogenetic response (BCR-ABL1 transcripts ≤10%) by 3–6 months of therapy. Failure to achieve such a response on imatinib therapy has been associated with significantly worse survival in some studies (particularly when second-generation TKIs were not readily available as salvage therapy), but not in others (when they were).


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InternalMed_Harrison. The use of second-generation TKIs (nilotinib, dasatinib) as front-line therapy changed the monitoring approach slightly. Patients are expected to achieve complete cytogenetic response by 3–6 months of therapy. Failure to do so is associated with worse event-free survival, transformation rates, and survival. However, the 3to 5-year estimated survival among such patients is still high, around 80–90%, which is better than what would be anticipated if such patients were offered allogeneic SCT at that time. Thus, this adverse response to therapy is considered a warning signal, but it is not known whether changing therapy to other TKIs at that time would improve longer term outcome.


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InternalMed_Harrison. Patients in accelerated or blastic phase may receive therapy with TKIs, preferably secondor third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib), alone or in combination with chemotherapy, to reduce the CML burden, before undergoing allogeneic SCT. Response rates with single-agent TKIs range from 30 to 50% in accelerated phase and from 20 to 30% in blastic phase. Cytogenetic 694 responses, particularly complete cytogenetic responses, are uncommon (10–30%) and transient in blastic phase. Studies of TKIs in combination with chemotherapy are ongoing; the general experience suggests that combined TKI-chemotherapy strategies increase the response rates and their durability and improve survival. In CML lymphoid blastic phase, the combination of anti-ALL chemotherapy with TKIs results in complete response rates of 60–70% and median survival times of 2–3 years (compared with historical response rates of 40–50% and median survival times of 12–18 months). This allows many patients


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InternalMed_Harrison. in complete response rates of 60–70% and median survival times of 2–3 years (compared with historical response rates of 40–50% and median survival times of 12–18 months). This allows many patients to undergo allogeneic SCT in a state of minimal CML burden or secondary chronic phase, which are associated with higher cure rates. In CML nonlymphoid blastic phase, anti-AML chemotherapy combined with TKIs results in CR rates of 30–50% and median survival times of 9–12 months (compared with historical response rates of 20–30% and median survival times of 3–5 months). In accelerated phase, response to single TKIs is significant in conditions where “softer” accelerated phase criteria are considered (e.g., clonal evolution alone, thrombocytosis alone, significant splenomegaly or resistance to hydroxyurea, but without evidence of high blast and basophil percentages). In accelerated phase, combinations usually include TKIs with low-intensity chemotherapy such as low-dose cytarabine, low-dose


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InternalMed_Harrison. but without evidence of high blast and basophil percentages). In accelerated phase, combinations usually include TKIs with low-intensity chemotherapy such as low-dose cytarabine, low-dose idarubicin, decitabine, interferon α, hydroxyurea, or others.


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InternalMed_Harrison. OTHER TREATMENTS AND SPECIAL THERAPEUTIC CONSIDERATIONS Interferon α Interferon α was a standard of care before 2000. Today, it is considered in combination with TKIs (an investigational approach), sometimes after CML failure on TKIs, occasionally in patients during pregnancy, or as part of investigational strategies with TKIs to eradicate residual molecular disease.


InternalMed_Harrison

InternalMed_Harrison. Chemotherapeutic Agents Hydroxyurea and busulfan were commonly used chemotherapeutic agents in the past. Hydroxyurea remains a safe and effective agent (at daily doses of 0.5–10 g) to reduce initial CML burden, as a temporary measure in between definitive therapies, or in combination with TKIs to sustain complete hematologic or cytogenetic responses. Busulfan is often used in allogeneic SCT preparative regimens. Because of its side effects (delayed myelosuppression, Addison-like disease, pulmonary and cardiac fibrosis, myelofibrosis), it is now only rarely used in the chronic management of CML. Low-dose cytarabine, decitabine, anthracyclines, 6-mercaptopurine, 6-thioguanine, thiotepa, anagrelide, and other agents are useful in different CML settings to control the disease burden.


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InternalMed_Harrison. Others Splenectomy is occasionally considered to alleviate symp toms of massive splenomegaly and/or hypersplenism. Splenic irradi ation is rarely used, if at all, because of the postirradiation adhesions and complications. Leukapheresis is rarely used in patients presenting with extreme leukocytosis and leukostatic complications. Single doses of high-dose cytarabine or high doses of hydroxyurea, with tumor lysis management, may be as effective and less cumbersome. and may be indicative of the genetic instability of the hematopoietic stem cells that predispose the patient to develop CML in the first place. Rarely, abnormalities involving chromosomes 5 or 7 may be truly clonal and evolve into myelodysplastic syndrome or acute myeloid leukemia. This is thought to be part of the natural course of patients in whom CML was suppressed and who live long enough to develop other hematologic malignancies.


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InternalMed_Harrison. Routine physical exams and blood tests in the United States and advanced countries result in early detection of CML in most patients. About 50–70% of patients with CML are diagnosed accidentally, and high-risk CML as defined by prognostic models (e.g., Sokal risk groups) is found in only 10–20% of patients. This is not the same situation in emerging nations (e.g., India, China, African countries, the Middle East), where most patients are diagnosed following evaluation for symptoms and many present with high tumor burdens, such as massive splenomegaly, and advanced phases of CML (high-risk CML documented in 30–50%). Therefore, the prognosis of such patients on TKI therapy may be worse than the published experience.


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InternalMed_Harrison. The high cost of TKI therapies (annual costs of $90,000–$140,000 in the United States; lower but variable in the rest of the world) makes the general affordability of such treatments difficult. Although TKI treatment penetration is high in nations where cost of therapy is not an issue (e.g., Sweden, European Union), it may be less so in other nations, even in advanced ones like the United States, where out-ofpocket expenses may be prohibitive to a subset of patients (perhaps 10–20%). Based on the sales of imatinib worldwide and charity free drug supplies, it is estimated that less than 30% of patients are treated with imatinib (or other TKIs) consistently. Although the estimated 10-year survival in CML is 85% in single-institution studies (e.g.,


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InternalMed_Harrison. M.D. Anderson Cancer Center), in national studies in countries with TKI affordability (Sweden) (Figs. 133-2 and 133-3) or in company-sponsored studies (where all patients have access to TKIs throughout their care), the estimated 10-year survival worldwide, even 12 years after the introduction of TKI therapies, is likely to be less than 50%. The Surveillance, Epidemiology, and End Results (SEER) data from 1.0 0.8 0.6 0.4


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InternalMed_Harrison. Special Considerations Women with CML who become pregnant should discontinue TKI therapy immediately. Among 125 babies delivered to women with CML who discontinued TKI therapy as soon as the pregnancy was known, three babies were born with ocular, skeletal, and renal malformations, suggesting the uncommon teratogenicity of imatinib. There are no or little data with other TKIs. Control of CML during pregnancy can be managed with leukapheresis for severe symptomatic leukocytosis in the first trimester and with hydroxyurea subsequently until delivery. There are case reports of successful pregnancies and deliveries of normal babies with interferon α therapy and registry studies in essential thrombocytosis of its safety, but interferon α can be antiangiogenic and may increase the risk of spontaneous abortions.


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InternalMed_Harrison. Patients on TKI therapy may develop chromosomal abnormalities in the Ph-negative cells. These may involve loss of chromosome Y, trisomy 8, 20q–, chromosome 5 or 7 abnormalities, and others. Most chromosomal abnormalities disappear spontaneously on follow-up 0.2 0.0 No. at risk FIGURE 133-3 Survival in chronic (CP), accelerated (AP), and blastic crisis (BC) phases of chronic myeloid leukemia (CML) in the population-based Swedish national registry study. The acceleratedand blastic-phase cases are de novo presentations. The favorable outcome with de novo blastic phase may be due to use of 20% blasts or more to define blastic phase. (With permission from Dr. Martin Hoglund, Swedish CML Registry, 2013.) the United States report an estimated 5-year survival rate of 60% in


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InternalMed_Harrison. Malignancies of Lymphoid Cells Dan L. Longo Malignancies of lymphoid cells range from the most indolent to the most aggressive human malignancies. These cancers arise from cells of the immune system at different stages of differentiation, resulting in a wide range of morphologic, immunologic, and clinical findings. 134 the era of TKIs.


InternalMed_Harrison

InternalMed_Harrison. The current high cost of TKI therapies poses two additional considerations. The first are the treatment pathways and guidelines in nations where TKIs may not be affordable by patients or the health care system. In these conditions, there are trends of pathways advocating frontline allogeneic SCT (a one-time cost of $30,000–$50,000) despite the associated mortality and morbidities. The second is the choice of frontline TKI therapy once imatinib becomes available in generic forms (hopefully at much lower annual prices, e.g., $2,000–$10,000). This will depend on the maturing data in randomized studies of second-generation TKIs versus imatinib in relation to important longterm outcome endpoints, particularly survival, but also event-free survival and transformation-free survival. Insights on the normal immune system have allowed a better understanding of these sometimes confusing disorders.


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InternalMed_Harrison. Insights on the normal immune system have allowed a better understanding of these sometimes confusing disorders. Some malignancies of lymphoid cells almost always present as leukemia (i.e., primary involvement of bone marrow and blood), while others almost always present as lymphomas (i.e., solid tumors of the immune system). However, other malignancies of lymphoid cells can present as either leukemia or lymphoma. In addition, the clinical pattern can change over the course of the illness. This change is more often seen in a patient who seems to have a lymphoma and then develops the manifestations of leukemia over the course of the illness. BIOLOGY OF LYMPHOID MALIGNANCIES: CONCEPTS OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF LYMPHOID MALIGNANCIES


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InternalMed_Harrison. The classification of lymphoid cancers evolved steadily throughout the twentieth century. The distinction between leukemia and lymphoma was made early, and separate classification systems were developed for each. Leukemias were first divided into acute and chronic subtypes based on average survival. Chronic leukemias were easily subdivided into those of lymphoid or myeloid origin based on morphologic characteristics. However, a spectrum of diseases that were formerly all called chronic lymphoid leukemia has become apparent (Table 134-1). The acute leukemias were usually malignancies of blast cells with few identifying characteristics. When cytochemical stains became available, it was possible to divide these objectively into myeloid malignancies and acute leukemias of lymphoid cells. Acute leukemias of lymphoid cells have been subdivided based on morphologic characteristics by the French-American-British (FAB) group (Table 134-2). Using this system, lymphoid malignancies of small


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InternalMed_Harrison. Immunologic % of FAB Subtype Cases Subtype Cytogenetic Abnormalities Abbreviation: FAB, French-American-British classification. uniform blasts (e.g., typical childhood acute lymphoblastic leukemia) were called L1, lymphoid malignancies with larger and more variable size cells were called L2, and lymphoid malignancies of uniform cells with basophilic and sometimes vacuolated cytoplasm were called L3 (e.g., typical Burkitt’s lymphoma cells). Acute leukemias of lymphoid cells have also been subdivided based on immunologic (i.e., T cell vs B cell) and cytogenetic abnormalities (Table 134-2). Major cytogenetic subgroups include the t(9;22) (e.g., Philadelphia chromosome– positive acute lymphoblastic leukemia) and the t(8;14) found in the L3 or Burkitt’s leukemia.


