Hematologic Malignancies

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[edit] Hematologic Malignancies

Philip A. Lowry

Hematologic malignancies range in their presentation from the indolent disorders whose course is insidious and prolonged to the highly aggressive leukemias and lymphomas whose explosive onset and rapid progression are among the most dramatic in all of medicine. A thorough history and physical examination, complete blood count (CBC), basic chemistry determination, and evaluation of the peripheral blood smear remain the central pillars of the initial diagnosis of all hematologic disorders. A well-focused differential diagnosis and initial management plan can frequently be constructed from these alone.

The primary care physician must be more concerned to appropriately raise the general suspicion of hematologic malignancy than to make the final specific diagnosis. Particularly with the resurgence of primary care–centered medical practice, the physician will need to efficiently distinguish benign, self-limited conditions needing no further attention from the sometimes subtle signs and symptoms of the earliest and most treatable stages of hematologic malignancy. This chapter will focus on those initial signs of hematologic malignancy and the basics of their diagnosis and initial therapy.

[edit] SYSTEMIC SYMPTOMS

Involuntary weight loss, fevers, or night sweats may indicate an underlying malignancy, particularly the lymphoproliferative disorders; pruritus specifically suggests a diagnosis of Hodgkin's disease or polycythemia vera. Splenomegaly associated with hematologic malignancy may cause abdominal distention and discomfort, and back pain may reflect retroperitoneal adenopathy, direct spinal involvement with lymphoma, or compression fractures due to myeloma. Myeloma can additionally produce punched-out skeletal lesions, pathologic fractures elsewhere, or premature osteoporosis.

Hematologic malignancies frequently suppress normal bone marrow function, resulting in fatigue secondary to anemia, recurrent or serious infections due to neutrophil or lymphocyte defects, or petechiae or bleeding due to platelet deficiencies. Acute nonlymphocytic leukemia may induce frank disseminated intravascular coagulation (DIC). Myeloproliferative disorders may present with thrombosis because of quantitative and qualitative platelet abnormalities.

[edit] LYMPHADENOPATHY AND SPLENOMEGALY

Lymphadenopathy should particularly focus the attention of the primary care physician on the possibility of an underlying hematologic malignancy. Causes of lymphadenopathy are summarized in Box 119-1 and a general scheme for its evaluation presented in Fig. 119-1.

Figure 119-1 The workup of lymphadenopathy.

Lymphadenopathy most frequently reflects a benign, localized infectious process and usually resolves spontaneously with simple therapy. Persistent lymphadenopathy of greater than 2 weeks duration or lymphadenopathy with pathologic characteristics such as firm to hard or very large and/or unusually placed lymph nodes unassociated with obvious localized infection requires prompt diagnostic consideration. It is not acceptable to pursue multiple empiric antibiotic courses in the vain hope that adenopathy will resolve.

Early diagnosis should be the rule. A complete history and physical examination may suggest other less invasive diagnostic evaluations prior to definitive biopsy. Young patients or others with potential exposure should be screened for human immunodeficiency virus (HIV) infection. Severe or persistent pharyngitis should suggest the possibility of infectious mononucleosis with the diagnosis confirmed serologically.

Accompanying symptoms of fever, weight loss, or night sweats particularly suggest lymphoma. Chest x-ray and computed tomography (CT) scans of the chest and abdomen screen for occult mediastinal and retroperitoneal adenopathy. Chest tightness, progressive dysphagia or dyspnea, or facial plethora is often the result of a primary lung or esophageal process. Changes in bowel habits or abdominal discomfort points to an occult gastrointestinal malignancy. Cervical adenopathy in an older man who smokes suggests a primary head and neck cancer and should prompt full ear, nose, and throat evaluation prior to lymph node biopsy, since that biopsy may compromise subsequent lymph node dissection.

Supraclavicular adenopathy is frequently an indicator of more distant disease in the lung, breast, or abdomen. Axillary adenopathy suggests lymphoma or carcinoma of the breast, lung, skin, or even occasionally prostate. Workup of axillary or supraclavicular adenopathy should include a chest x-ray, mammography, a careful physical examination, and frequently body CT scans to look for a primary lesion elsewhere.

Many individuals may have longstanding, rubbery inguinal nodes that are non-pathologic. Small nodes that are by history unchanged over a long period of time and unassociated with focal signs of pelvic disorder may not require further evaluation. Adenopathy of more suspicious nature should prompt a thorough evaluation of the rectal and perineal regions, as well as specific genital examination.

If a diagnosis is not clear from other evaluation, fine-needle aspiration of a pathologic lymph node may initially suggest a diagnosis but definitive excisional biopsy is often required to give more complete structural information as to the pathologic process. In all cases, the least invasive procedure to make a diagnosis should be selected first.

Other than the occasional young, aesthenic individual whose normal-sized spleen is palpable solely due to body habitus, palpable splenomegaly also suggests an underlying hematologic malignancy. Mild splenomegaly may be noted in the context of congestive heart failure, chronic inflammatory conditions, or autoimmune disease. It may be appropriate to cautiously follow splenomegaly in these circumstances without further diagnostic procedures, though indirect evaluation with flow cytometric analysis of blood and marrow is relatively simple to obtain and can more completely evaluate for the possibility of an underlying hematologic malignancy without abdominal surgery.

Moderate splenomegaly may be associated with chronic hemolytic anemias, cirrhosis with portal hypertension, infectious mononucleosis, amyloidosis, or subacute bacterial endocarditis.^[1] Primary hematologic disorders should be suspected and a vigorous search undertaken for associated adenopathy or hematologic abnormalities.

Massive splenomegaly presenting in the adult population is usually indicative of an underlying malignant disorder. Myeloproliferative diseases, particularly chronic myelocytic leukemia and myelofibrosis (agnogenic myeloid metaplasia), may present with massive splenomegaly. Hairy-cell leukemia may present in similar fashion.^[1] Bone marrow biopsy and aspiration are usually diagnostic of these conditions. Inherited storage diseases may also result in massive splenomegaly but are usually diagnosed at an earlier age and rarely present de novo to the adult primary care physician.

Diagnostic splenectomy is rarely required, and a definitive diagnosis can frequently be obtained from careful examination of the peripheral blood or from node or marrow biopsy. Splenectomy for the staging of Hodgkin's disease has essentially disappeared. Immune cytopenias complicating lymphoproliferative disorders, cytopenias resulting from splenic sequestration, and intractable symptoms from massive splenomegaly may require therapeutic splenectomy. Causes of splenomegaly are summarized in Box 119-2.

[edit] LABORATORY ABNORMALITIES

Basic laboratory evaluation can focus the differential diagnosis of hematologic malignancy and will occasionally be the first clue as to its presence. Anemia or other cytopenias due to marrow replacement or immune destruction frequently accompany an underlying hematologic malignancy. A monotonous, sustained increase in a single cell population without an obvious inciting event suggests a myeloproliferative or leukemic process; basophilia may be a specific marker of myeloproliferative disorder. An abnormal machine-generated CBC should prompt inspection of the peripheral smear, with a particular evaluation for abnormal morphology and the presence of blasts. Bone marrow evaluation may be necessary to establish a final diagnosis.

Elevated serum protein levels may indicate the presence of an underlying monoclonal protein associated with myeloma or another lymphoproliferative process. Aggressive hematologic disorders may produce elevations of calcium, uric acid, or lactic dehydrogenase. Flow cytometric analysis of blood and marrow is increasingly used in conjunction with traditional light microscopy