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InternalMed_Harrison. Non-Hodgkin’s lymphomas were separated from Hodgkin’s lymphoma by recognition of the Sternberg-Reed cells early in the twentieth century. The histologic classification for non-Hodgkin’s lymphomas has been one of the most contentious issues in oncology. Imperfect morphologic systems were supplanted by imperfect immunologic systems, and poor reproducibility of diagnosis has hampered progress. In 1999, the World Health Organization (WHO) classification of lymphoid malignancies was devised through a process of consensus development among international leaders in hematopathology and clinical oncology. The WHO classification takes into account morphologic, clinical, immunologic, and genetic information and attempts to divide nonHodgkin’s lymphomas and other lymphoid malignancies into clinical/ pathologic entities that have clinical and therapeutic relevance. This system is presented in Table 134-3. This system is clinically relevant and has a higher degree of diagnostic accuracy than those


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InternalMed_Harrison. pathologic entities that have clinical and therapeutic relevance. This system is presented in Table 134-3. This system is clinically relevant and has a higher degree of diagnostic accuracy than those used previously. The possibilities for subdividing lymphoid malignancies are extensive. However, Table 134-3 presents in bold those malignancies that occur in at least 1% of patients. Specific lymphoma subtypes will be dealt with in more detail below.


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InternalMed_Harrison. Lymphomas occurring in fewer than 1% of patients with lymphoproliferative diseases are discussed in Chap. 135e, and lymphomas associated with HIV infection are discussed in Chap. 226. The relative frequency of the various lymphoid malignancies is shown in Fig. 134-1. Chronic lymphoid leukemia (CLL) is the most prevalent form of leukemia in Western countries. It occurs most frequently in older adults and is exceedingly rare in children. In 2014, 15,720 new cases were diagnosed in the United States, but because of the prolonged survival associated with this disorder, the total prevalence is many times higher. CLL is more common in men than in women and more common in whites than in blacks. This is an uncommon malignancy in Asia. The etiologic factors for typical CLL are unknown.


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InternalMed_Harrison. In contrast to CLL, acute lymphoid leukemias (ALLs) are predominantly cancers of children and young adults. The L3 or Burkitt’s leukemia occurring in children in developing countries seems to be associated with infection by the Epstein-Barr virus (EBV) in infancy. However, the explanation for the etiology of more common subtypes of ALL is much less certain. Childhood ALL occurs more often in higher socioeconomic subgroups. Children with trisomy 21 (Down’s syndrome) have an increased risk for childhood ALL as well as acute myeloid leukemia (AML). Exposure to high-energy radiation in early childhood increases the risk of developing T-cell ALL. The etiology of ALL in adults is also uncertain. ALL is unusual in middle-aged adults but increases in incidence in the elderly. However, AML is still much more common in older patients. Environmental exposures, including certain industrial exposures, exposure to agricultural chemicals, and smoking, might increase the risk of developing


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InternalMed_Harrison. Malignancies of Lymphoid Cells Abbreviations: HHV, human herpesvirus; HTLV, human T-cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue; NK, natural killer; WHO, World Health Organization. Source: Adapted from SH Swerdlow et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. World Health Organization, 2008. Plasma cell disorders 16% Non-Hodgkin’s lymphoma 62.4% CLL 9% ALL 3.8% Hodgkin’s disease 8.2% FIGURE 134-1 Relative frequency of lymphoid malignancies. ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; MALT, mucosa-associated lymphoid tissue. 7.6% MALT lymphoma 7.6% Mature T-cell lymphoma 6.7% Small lymphocytic lymphoma 2.4% Mediastinal large B-cell lymphoma 2.4% Anaplastic large cell lymphoma 2.4% Burkitt’s lymphoma 1.8% Nodal marginal zone lymphoma 1.7% Precursor T lymphoblastic lymphoma 1.2% Lymphoplasmacytic lymphoma 7.4% Others


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InternalMed_Harrison. ALL as an adult. ALL was diagnosed in 6020 persons and AML in 18,860 persons in the United States in 2014.


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InternalMed_Harrison. The preponderance of evidence suggests that Hodgkin’s lymphoma is of B-cell origin. The incidence of Hodgkin’s lymphoma appears fairly stable, with 9190 new cases diagnosed in 2014 in the United States. Hodgkin’s lymphoma is more common in whites than in blacks and more common in males than in females. A bimodal distribution of age at diagnosis has been observed, with one peak incidence occurring in patients in their twenties and the other in those in their eighties. Some of the late age peak may be attributed to confusion among entities with similar appearance such as anaplastic large cell lymphoma and T-cell–rich B-cell lymphoma. Patients in the younger age groups diagnosed in the United States largely have the nodular sclerosing subtype of Hodgkin’s lymphoma. Elderly patients, patients infected with HIV, and patients in Third World countries more commonly have mixed-cellularity Hodgkin’s lymphoma or lymphocyte-depleted Hodgkin’s lymphoma. Infection by HIV is a risk factor for


InternalMed_Harrison

InternalMed_Harrison. infected with HIV, and patients in Third World countries more commonly have mixed-cellularity Hodgkin’s lymphoma or lymphocyte-depleted Hodgkin’s lymphoma. Infection by HIV is a risk factor for developing Hodgkin’s lymphoma. In addition, an association between infection by EBV and Hodgkin’s lymphoma has been suggested. A monoclonal or oligoclonal proliferation of EBV-infected cells in 20–40% of the patients with Hodgkin’s lymphoma has led to proposals for this virus having an etiologic role in Hodgkin’s lymphoma. However, the matter is not settled definitively.


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InternalMed_Harrison. For unknown reasons, non-Hodgkin’s lymphomas increased in frequency in the United States at the rate of 4% per year and increased 2–8% per year globally between 1950 and the late 1990s. The rate of increase in the past few years seems to be decreasing. About 70,800 new cases of non-Hodgkin’s lymphoma were diagnosed in the United States in 2014 and nearly 360,000 cases worldwide. Non-Hodgkin’s lymphomas are more frequent in the elderly and more frequent in men. Patients with both primary and secondary immunodeficiency states are predisposed to developing non-Hodgkin’s lymphomas. These include patients with HIV infection; patients who have undergone organ transplantation; and patients with inherited immune deficiencies, the sicca syndrome, and rheumatoid arthritis.


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InternalMed_Harrison. The incidence of non-Hodgkin’s lymphomas and the patterns of expression of the various subtypes differ geographically. T-cell lymphomas are more common in Asia than in Western countries, while certain subtypes of B-cell lymphomas such as follicular lymphoma are more common in Western countries. A specific subtype of nonHodgkin’s lymphoma known as the angiocentric nasal T/natural killer (NK) cell lymphoma has a striking geographic occurrence, being most frequent in Southern Asia and parts of Latin America. Another subtype of non-Hodgkin’s lymphoma associated with infection by human T-cell lymphotropic virus (HTLV) 1 is seen particularly in southern Japan and the Caribbean (Chap. 225e).


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InternalMed_Harrison. A number of environmental factors have been implicated in the occurrence of non-Hodgkin’s lymphoma, including infectious agents, chemical exposures, and medical treatments. Several studies have demonstrated an association between exposure to agricultural chemicals and an increased incidence of non-Hodgkin’s lymphoma. Patients treated for Hodgkin’s lymphoma can develop non-Hodgkin’s lymphoma; it is unclear whether this is a consequence of the Hodgkin’s lymphoma or its treatment. However, a number of non-Hodgkin’s lymphomas are associated with infectious agents (Table 134-4). HTLV-1 infects T cells and leads directly to the development of adult T-cell lymphoma in a small percentage of infected patients. The cumulative lifetime risk of developing lymphoma in an infected patient is 2.5%. The virus is transmitted by infected lymphocytes ingested by nursing babies of infected mothers, bloodborne transmission, or sexually. The median age of patients with adult T-cell lymphoma is ~56 years,


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InternalMed_Harrison. virus is transmitted by infected lymphocytes ingested by nursing babies of infected mothers, bloodborne transmission, or sexually. The median age of patients with adult T-cell lymphoma is ~56 years, emphasizing the long latency. HTLV-1 is also the cause of tropical spastic paraparesis—a neurologic disorder that occurs somewhat more frequently than lymphoma and with shorter latency and usually from transfusion-transmitted virus (Chap. 225e).


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InternalMed_Harrison. EBV is associated with the development of Burkitt’s lymphoma in Central Africa and the occurrence of aggressive non-Hodgkin’s lymphomas in immunosuppressed patients in Western countries. The majority of primary central nervous system (CNS) lymphomas Abbreviations: CNS, central nervous system; HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue; NK, natural killer.


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InternalMed_Harrison. are associated with EBV. EBV infection is strongly associated with the occurrence of extranodal nasal T/NK cell lymphomas in Asia and South America. Infection with HIV predisposes to the development of aggressive, B-cell non-Hodgkin’s lymphoma. This may be through overexpression of interleukin 6 by infected macrophages. Infection of the stomach by the bacterium Helicobacter pylori induces the development of gastric MALT (mucosa-associated lymphoid tissue) lymphomas. This association is supported by evidence that patients treated with antibiotics to eradicate H. pylori have regression of their MALT lymphoma. The bacterium does not transform lymphocytes to produce the lymphoma; instead, a vigorous immune response is made to the bacterium, and the chronic antigenic stimulation leads to the neoplasia. MALT lymphomas of the skin may be related to Borrelia sp. infections, those of the eyes to Chlamydophila psittaci, and those of the small intestine to Campylobacter jejuni.


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InternalMed_Harrison. Chronic hepatitis C virus infection has been associated with the development of lymphoplasmacytic lymphoma. Human herpesvirus 8 is associated with primary effusion lymphoma in HIV-infected persons and multicentric Castleman’s disease, a diffuse lymphadenopathy associated with systemic symptoms of fever, malaise, and weight loss. In addition to infectious agents, a number of other diseases or exposures may predispose to developing lymphoma (Table 134-5).


InternalMed_Harrison

InternalMed_Harrison. In addition to infectious agents, a number of other diseases or exposures may predispose to developing lymphoma (Table 134-5). All lymphoid cells are derived from a common hematopoietic progenitor that gives rise to lymphoid, myeloid, erythroid, monocyte, and megakaryocyte lineages. Through the ordered and sequential activation of a series of transcription factors, the cell first becomes committed to the lymphoid lineage and then gives rise to B and T cells. About 75% of all lymphoid leukemias and 90% of all lymphomas are of B-cell origin. A cell becomes committed to B-cell development when it begins to rearrange its immunoglobulin genes. The sequence of cellular changes, Common variable immunodeficiency disease Phenytoin Acquired immunodeficiency diseases Dioxin, phenoxy herbicides Iatrogenic immunosuppression Radiation HIV-1 infection Prior chemotherapy and radiation therapy Malignancies of Lymphoid Cells


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InternalMed_Harrison. Malignancies of Lymphoid Cells FIGURE 134-2 Pathway of normal B-cell differentiation and relationship to B-cell lymphomas. HLA-DR, CD10, CD19, CD20, CD21, CD22, CD5, and CD38 are cell markers used to distinguish stages of development. Terminal transferase (TdT) is a cellular enzyme. Immunoglobulin heavy chain gene rearrangement (HCR) and light chain gene rearrangement or deletion (κR or D, λR or D) occur early in B-cell development. The approximate normal stage of differentiation associated with particular lymphomas is shown. ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; SL, small lymphocytic lymphoma. including changes in cell-surface phenotype, that characterizes normal B-cell development is shown in Fig. 134-2. A cell becomes committed to T-cell differentiation upon migration to the thymus and rearrangement of T-cell antigen receptor genes. The sequence of the events that characterize T-cell development is depicted in Fig. 134-3.


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InternalMed_Harrison. Although lymphoid malignancies often retain the cell-surface phenotype of lymphoid cells at particular stages of differentiation, this information is of little consequence. The so-called stage of differentiation of a malignant lymphoma does not predict its natural history. For example, the clinically most aggressive lymphoid leukemia is Burkitt’s leukemia, which has the phenotype of a mature follicle center IgM-bearing B cell. Leukemias bearing the immunologic cell-surface phenotype of more primitive cells (e.g., pre-B ALL, CD10+) are less aggressive and more amenable to curative therapy than the “more mature” appearing Burkitt’s leukemia cells. Furthermore, the apparent stage of differentiation of the malignant cell does not reflect the stage at which the genetic lesions that gave rise to the malignancy developed. For example, follicular lymphoma has the cell-surface phenotype of a follicle center cell, but its characteristic chromosomal translocation, the t(14;18), which involves


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InternalMed_Harrison. to the malignancy developed. For example, follicular lymphoma has the cell-surface phenotype of a follicle center cell, but its characteristic chromosomal translocation, the t(14;18), which involves juxtaposition of the antiapoptotic bcl-2 gene next to the immunoglobulin heavy chain gene (see below), had to develop early in ontogeny as an error in the process of immunoglobulin gene rearrangement. Why the subsequent steps that led to transformation became manifest in a cell of follicle center differentiation is not clear.


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InternalMed_Harrison. The major value of cell-surface phenotyping is to aid in the differential diagnosis of lymphoid tumors that appear similar by light microscopy. For example, benign follicular hyperplasia may resemble follicular lymphoma; however, the demonstration that all the cells bear the same immunoglobulin light chain isotype strongly suggests the mass is a clonal proliferation rather than a polyclonal response to an exogenous stimulus.


InternalMed_Harrison

InternalMed_Harrison. Malignancies of lymphoid cells are associated with recurring genetic abnormalities. While specific genetic abnormalities have not been identified for all subtypes of lymphoid malignancies, it is presumed that they exist. Genetic abnormalities can be identified at a variety of levels including gross chromosomal changes (i.e., translocations, additions, or deletions); rearrangement of specific genes that may or may not be apparent from cytogenetic studies; and overexpression, under-expression, or mutation of specific oncogenes. Altered expression or mutation of specific proteins is particularly important. Many lymphomas contain balanced chromosomal translocations involving the antigen receptor genes; immunoglobulin genes on chromosomes 2, 14, and 22 in B cells; and T-cell antigen receptor genes on chromosomes 7 and 14 in T cells. The rearrangement of chromosome segments to generate mature antigen receptors must create a site of vulnerability to aberrant recombination. B cells are even


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InternalMed_Harrison. genes on chromosomes 7 and 14 in T cells. The rearrangement of chromosome segments to generate mature antigen receptors must create a site of vulnerability to aberrant recombination. B cells are even more susceptible to acquiring mutations during their maturation in germinal centers; the generation of antibody of higher affinity requires the introduction of mutations into the variable region genes in the germinal centers. Other nonimmunoglobulin genes, e.g., bcl-6, may acquire mutations as well.


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InternalMed_Harrison. In the case of diffuse large B-cell lymphoma, the translocation t(14;18) occurs in ~30% of patients and leads to overexpression of the Majority of Minority of T-ALL Majority of T-LL Minority of T-LL Majority of Mature T Helper T-CLL, CTCL, Cell Sezary Cell, NHL CD: 2,3,4,5,6,7; TCR Minority of Suppressor Cell T-CLL, NHL CD: 2,3,4,5,6,7; TCR FIGURE 134-3 Pathway of normal T-cell differentiation and relationship to T-cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71 are cell markers used to distinguish stages of development. T-cell antigen receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes and peripheral blood. ALL, acute lymphoid leukemia; T-ALL, T-cell ALL; T-LL, T-cell lymphoblastic lymphoma; T-CLL, T-cell chronic lymphoid leukemia; CTCL, cutaneous T-cell lymphoma; NHL, non-Hodgkin’s lymphoma.


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InternalMed_Harrison. bcl-2 gene found on chromosome 18. Some other patients without the translocation also overexpress the BCL-2 protein. This protein is involved in suppressing apoptosis—i.e., the mechanism of cell death most often induced by cytotoxic chemotherapeutic agents. A higher relapse rate has been observed in patients whose tumors overexpress the BCL-2 protein, but not in those patients whose lymphoma cells show only the translocation. Thus, particular genetic mechanisms have clinical ramifications.


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InternalMed_Harrison. Table 134-6 presents the most common translocations and associated oncogenes for various subtypes of lymphoid malignancies. In some cases, such as the association of the t(14;18) in follicular lymphoma, the t(2;5) in anaplastic large T/null cell lymphoma, the t(8;14) in Burkitt’s lymphoma, and the t(11;14) in mantle cell lymphoma, the great majority of tumors in patients with these diagnoses display these abnormalities. In other types of lymphoma where a minority of the patients have tumors expressing specific genetic abnormalities, the defects may have prognostic significance. No specific genetic abnormalities have been identified in Hodgkin’s lymphoma other than aneuploidy.


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InternalMed_Harrison. In typical B-cell CLL, trisomy 12 conveys a poorer prognosis. In ALL in both adults and children, genetic abnormalities have important prognostic significance. Patients whose tumor cells display the t(9;22) and translocations involving the MLL gene on chromosome 11q23 have a much poorer outlook than patients who do not have these translocations. Other genetic abnormalities that occur frequently in adults with ALL include the t(4;11) and the t(8;14). The t(4;11) is associated with younger age, female predominance, high white cell counts, and L1 morphology. The t(8;14) is associated with older age, male predominance, frequent CNS involvement, and L3 morphology. Both are associated with a poor prognosis. In childhood ALL, hyperdiploidy has been shown to have a favorable prognosis. Gene profiling using array technology allows the simultaneous assessment of the expression of thousands of genes. This technology aNumerous sites of translocation may be involved with these genes.


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InternalMed_Harrison. Gene profiling using array technology allows the simultaneous assessment of the expression of thousands of genes. This technology aNumerous sites of translocation may be involved with these genes. Abbreviations: CLL, chronic lymphoid leukemia; IgH, immunoglobulin heavy chain; MALT, mucosa-associated lymphoid tissue.


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InternalMed_Harrison. provides the possibility to identify new genes with pathologic importance in lymphomas, the identification of patterns of gene expression with diagnostic and/or prognostic significance, and the identification of new therapeutic targets. Recognition of patterns of gene expression is complicated and requires sophisticated mathematical techniques. Early successes using this technology in lymphoma include the identification of previously unrecognized subtypes of diffuse large B-cell lymphoma whose gene expression patterns resemble either those of follicular center B cells or activated peripheral blood B cells. Patients whose lymphomas have a germinal center B-cell pattern of gene expression have a considerably better prognosis than those whose lymphomas have a pattern resembling activated peripheral blood B cells. This improved prognosis is independent of other known prognostic factors. Similar information is being generated in follicular lymphoma and mantle cell lymphoma. The challenge


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InternalMed_Harrison. blood B cells. This improved prognosis is independent of other known prognostic factors. Similar information is being generated in follicular lymphoma and mantle cell lymphoma. The challenge remains to provide information from such techniques in a clinically useful time frame.


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InternalMed_Harrison. APPROACH TO THE PATIENT: Regardless of the type of lymphoid malignancy, the initial evaluation of the patient should include performance of a careful history and physical examination. These will help confirm the diagnosis, identify those manifestations of the disease that might require prompt attention, and aid in the selection of further studies to optimally characterize the patient’s status to allow the best choice of therapy. It is difficult to overemphasize the importance of a carefully done history and physical examination. They might provide observations that lead to reconsidering the diagnosis, provide hints at etiology, clarify the stage, and allow the physician to establish rapport with the patient that will make it possible to develop and carry out a therapeutic plan.


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InternalMed_Harrison. For patients with ALL, evaluation is usually completed after a complete blood count, chemistry studies reflecting major organ function, a bone marrow biopsy with genetic and immunologic studies, and a lumbar puncture. The latter is necessary to rule out occult CNS involvement. At this point, most patients would Malignancies of Lymphoid Cells be ready to begin therapy. In ALL, prognosis is dependent on the genetic characteristics of the tumor, the patient’s age, the white cell count, and the patient’s overall clinical status and major organ function.


InternalMed_Harrison

InternalMed_Harrison. In CLL, the patient evaluation should include a complete blood count, chemistry tests to measure major organ function, serum protein electrophoresis, and a bone marrow biopsy. However, some physicians believe that the diagnosis would not always require a bone marrow biopsy. Patients often have imaging studies of the chest and abdomen looking for pathologic lymphadenopathy. Patients with typical B-cell CLL can be subdivided into three major prognostic groups. Those patients with only blood and bone marrow involvement by leukemia but no lymphadenopathy, organomegaly, or signs of bone marrow failure have the best prognosis. Those with lymphadenopathy and organomegaly have an intermediate prognosis, and patients with bone marrow failure, defined as hemoglobin <100 g/L (10 g/dL) or platelet count <100,000/μL, have the worst prognosis. The pathogenesis of the anemia or thrombocytopenia is important to discern. The prognosis is adversely affected when either or both of these abnormalities


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InternalMed_Harrison. count <100,000/μL, have the worst prognosis. The pathogenesis of the anemia or thrombocytopenia is important to discern. The prognosis is adversely affected when either or both of these abnormalities are due to progressive marrow infiltration and loss of productive marrow. However, either or both may be due to autoimmune phenomena or to hypersplenism that can develop during the course of the disease. These destructive mechanisms are usually completely reversible (glucocorticoids for autoimmune disease; splenectomy for hypersplenism) and do not influence disease prognosis.


InternalMed_Harrison

InternalMed_Harrison. Two popular staging systems have been developed to reflect these prognostic groupings (Table 134-7). Patients with typical B-cell CLL can have their course complicated by immunologic abnormalities, including autoimmune hemolytic anemia, autoimmune thrombocytopenia, and hypogammaglobulinemia. Patients with hypogammaglobulinemia benefit from regular (monthly) γ globulin administration. Because of expense, γ globulin is often withheld until the patient experiences a significant infection. These abnormalities do not have a clear prognostic significance and should not be used to assign a higher stage.


InternalMed_Harrison

InternalMed_Harrison. Two other features may be used to assess prognosis in B-cell CLL, but neither has yet been incorporated into a staging classification. At least two subsets of CLL have been identified based on the cytoplasmic expression of ZAP-70; expression of this protein, which is usually expressed in T cells, identifies a subgroup with poorer prognosis. A less powerful subsetting tool is CD38 expression. CD38+ tumors tend to have a poorer prognosis than CD38– tumors. A less easily measured feature, the presence of immunoglobulin variable region gene mutations, is also able to separate prognostic groups; patients with mutated immunoglobulin variable region genes respond better to treatment and have better survival than those with unmutated immunoglobulin variable region genes.


InternalMed_Harrison

InternalMed_Harrison. The initial evaluation of a patient with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma is similar. In both situations, the determination of an accurate anatomic stage is an important part of the evaluation. Staging is done using the Ann Arbor staging system originally developed for Hodgkin’s lymphoma (Table 134-8).


InternalMed_Harrison

InternalMed_Harrison. Evaluation of patients with Hodgkin’s lymphoma will typically include a complete blood count; erythrocyte sedimentation rate; chemistry studies reflecting major organ function; computed tomography (CT) scans of the chest, abdomen, and pelvis; and a bone marrow biopsy. Neither a positron emission tomography (PET) scan nor a gallium scan is absolutely necessary for primary staging, but one performed at the completion of therapy allows evaluation of persisting radiographic abnormalities, particularly the mediastinum. Knowing that the PET scan or gallium scan is abnormal before treatment can help in this assessment. In most cases, these studies will allow assignment of anatomic stage and the development of a therapeutic plan.


InternalMed_Harrison

InternalMed_Harrison. In patients with non-Hodgkin’s lymphoma, the same evaluation described for patients with Hodgkin’s lymphoma is usually carried out. In addition, serum levels of lactate dehydrogenase (LDH) and β2-microglobulin and serum protein electrophoresis are often included in the evaluation. Anatomic stage is assigned in the same manner as used for Hodgkin’s lymphoma. However, the prognosis of patients with non-Hodgkin’s lymphoma is best assigned using the International Prognostic Index (IPI) (Table 134-9). This is a powerful predictor of outcome in all subtypes of non-Hodgkin’s lymphoma. Patients are assigned an IPI score based on the presence or absence of five adverse prognostic factors and may have none or all five of these adverse prognostic factors. Figure 134-4 shows the prognostic significance of this score in 1300 patients with all types of non-Hodgkin’s lymphoma. With the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), treatment outcomes have


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InternalMed_Harrison. of this score in 1300 patients with all types of non-Hodgkin’s lymphoma. With the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), treatment outcomes have improved and the original IPI has lost some of its discrimination power. A revised IPI has been proposed that better predicts outcome of rituximab plus chemotherapy-based programs (Table 134-9). CT scans are routinely used in the evaluation of patients with all subtypes of non-Hodgkin’s lymphoma, but PET and


InternalMed_Harrison

InternalMed_Harrison. Five clinical risk factors: Age ≥60 years Serum lactate dehydrogenase levels elevated Performance status ≥2 (ECOG) or ≤70 (Karnofsky) Ann Arbor stage III or IV >1 site of extranodal involvement Patients are assigned a number for each risk factor they have Patients are grouped differently based on the type of lymphoma For diffuse large B-cell lymphoma: 0, 1 factor = low risk: 35% of cases; 5-year survival, 73% 2 factors = low-intermediate risk: 27% of cases; 5-year survival, 51% 3 factors = high-intermediate risk: 22% of cases; 5-year survival, 43% 4, 5 factors = high risk: 16% of cases; 5-year survival, 26% For diffuse large B-cell lymphoma treated with R-CHOP: 0 factor = very good: 10% of cases; 5-year survival, 94% 1, 2 factors = good: 45% of cases; 5-year survival, 79% 3, 4, 5 factors = poor: 45% of cases; 5-year survival, 55% Abbreviations: ECOG, Eastern Cooperative Oncology Group; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: ECOG, Eastern Cooperative Oncology Group; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. gallium scans are much more useful in aggressive subtypes such as diffuse large B-cell lymphoma than in more indolent subtypes such as follicular lymphoma or small lymphocytic lymphoma. Although the IPI does divide patients with follicular lymphoma into subsets with distinct prognoses, the distribution of such patients is skewed toward lower-risk categories. A follicular lymphoma–specific IPI (FLIPI) has been proposed that replaces performance status with hemoglobin level (<120 g/L [<12 g/dL]) and number of extranodal sites with number of nodal sites (more than four). Low risk (zero or one factor) was assigned to 36% of patients, intermediate risk (two factors) to 37%, and poor risk (more than two factors) to 27% of patients. CLINICAL FEATURES, TREATMENT, AND PROGNOSIS OF SPECIFIC LYMPHOID MALIGNANCIES


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InternalMed_Harrison. CLINICAL FEATURES, TREATMENT, AND PROGNOSIS OF SPECIFIC LYMPHOID MALIGNANCIES PRECURSOR CELL B-CELL NEOPLASMS Precursor B-Cell Lymphoblastic Leukemia/Lymphoma The most common cancer in childhood is B-cell ALL. Although this disorder can also present as a lymphoma in either adults or children, presentation as lymphoma is rare. The malignant cells in patients with precursor B-cell lymphoblastic leukemia are most commonly of pre–B cell origin. Patients typically 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Log rank test: p < .001 IPI: 4/5 (n = 171) 0.0 0 12345678910 FIGURE 134-4 Relationship of International Prognostic Index (IPI) to survival. Kaplan-Meier survival curves for 1300 patients with various kinds of lymphoma stratified according to the IPI. FIGURE 134-5 Acute lymphoblastic leukemia. The cells are hetero-geneous in size and have round or convoluted nuclei, high nuclear/ cytoplasmic ratio, and absence of cytoplasmic granules.


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InternalMed_Harrison. FIGURE 134-5 Acute lymphoblastic leukemia. The cells are hetero-geneous in size and have round or convoluted nuclei, high nuclear/ cytoplasmic ratio, and absence of cytoplasmic granules. present with signs of bone marrow failure such as pallor, fatigue, bleeding, fever, and infection related to peripheral blood cytopenias. Peripheral blood counts regularly show anemia and thrombocytopenia but might show leukopenia, a normal leukocyte count, or leukocytosis based largely on the number of circulating malignant cells (Fig. 134-5). Extramedullary sites of disease are frequently involved in patients who present with leukemia, including lymphadenopathy, hepatoor splenomegaly, CNS disease, testicular enlargement, and/or cutaneous infiltration.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis is usually made by bone marrow biopsy, which shows infiltration by malignant lymphoblasts. Demonstration of a pre–B cell immunophenotype (Fig. 134-2) and, often, characteristic cytogenetic abnormalities (Table 134-6) confirm the diagnosis. An adverse prognosis in patients with precursor B-cell ALL is predicted by a very high white cell count, the presence of symptomatic CNS disease, and unfavorable cytogenetic abnormalities. For example, t(9;22), frequently found in adults with B-cell ALL, has been associated with a very poor outlook. The bcr/abl kinase inhibitors have improved the prognosis.


InternalMed_Harrison

InternalMed_Harrison. The treatment of patients with precursor B-cell ALL involves remission induction with combination chemotherapy, a consolidation phase that includes administration of high-dose systemic therapy and treatment to eliminate disease in the CNS, and a period of continuing therapy to prevent relapse and effect cure. The overall cure rate in children is 90%, whereas ~50% of adults are long-term disease-free survivors. This reflects the high proportion of adverse cytogenetic abnormalities seen in adults with precursor B-cell ALL. Precursor B-cell lymphoblastic lymphoma is a rare presentation of precursor B-cell lymphoblastic malignancy. These patients often have a rapid transformation to leukemia and should be treated as though they had presented with leukemia. The few patients who present with the disease confined to lymph nodes have a high cure rate.


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InternalMed_Harrison. MATURE (PERIPHERAL) B-CELL NEOPLASMS B-Cell Chronic Lymphoid Leukemia/Small Lymphocytic Lymphoma B-cell CLL/small lymphocytic lymphoma represents the most common lymphoid leukemia, and when presenting as a lymphoma, it accounts for ~7% of non-Hodgkin’s lymphomas. Presentation can be as either leukemia or lymphoma. The major clinical characteristics of B-cell CLL/ small lymphocytic lymphoma are presented in Table 134-10. The diagnosis of typical B-cell CLL is made when an increased number of circulating lymphocytes (i.e., >4 × 109/L and usually Malignancies of Lymphoid Cells Abbreviation: MALT, mucosa-associated lymphoid tissue.


InternalMed_Harrison

InternalMed_Harrison. Malignancies of Lymphoid Cells Abbreviation: MALT, mucosa-associated lymphoid tissue. >10 × 109/L) is found (Fig. 134-6) that are monoclonal B cells expressing the CD5 antigen. Finding bone marrow infiltration by the same cells confirms the diagnosis. The peripheral blood smear in such patients typically shows many “smudge” or “basket” cells, nuclear remnants of cells damaged by the physical shear stress of making the blood smear. If cytogenetic studies are performed, trisomy 12 is found in 25–30% of patients. Abnormalities in chromosome 13 are also seen. If the primary presentation is lymphadenopathy and a lymph node biopsy is performed, pathologists usually have little difficulty in making the diagnosis of small lymphocytic lymphoma based on morphologic findings and immunophenotype. However, even in these patients, 70–75% will be found to have bone marrow involvement and circulating monoclonal B lymphocytes are often present.


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis of typical B-cell CLL is extensive (Table 134-1). Immunophenotyping will eliminate the T-cell disorders and can often help sort out other B-cell malignancies. For example, only mantle cell lymphoma and typical B-cell CLL are usually CD5 positive. Typical B-cell small lymphocytic lymphoma can be confused with other B-cell disorders, including lymphoplasmacytic lymphoma (i.e., the tissue manifestation of Waldenström’s macroglobulinemia), nodal marginal zone B-cell lymphoma, and mantle cell lymphoma. In addition, some small lymphocytic lymphomas have areas of large cells that can lead to confusion with diffuse large B-cell lymphoma. An expert hematopathologist is vital for making this distinction.


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InternalMed_Harrison. FIGURE 134-6 Chronic lymphocytic leukemia. The peripheral white blood cell count is high due to increased numbers of small, well-differentiated, normal-appearing lymphocytes. The leukemia lympho-cytes are fragile, and substantial numbers of broken, smudged cells are usually also present on the blood smear.


InternalMed_Harrison

InternalMed_Harrison. Typical B-cell CLL is often found incidentally when a complete blood count is done for another reason. However, complaints that might lead to the diagnosis include fatigue, frequent infections, and new lymphadenopathy. The diagnosis of typical B-cell CLL should be considered in a patient presenting with an autoimmune hemolytic anemia or autoimmune thrombocytopenia. B-cell CLL has also been associated with red cell aplasia. When this disorder presents as lymphoma, the most common abnormality is asymptomatic lymphadenopathy, with or without splenomegaly. The staging systems predict prognosis in patients with typical B-cell CLL (Table 134-7). The evaluation of a new patient with typical B-cell CLL/small lymphocytic lymphoma will include many of the studies (Table 134-11) that are used in patients with other non-Hodgkin’s lymphomas. In addition, particular attention needs to be given to detecting immune abnormalities such as autoimmune hemolytic anemia, autoimmune thrombocytopenia,


InternalMed_Harrison

InternalMed_Harrison. in patients with other non-Hodgkin’s lymphomas. In addition, particular attention needs to be given to detecting immune abnormalities such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, hypogammaglobulinemia, and red cell aplasia. Molecular analysis of immunoglobulin gene sequences in CLL has demonstrated that about half the patients have tumors expressing mutated immunoglobulin genes and half have tumors expressing unmutated or germline immunoglobulin sequences. Patients with unmutated immunoglobulins tend to have a more aggressive clinical course and are less responsive to therapy. Unfortunately, immunoglobulin gene sequencing is not routinely available. CD38


InternalMed_Harrison

InternalMed_Harrison. Physical examination Documentation of B symptoms Laboratory evaluation Serum β2-microglobulin Chest radiograph CT scan of abdomen, pelvis, and usually chest Bone marrow biopsy Lumbar puncture in lymphoblastic, Burkitt’s, and diffuse large B-cell lym phoma with positive marrow biopsy Gallium scan (SPECT) or PET scan in large cell lymphoma Abbreviations: CT, computed tomography; PET, positron emission tomography; SPECT, single-photon emission computed tomography. expression is said to be low in the better-prognosis patients expressing mutated immunoglobulin and high in poorer-prognosis patients expressing unmutated immunoglobulin, but this test has not been confirmed as a reliable means of distinguishing the two groups. ZAP-70 expression correlates with the presence of unmutated immunoglobulin genes, but the assay is not yet standardized and widely available.


InternalMed_Harrison

InternalMed_Harrison. Patients whose presentation is typical B-cell CLL with no manifestations of the disease other than bone marrow involvement and lymphocytosis (i.e., Rai stage 0 and Binet stage A; Table 134-7) can be followed without specific therapy for their malignancy. These patients have a median survival >10 years, and some will never require therapy for this disorder. If the patient has an adequate number of circulating normal blood cells and is asymptomatic, many physicians would not initiate therapy for patients in the intermediate stage of the disease manifested by lymphadenopathy and/or hepatosplenomegaly. However, the median survival for these patients is ~7 years, and most will require treatment in the first few years of follow-up. Patients who present with bone marrow failure (i.e., Rai stage III or IV or Binet stage C) will require initial therapy in almost all cases. These patients have a serious disorder with a median survival of only 1.5 years. It must be remembered that immune


InternalMed_Harrison

InternalMed_Harrison. stage III or IV or Binet stage C) will require initial therapy in almost all cases. These patients have a serious disorder with a median survival of only 1.5 years. It must be remembered that immune manifestations of typical B-cell CLL should be managed independently of specific antileukemia therapy. For example, glucocorticoid therapy for autoimmune cytopenias and γ globulin replacement for patients with hypogammaglobulinemia should be used whether or not antileukemia therapy is given.


InternalMed_Harrison

InternalMed_Harrison. Patients who present primarily with lymphoma and have a low IPI score have a 5-year survival of ~75%, but those with a high IPI score have a 5-year survival of <40% and are more likely to require early therapy.


InternalMed_Harrison

InternalMed_Harrison. The most common treatments for patients with typical B-cell CLL/small lymphocytic lymphoma have been chlorambucil or fludarabine, alone or in combination. Chlorambucil can be administered orally with few immediate side effects, while fludarabine is administered IV and is associated with significant immune suppression. However, fludarabine is by far the more active agent and is the only drug associated with a significant incidence of complete remission. The combination of rituximab (375–500 mg/m2 day 1), fludarabine (25 mg/m2 days 2–4 on cycle 1 and days 1–3 in subsequent cycles), and cyclophosphamide (250 mg/m2 with fludarabine) achieves complete responses in 69% of patients, and those responses are associated with molecular remissions in half of the cases. Half the patients experience grade III or IV neutropenia. For young patients presenting with leukemia requiring therapy, regimens containing fludarabine are the treatment of choice. Because fludarabine is an effective second-line


InternalMed_Harrison

InternalMed_Harrison. III or IV neutropenia. For young patients presenting with leukemia requiring therapy, regimens containing fludarabine are the treatment of choice. Because fludarabine is an effective second-line agent in patients with tumors unresponsive to chlorambucil, the latter agent is often chosen in elderly patients who require therapy. Bendamustine, an alkylating agent structurally related to nitrogen mustard, is highly effective and is vying with fludarabine as the primary treatment of choice. Patients who present with lymphoma (rather than leukemia) are also highly responsive to bendamustine, and some patients will receive a combination chemotherapy regimen used in other lymphomas such as CVP (cyclophosphamide, vincristine, and prednisone) or CHOP plus rituximab. Alemtuzumab (anti-CD52) is an antibody with activity in the disease, but it kills both B and T cells and is associated with more immune compromise than rituximab. Young patients with this disease can be candidates for bone marrow


InternalMed_Harrison

InternalMed_Harrison. antibody with activity in the disease, but it kills both B and T cells and is associated with more immune compromise than rituximab. Young patients with this disease can be candidates for bone marrow transplantation. Allogeneic bone marrow transplantation can be curative but is associated with a significant treatment-related mortality rate. Mini-transplants using immunosuppressive rather than myeloablative doses of preparative drugs are being studied (Chap. 139e). The use of autologous transplantation in patients with this disorder has been discouraging.


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InternalMed_Harrison. At least two newer anti-CD20 monoclonal antibodies have 703 become available, ofatumumab and obinutuzumab. Both have activity in previously treated patients. Agents targeting signaling pathways, such as ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and idelalisib, an inhibitor of phosphoinositide3-kinase delta, also have antitumor effects. The ideal combination and sequence of these therapies have not been defined. Extranodal Marginal Zone B-Cell Lymphoma of MALT Type Extranodal marginal zone B-cell lymphoma of MALT type (MALT lymphoma) makes up ~8% of non-Hodgkin’s lymphomas. This small cell lymphoma presents in extranodal sites. It was previously considered a small lymphocytic lymphoma or sometimes a pseudolymphoma. The recognition that the gastric presentation of this lymphoma was associated with H. pylori infection was an important step in recognizing it as a separate entity. The clinical characteristics of MALT lymphoma are presented in Table 134-10.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of MALT lymphoma can be made accurately by an expert hematopathologist based on a characteristic pattern of infiltration of small lymphocytes that are monoclonal B cells and CD5 negative. In some cases, transformation to diffuse large B-cell lymphoma occurs, and both diagnoses may be made in the same biopsy. The differential diagnosis includes benign lymphocytic infiltration of extra-nodal organs and other small cell B-cell lymphomas.


InternalMed_Harrison

InternalMed_Harrison. MALT lymphoma may occur in the stomach, orbit, intestine, lung, thyroid, salivary gland, skin, soft tissues, bladder, kidney, and CNS. It may present as a new mass, be found on routine imaging studies, or be associated with local symptoms such as upper abdominal discomfort in gastric lymphoma. Most MALT lymphomas are gastric in origin. At least two genetic forms of gastric MALT exist: one (accounting for ~50% of cases) characterized by t(11;18)(q21;q21) that juxtaposes the amino terminal of the API2 gene with the carboxy terminal of the MALT1 gene creating an API2/MALT1 fusion product, and the other characterized by multiple sites of genetic instability including trisomies of chromosomes 3, 7, 12, and 18. About 95% of gastric MALT lymphomas are associated with H. pylori infection, and those that are do not usually express t(11;18). The t(11;18) usually results in activation of nuclear factor-κB (NF-κB), which acts as a survival factor for the cells. Lymphomas with t(11;18)


InternalMed_Harrison

InternalMed_Harrison. and those that are do not usually express t(11;18). The t(11;18) usually results in activation of nuclear factor-κB (NF-κB), which acts as a survival factor for the cells. Lymphomas with t(11;18) translocations are genetically stable and do not evolve to diffuse large B-cell lymphoma. By contrast, t(11;18)-negative MALT lymphomas often acquire BCL6 mutations and progress to aggressive histology lymphoma. MALT lymphomas are localized to the organ of origin in ~40% of cases and to the organ and regional lymph nodes in ~30% of patients. However, distant metastasis can occur—particularly with transformation to diffuse large B-cell lymphoma. Many patients who develop this lymphoma will have an autoimmune or inflammatory process such as Sjögren’s syndrome (salivary gland MALT), Hashimoto’s thyroiditis (thyroid MALT), Helicobacter gastritis (gastric MALT), C. psittaci conjunctivitis (ocular MALT), or Borrelia skin infections (cutaneous MALT).


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InternalMed_Harrison. Evaluation of patients with MALT lymphoma follows the pattern (Table 134-11) for staging a patient with non-Hodgkin’s lymphoma. In particular, patients with gastric lymphoma need to have studies performed to document the presence or absence of H. pylori infection. Endoscopic studies including ultrasound can help define the extent of gastric involvement. Most patients with MALT lymphoma have a good prognosis, with a 5-year survival of ~75%. In patients with a low IPI score, the 5-year survival is ~90%, whereas it drops to ~40% in patients with a high IPI score. MALT lymphoma is often localized. Patients with gastric MALT lymphomas who are infected with H. pylori can achieve remission in the 80% of cases with eradication of the infection. These remissions can be durable, but molecular evidence of persisting neoplasia is not


InternalMed_Harrison

InternalMed_Harrison. Malignancies of Lymphoid Cells 704 infrequent. After H. pylori eradication, symptoms generally improve quickly, but molecular evidence of persistent disease may be present for 12–18 months. Additional therapy is not indicated unless progressive disease is documented. Patients with more extensive disease or progressive disease are most often treated with single-agent chemotherapy such as chlorambucil. Combination regimens that include rituximab are also highly effective. Coexistent diffuse large B-cell lymphoma must be treated with combination chemotherapy (see below). The additional acquired mutations that mediate the histologic progression also convey Helicobacter independence to the growth.


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InternalMed_Harrison. Mantle Cell Lymphoma Mantle cell lymphoma makes up ~6% of all non-Hodgkin’s lymphomas. This lymphoma was previously placed in a number of other subtypes. Its existence was confirmed by the recognition that these lymphomas have a characteristic chromosomal trans-location, t(11;14), between the immunoglobulin heavy chain gene on chromosome 14 and the bcl-1 gene on chromosome 11, and regularly overexpress the BCL-1 protein, also known as cyclin D1. Table 134-10 shows the clinical characteristics of mantle cell lymphoma. The diagnosis of mantle cell lymphoma can be made accurately by an expert hematopathologist. As with all subtypes of lymphoma, an adequate biopsy is important. The differential diagnosis of mantle cell lymphoma includes other small cell B-cell lymphomas. In particular, mantle cell lymphoma and small lymphocytic lymphoma share a characteristic expression of CD5. Mantle cell lymphoma usually has a slightly indented nucleus.


InternalMed_Harrison

InternalMed_Harrison. The most common presentation of mantle cell lymphoma is with palpable lymphadenopathy, frequently accompanied by systemic symptoms. The median age is 63 years, and men are affected four times as commonly as women. Approximately 70% of patients will be stage IV at the time of diagnosis, with frequent bone marrow and peripheral blood involvement. Of the extranodal organs that can be involved, gastrointestinal involvement is particularly important to recognize. Patients who present with lymphomatosis polyposis in the large intestine usually have mantle cell lymphoma. Table 134-11 outlines the evaluation of patients with mantle cell lymphoma. Patients who present with gastrointestinal tract involvement often have Waldeyer’s ring involvement, and vice versa. The 5-year survival for all patients with mantle cell lymphoma is ~25%, with only occasional patients who present with a high IPI score surviving 5 years and ~50% of patients with a low IPI score surviving 5 years.


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InternalMed_Harrison. Current therapies for mantle cell lymphoma are evolving. Patients with localized disease might be treated with combination chemotherapy followed by radiotherapy; however, these patients are exceedingly rare. For the usual presentation with disseminated disease, standard lymphoma treatments have been unsatisfactory, with the minority of patients achieving complete remission. Aggressive combination chemotherapy regimens followed by autologous or allogeneic bone marrow transplantation are frequently offered to younger patients. For the occasional elderly, asymptomatic patient, observation followed by single-agent chemotherapy might be the most practical approach. An intensive combination chemotherapy regimen originally used in the treatment of acute leukemia, HyperC-VAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate), in combination with rituximab, seems to be associated with better response rates, particularly in younger patients. Alternating


InternalMed_Harrison

InternalMed_Harrison. vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate), in combination with rituximab, seems to be associated with better response rates, particularly in younger patients. Alternating two regimens, HyperC-VAD with rituximab added (R-HyperC-VAD) and rituximab plus high-dose methotrexate and cytarabine, can achieve complete responses in >80% of patients and an 8-year survival of 56%, comparable to regimens using high-dose therapy and autologous hematopoietic stem cell transplantation. Bendamustine plus rituximab has been found to induce complete responses in about 31% of patients, but the responses are generally not long lasting. Bortezomib and temsirolimus are single agents that induce transient partial responses in a minority of patients and are being added to primary combinations.


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InternalMed_Harrison. FIGURE 134-7 Follicular lymphoma. The normal nodal architecture is effaced by nodular expansions of tumor cells. Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells with vesicular chromatin and prominent nucleoli. Follicular Lymphoma Follicular lymphomas make up 22% of nonHodgkin’s lymphomas worldwide and at least 30% of non-Hodgkin’s lymphomas diagnosed in the United States. This type of lymphoma can be diagnosed accurately on morphologic findings alone and has been the diagnosis in the majority of patients in therapeutic trials for “low-grade” lymphoma in the past. The clinical characteristics of follicular lymphoma are presented in Table 134-10.


InternalMed_Harrison

InternalMed_Harrison. Evaluation of an adequate biopsy by an expert hematopathologist is sufficient to make a diagnosis of follicular lymphoma. The tumor is composed of small cleaved and large cells in varying proportions organized in a follicular pattern of growth (Fig. 134-7). Confirmation of B-cell immunophenotype and the existence of the t(14;18) and abnormal expression of BCL-2 protein are confirmatory. The major differential diagnosis is between lymphoma and reactive follicular hyperplasia. The coexistence of diffuse large B-cell lymphoma must be considered. Patients with follicular lymphoma are often subclassified into those with predominantly small cells, those with a mixture of small and large cells, and those with predominantly large cells. Although this distinction cannot be made simply or very accurately, these subdivisions do have prognostic significance. Patients with follicular lymphoma with predominantly large cells have a higher proliferative fraction, progress more rapidly, and have a


InternalMed_Harrison

InternalMed_Harrison. these subdivisions do have prognostic significance. Patients with follicular lymphoma with predominantly large cells have a higher proliferative fraction, progress more rapidly, and have a shorter overall survival with simple chemotherapy regimens.


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InternalMed_Harrison. The most common presentation for follicular lymphoma is with new, painless lymphadenopathy. Multiple sites of lymphoid involvement are typical, and unusual sites such as epitrochlear nodes are sometimes seen. However, essentially any organ can be involved, and extranodal presentations do occur. Most patients do not have fevers, sweats, or weight loss, and an IPI score of 0 or 1 is found in ~50% of patients. Fewer than 10% of patients have a high (i.e., 4 or 5) IPI score. The staging evaluation for patients with follicular lymphoma should include the studies shown in Table 134-11.


InternalMed_Harrison

InternalMed_Harrison. Follicular lymphoma is one of the malignancies most responsive to chemotherapy and radiotherapy. In addition, tumors in as many as 25% of the patients undergo spontaneous regression—usually transient—without therapy. In an asymptomatic patient, no initial treatment and watchful waiting can be an appropriate management strategy and is particularly likely to be adopted for older patients with advanced-stage disease. For patients who do require treat ment, single-agent chlorambucil or cyclophosphamide or combination chemotherapy with CVP or CHOP is most frequently used. With adequate treatment, 50–75% of patients will achieve a complete remission. Although most patients relapse (median response duration is ~2 years), at least 20% of complete responders will remain in remission for >10 years. For the rare patients (15%) with localized follicular lymphoma, involved-field radiotherapy produces longterm disease-free survival in the majority.


InternalMed_Harrison

InternalMed_Harrison. A number of therapies have been shown to be active in the treatment of patients with follicular lymphoma. These include cytotoxic agents such as fludarabine, biologic agents such as interferon α, monoclonal antibodies with or without radionuclides, and lymphoma vaccines. In patients treated with a doxorubicin-containing combination chemotherapy regimen, interferon α given to patients in complete remission seems to prolong survival, but interferon toxicities can affect quality of life. The monoclonal antibody rituximab can cause objective responses in 35–50% of patients with relapsed follicular lymphoma, and radiolabeled antibodies appear to have response rates well in excess of 50%. The addition of rituximab to CHOP and other effective combination chemotherapy programs achieves prolonged overall survival and a decreased risk of histologic progression. Complete remissions can be noted in 85% or more of patients treated with R-CHOP, and median remission durations can exceed 6 or 7


InternalMed_Harrison

InternalMed_Harrison. overall survival and a decreased risk of histologic progression. Complete remissions can be noted in 85% or more of patients treated with R-CHOP, and median remission durations can exceed 6 or 7 years. Maintenance intermittent rituximab therapy can prolong remissions even further, although it is not completely clear that overall survival is prolonged. Some trials with tumor vaccines have been encouraging. Both autologous and allogeneic hematopoietic stem cell transplantations yield high complete response rates in patients with relapsed follicular lymphoma, and long-term remissions can occur in 40% or more of patients.


InternalMed_Harrison

InternalMed_Harrison. Patients with follicular lymphoma with a predominance of large cells have a shorter survival when treated with single-agent chemotherapy but seem to benefit from receiving an anthracyclinecontaining combination chemotherapy regimen plus rituximab. When their disease is treated aggressively, the overall survival for such patients is no lower than for patients with other follicular lymphomas, and the failure-free survival is superior.


InternalMed_Harrison

InternalMed_Harrison. Patients with follicular lymphoma have a high rate of histologic transformation to diffuse large B-cell lymphoma (5–7% per year). This is recognized ~40% of the time during the course of the illness by repeat biopsy and is present in almost all patients at autopsy. This transformation is usually heralded by rapid growth of lymph nodes—often localized—and the development of systemic symptoms such as fevers, sweats, and weight loss. Although these patients have a poor prognosis, aggressive combination chemotherapy regimens can sometimes cause a complete remission in the diffuse large B-cell lymphoma, at times leaving the patient with persisting follicular lymphoma. With more frequent use of R-CHOP to treat follicular lymphoma at diagnosis, it appears that the rate of histologic progression is decreasing. R-CHOP or bendamustine plus rituximab with intermittent rituximab maintenance for 2 years are the most commonly used treatment approaches.


InternalMed_Harrison

InternalMed_Harrison. Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma is the most common type of non-Hodgkin’s lymphoma, representing approximately one-third of all cases. This lymphoma makes up the majority of cases in previous clinical trials of “aggressive” or “intermediate-grade” lymphoma. Table 134-10 shows the clinical characteristics of diffuse large B-cell lymphoma.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of diffuse large B-cell lymphoma can be made accurately by an expert hematopathologist (Fig. 134-8). Cytogenetic and molecular genetic studies are not necessary for diagnosis, but some evidence has accumulated that patients whose tumors overexpress the BCL-2 protein might be more likely to relapse than others. A subset of patients have tumors with mutations in BCL6 and translocations involving MYC; these are called “double-hit” lymphomas and typically have more aggressive growth and are more poorly responsive to treatment than other diffuse large B-cell lymphomas. Patients with prominent mediastinal involvement are sometimes diagnosed as a separate subgroup having primary mediastinal diffuse large B-cell lymphoma. This latter group of patients has a younger median age (i.e., 37 years) and a female predominance (66%). Subtypes of diffuse large B-cell lymphoma, including those with an immunoblastic subtype and tumors with extensive fibrosis, are recognized by pathologists


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InternalMed_Harrison. 37 years) and a female predominance (66%). Subtypes of diffuse large B-cell lymphoma, including those with an immunoblastic subtype and tumors with extensive fibrosis, are recognized by pathologists but do not appear to have important independent prognostic significance.


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InternalMed_Harrison. FIGURE 134-8 Diffuse large B-cell lymphoma. The neoplastic cells are heterogeneous but predominantly large cells with vesicular chro-matin and prominent nucleoli. Diffuse large B-cell lymphoma can present as either primary lymph node disease or at extranodal sites. More than 50% of patients will have some site of extranodal involvement at diagnosis, with the most common sites being the gastrointestinal tract and bone marrow, each being involved in 15–20% of patients. Essentially any organ can be involved, making a diagnostic biopsy imperative. For example, diffuse large B-cell lymphoma of the pancreas has a much better prognosis than pancreatic carcinoma but would be missed without biopsy. Primary diffuse large B-cell lymphoma of the brain is being diagnosed with increasing frequency. Other unusual subtypes of diffuse large B-cell lymphoma such as pleural effusion lymphoma and intravascular lymphoma have been difficult to diagnose and associated with a very poor prognosis.


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InternalMed_Harrison. Table 134-11 shows the initial evaluation of patients with diffuse large B-cell lymphoma. After a careful staging evaluation, ~50% of patients will be found to have stage I or II disease, and ~50% will have widely disseminated lymphoma. Bone marrow biopsy shows involvement by lymphoma in ~15% of cases, with marrow involvement by small cells more frequent than by large cells.


InternalMed_Harrison

InternalMed_Harrison. The initial treatment of all patients with diffuse large B-cell lymphoma should be with a combination chemotherapy regimen. The most popular regimen in the United States is CHOP plus rituximab, although a variety of other anthracycline-containing combination chemotherapy regimens appear to be equally efficacious. Patients with stage I or nonbulky stage II disease can be effectively treated with three to four cycles of combination chemotherapy with or without subsequent involved-field radiotherapy. The need for radiation therapy is unclear. Cure rates of 70–80% in stage II disease and 85–90% in stage I disease can be expected.


InternalMed_Harrison

InternalMed_Harrison. For patients with bulky stage II, stage III, or stage IV disease, six to eight cycles of CHOP plus rituximab are usually administered. A large randomized trial showed the superiority of CHOP combined with rituximab over CHOP alone in elderly patients. A frequent approach would be to administer four cycles of therapy and then reevaluate. If the patient has achieved a complete remission after four cycles, two more cycles of treatment might be given and then therapy discontinued. Using this approach, 70–80% of patients can


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InternalMed_Harrison. Malignancies of Lymphoid Cells 706 be expected to achieve a complete remission, and 50–70% of complete responders will be cured. The chances for a favorable response to treatment are predicted by the IPI. In fact, the IPI was developed based on the outcome of patients with diffuse large B-cell lymphoma treated with CHOP-like regimens. For the 35% of patients with a low IPI score of 0–1, the 5-year survival is >70%, whereas for the 20% of patients with a high IPI score of 4–5, the 5-year survival is ~20%. The addition of rituximab to CHOP has improved each of those numbers by ~15%. A number of other factors, including molecular features of the tumor, levels of circulating cytokines and soluble receptors, and other surrogate markers, have been shown to influence prognosis. However, they have not been validated as rigorously as the IPI and have not been uniformly applied clinically. Because a number of patients with diffuse large B-cell lymphoma are either initially refractory to therapy


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InternalMed_Harrison. not been validated as rigorously as the IPI and have not been uniformly applied clinically. Because a number of patients with diffuse large B-cell lymphoma are either initially refractory to therapy or relapse after apparently effective chemotherapy, 30–40% of patients will be candidates for salvage treatment at some point. Alternative combination chemotherapy regimens can induce complete remission in as many as 50% of these patients, but long-term disease-free survival is seen in ≤10%. Autologous bone marrow transplantation is superior to salvage chemotherapy at usual doses and leads to longterm disease-free survival in ~40% of patients whose lymphomas remain chemotherapy-sensitive after relapse.


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InternalMed_Harrison. Burkitt’s Lymphoma/Leukemia Burkitt’s lymphoma/leukemia is a rare disease in adults in the United States, making up <1% of non-Hodgkin’s lymphomas, but it makes up ~30% of childhood non-Hodgkin’s lymphoma. Burkitt’s leukemia, or L3 ALL, makes up a small proportion of childhood and adult acute leukemias. Table 134-10 shows the clinical features of Burkitt’s lymphoma.


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InternalMed_Harrison. Burkitt’s lymphoma can be diagnosed morphologically by an expert hematopathologist with a high degree of accuracy. The cells are homogeneous in size and shape (Fig. 134-9). Demonstration of a very high proliferative fraction and the presence of the t(8;14) or one of its variants, t(2;8) (c-myc and the λ light chain gene) or t(8;22) (c-myc and the κ light chain gene), can be confirmatory. Burkitt’s cell leukemia is recognized by the typical monotonous mass of medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm with cytoplasmic vacuoles. Demonstration of surface expression of immunoglobulin and one of the above-noted cytogenetic abnormalities is confirmatory. Three distinct clinical forms of Burkitt’s lymphoma are recognized: endemic, sporadic, and immunodeficiency-associated. Endemic and sporadic Burkitt’s lymphomas occur frequently in children in Africa, and the sporadic form occurs in Western countries.


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InternalMed_Harrison. FIGURE 134-9 Burkitt’s lymphoma. The neoplastic cells are homo-geneous, medium-sized B cells with frequent mitotic figures, a mor-phologic correlate of high growth fraction. Reactive macrophages are scattered through the tumor, and their pale cytoplasm in a back-ground of blue-staining tumor cells gives the tumor a so-called starry sky appearance. Immunodeficiency-associated Burkitt’s lymphoma is seen in patients with HIV infection.


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InternalMed_Harrison. Immunodeficiency-associated Burkitt’s lymphoma is seen in patients with HIV infection. Pathologists sometimes have difficulty distinguishing between Burkitt’s lymphoma and diffuse large B-cell lymphoma. In the past, a separate subgroup of non-Hodgkin’s lymphoma intermediate between the two was recognized. When tested, this subgroup could not be diagnosed accurately. Distinction between the two major types of B-cell aggressive non-Hodgkin’s lymphoma can sometimes be made based on the extremely high proliferative fraction seen in patients with Burkitt’s lymphoma (i.e., essentially 100% of tumor cells are in cycle) caused by c-myc deregulation.


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InternalMed_Harrison. Most patients in the United States with Burkitt’s lymphoma present with peripheral lymphadenopathy or an intraabdominal mass. The disease is rapidly progressive and has a propensity to metastasize to the CNS. Initial evaluation should always include an examination of cerebrospinal fluid to rule out metastasis in addition to the other staging evaluations noted in Table 134-11. Once the diagnosis of Burkitt’s lymphoma is suspected, a diagnosis must be made promptly, and staging evaluation must be accomplished expeditiously. This is the most rapidly progressive human tumor, and any delay in initiating therapy can adversely affect the patient’s prognosis.


InternalMed_Harrison

InternalMed_Harrison. Treatment of Burkitt’s lymphoma in both children and adults should begin within 48 h of diagnosis and involves the use of intensive combination chemotherapy regimens incorporating high doses of cyclophosphamide. Prophylactic therapy to the CNS is mandatory. Burkitt’s lymphoma was one of the first cancers shown to be curable by chemotherapy. Today, cure can be expected in 70–80% of both children and young adults when effective therapy is administered precisely. Salvage therapy has been generally ineffective in patients in whom the initial treatment fails, emphasizing the importance of the initial treatment approach. involves blood and marrow infiltration by large lymphocytes with prominent nucleoli. Patients typically have a high white cell count, splenomegaly, and minimal lymphadenopathy. The chances for a complete response to therapy are poor.


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InternalMed_Harrison. Hairy cell leukemia is a rare disease that presents predominantly in older males. Typical presentation involves pancytopenia, although occasional patients will have a leukemic presentation. Splenomegaly is usual. The malignant cells appear to have “hairy” projections on light and electron microscopy and show a characteristic staining pattern with tartrate-resistant acid phosphatase. Bone marrow is typically not able to be aspirated, and biopsy shows a pattern of fibrosis with diffuse infiltration by the malignant cells. Patients with this disorder have monocytopenia and are prone to unusual infections, including infection by Mycobacterium avium intracellulare, and to vasculitic syndromes. Hairy cell leukemia is responsive to chemotherapy with interferon α, pentostatin, or cladribine, with the latter being the usually preferred treatment. Clinical complete remissions with cladribine occur in the majority of patients, and long-term disease-free survival is frequent. Many of these tumors


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InternalMed_Harrison. the latter being the usually preferred treatment. Clinical complete remissions with cladribine occur in the majority of patients, and long-term disease-free survival is frequent. Many of these tumors have the V600E BRAF mutation and accordingly are responsive to BRAF inhibitors like vemurafenib.


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InternalMed_Harrison. Splenic marginal zone lymphoma involves infiltration of the splenic white pulp by small, monoclonal B cells. This is a rare disorder that can present as leukemia as well as lymphoma. Definitive diagnosis is often made at splenectomy, which is also an effective therapy. This is an extremely indolent disorder, but when chemotherapy is required, the most usual treatment has been chlorambucil.


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InternalMed_Harrison. Lymphoplasmacytic lymphoma is the tissue manifestation of Waldenström’s macroglobulinemia (Chap. 136). Many of these tumors harbor a specific mutation, L265P, in MYD88, a change that leads to NF-κB activation. This type of lymphoma has been associated with chronic hepatitis C virus infection, and an etiologic association has been proposed. Patients typically present with lymphadenopathy, splenomegaly, bone marrow involvement, and occasionally peripheral blood involvement. The tumor cells do not express CD5. Patients often have a monoclonal IgM protein, high levels of which can dominate the clinical picture with the symptoms of hyperviscosity. Treatment of lymphoplasmacytic lymphoma can be aimed primarily at reducing the abnormal protein, if present, but will usually also involve chemotherapy. Chlorambucil, fludarabine, and cladribine have been used. The median 5-year survival for patients with this disorder is ~60%.


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InternalMed_Harrison. Nodal marginal zone lymphoma, also known as monocytoid cell lymphoma, represents ~1% of non-Hodgkin’s lymphomas. This lymphoma has a slight female predominance and presents with disseminated disease (i.e., stage III or IV) in 75% of patients. Approximately one-third of patients have bone marrow involvement, and a leukemic presentation occasionally occurs. The staging evaluation and therapy should use the same approach as used for patients with follicular lymphoma. Approximately 60% of the patients with nodal marginal zone lymphoma will survive 5 years after diagnosis. Other more uncommon B-cell malignancies are discussed in Chap. 135e. PRECURSOR T-CELL MALIGNANCIES Precursor T-Cell Lymphoblastic Leukemia/Lymphoma Precursor T-cell malignancies can present either as ALL or as an aggressive lymphoma. These malignancies are more common in children and young adults, with males more frequently affected than females.


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InternalMed_Harrison. Precursor T-cell ALL can present with bone marrow failure, although the severity of anemia, neutropenia, and thrombocytopenia is often less than in precursor B-cell ALL. These patients sometimes have very high white cell counts, a mediastinal mass, lymphadenopathy, and hepatosplenomegaly. Precursor T-cell lymphoblastic lymphoma is most often found in young men presenting with a large mediastinal mass and pleural effusions. Both presentations have a propensity to metastasize to the CNS, and CNS involvement is often present at diagnosis.


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InternalMed_Harrison. Children with precursor T-cell ALL seem to benefit from very intensive remission induction and consolidation regimens. The majority of patients treated in this manner can be cured. Older children and young adults with precursor T-cell lymphoblastic lymphoma are also often treated with “leukemia-like” regimens. Patients who present with localized disease have an excellent prognosis. However, advanced age is an adverse prognostic factor. Adults with precursor T-cell lymphoblastic lymphoma who present with high LDH levels or bone marrow or CNS involvement are often offered bone marrow transplantation as part of their primary therapy. MATURE (PERIPHERAL) T-CELL DISORDERS Mycosis Fungoides Mycosis fungoides is also known as cutaneous T-cell lymphoma. This lymphoma is more often seen by dermatologists than internists. The median age of onset is in the mid-fifties, and the disease is more common in males and in blacks.


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InternalMed_Harrison. Mycosis fungoides is an indolent lymphoma with patients often having several years of eczematous or dermatitic skin lesions before the diagnosis is finally established. The skin lesions progress from patch stage to plaque stage to cutaneous tumors. Early in the disease, biopsies are often difficult to interpret, and the diagnosis may only become apparent by observing the patient over time. In advanced stages, the lymphoma can spread to lymph nodes and visceral organs. Patients with this lymphoma may develop generalized erythroderma and circulating tumor cells, called Sézary’s syndrome.


InternalMed_Harrison

InternalMed_Harrison. Rare patients with localized early-stage mycosis fungoides can be cured with radiotherapy, often total-skin electron beam irradiation. More advanced disease has been treated with topical glucocorticoids, topical nitrogen mustard, phototherapy, psoralen with ultraviolet A (PUVA), extracorporeal photopheresis, retinoids (bexarotene), elec-707 tron beam radiation, interferon, antibodies, fusion toxins, histone deacetylase inhibitors, and systemic cytotoxic therapy. Unfortunately, these treatments are palliative.


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InternalMed_Harrison. Adult T-Cell Lymphoma/Leukemia Adult T-cell lymphoma/leukemia is one manifestation of infection by the HTLV-1 retrovirus. Patients can be infected through transplacental transmission, mother’s milk, blood transfusion, and by sexual transmission of the virus. Patients who acquire the virus from their mother through breast milk are most likely to develop lymphoma, but the risk is still only 2.5% and the latency averages 55 years. Nationwide testing for HTLV-1 antibodies and the aggressive implementation of public health measures could theoretically lead to the disappearance of adult T-cell lymphoma/leukemia. Tropical spastic paraparesis, another manifestation of HTLV-1 infection (Chap. 225e), occurs after a shorter latency (1–3 years) and is most common in individuals who acquire the virus during adulthood from transfusion or sex.


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InternalMed_Harrison. The diagnosis of adult T-cell lymphoma/leukemia is made when an expert hematopathologist recognizes the typical morphologic picture, a T-cell immunophenotype (i.e., CD4 positive), and the presence in serum of antibodies to HTLV-1. Examination of the peripheral blood will usually reveal characteristic, pleomorphic abnormal CD4-positive cells with indented nuclei, which have been called “flower” cells (Fig. 134-10).


InternalMed_Harrison

InternalMed_Harrison. A subset of patients have a smoldering clinical course and long survival, but most patients present with an aggressive disease manifested by lymphadenopathy, hepatosplenomegaly, skin infiltration, pulmo nary infiltrates, hypercalcemia, lytic bone lesions, and elevated LDH levels. The skin lesions can be papules, plaques, tumors, and ulcerations. Lung lesions can be either tumor or opportunistic infection in light of the underlying immunodeficiency in the disease. Bone marrow involvement is not usually extensive, and anemia and thrombocytopenia are not usually prominent. Although treatment with combination chemotherapy regimens can result in objective responses, true complete remissions are unusual, and the median survival of patients is ~7 months. A small phase II study reported a high response rate with interferon plus zidovudine and arsenic trioxide.


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InternalMed_Harrison. Anaplastic Large T/Null-Cell Lymphoma Anaplastic large T/null-cell lymphoma was previously usually diagnosed as undifferentiated carcinoma or malignant histiocytosis. Discovery of the CD30 (Ki-1) antigen and the recognition that some patients with previously unclassified malignancies displayed this antigen led to the identification of a new type of lymphoma. Subsequently, discovery of the t(2;5) and the resultant frequent overexpression of the anaplastic lymphoma kinase (ALK) protein confirmed the existence of this entity. This lymphoma accounts for ~2% of all non-Hodgkin’s lymphomas. Table 134-10 shows the clinical characteristics of patients with anaplastic large T/null cell lymphoma. FIGURE 134-10 Adult T-cell leukemia/lymphoma. Peripheral blood smear showing leukemia cells with typical “flower-shaped” nucleus.


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InternalMed_Harrison. Malignancies of Lymphoid Cells 708 The diagnosis of anaplastic large T/null-cell lymphoma is made when an expert hematopathologist recognizes the typical morphologic picture and a T-cell or null-cell immunophenotype with CD30 positivity. Documentation of the t(2;5) and/or overexpression of ALK protein confirm the diagnosis. Some diffuse large B-cell lymphomas can also have an anaplastic appearance but have the same clinical course or response to therapy as other diffuse large B-cell lymphomas. A small percentage of anaplastic lymphomas are ALK negative. Patients with anaplastic large T/null-cell lymphoma are typically young (median age, 33 years) and male (~70%). Some 50% of patients present in stage I/II, and the remainder present with more extensive disease. Systemic symptoms and elevated LDH levels are seen in about one-half of patients. Bone marrow and the gastrointestinal tract are rarely involved, but skin involvement is frequent. Some patients with disease confined to the skin


InternalMed_Harrison

InternalMed_Harrison. LDH levels are seen in about one-half of patients. Bone marrow and the gastrointestinal tract are rarely involved, but skin involvement is frequent. Some patients with disease confined to the skin have a different and more indolent disorder that has been termed cutaneous anaplastic large T/null-cell lymphoma and might be related to lymphomatoid papulosis.


InternalMed_Harrison

InternalMed_Harrison. Treatment regimens appropriate for other aggressive lymphomas, such as diffuse large B-cell lymphoma, should be used in patients with anaplastic large T/null-cell lymphoma, with the exception that the B-cell–specific antibody, rituximab, is omitted. Surprisingly, given the anaplastic appearance, this disorder has the best survival rate of any aggressive lymphoma. The 5-year survival is >75%. While traditional prognostic factors such as the IPI predict treatment outcome, overexpression of the ALK protein is an important prognostic factor, with patients overexpressing this protein having a superior treatment outcome. The ALK inhibitor crizotinib appears highly active as well. In addition, the CD30 immunotoxin, brentuximab vedotin, is active in the disease.


InternalMed_Harrison

InternalMed_Harrison. Peripheral T-Cell Lymphoma The peripheral T-cell lymphomas make up a heterogeneous morphologic group of aggressive neoplasms that share a mature T-cell immunophenotype. They represent ~7% of all cases of non-Hodgkin’s lymphoma. A number of distinct clinical syndromes are included in this group of disorders. Table 134-10 shows the clinical characteristics of patients with peripheral T-cell lymphoma.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of peripheral T-cell lymphoma, or any of its specific subtypes, requires an expert hematopathologist, an adequate biopsy, and immunophenotyping. Most peripheral T-cell lymphomas are CD4+, but a few will be CD8+, both CD4+ and CD8+, or have an NK cell immunophenotype. No characteristic genetic abnormalities have yet been identified, but translocations involving the T-cell antigen receptor genes on chromosomes 7 or 14 may be detected. The differential diagnosis of patients suspected of having peripheral T-cell lymphoma includes reactive T-cell infiltrative processes. In some cases, demonstration of a monoclonal T-cell population using T-cell receptor gene rearrangement studies will be required to make a diagnosis.


InternalMed_Harrison

InternalMed_Harrison. The initial evaluation of a patient with a peripheral T-cell lymphoma should include the studies in Table 134-11 for staging patients with non-Hodgkin’s lymphoma. Unfortunately, patients with peripheral T-cell lymphoma usually present with adverse prognostic factors, with >80% of patients having an IPI score ≥2 and >30% having an IPI score ≥4. As this would predict, peripheral T-cell lymphomas are associated with a poor outcome, and only 25% of the patients survive 5 years after diagnosis. Treatment regimens are the same as those used for diffuse large B-cell lymphoma (omitting rituximab), but patients with peripheral T-cell lymphoma have a poorer response to treatment. Because of this poor treatment outcome, hematopoietic stem cell transplantation is often considered early in the care of young patients.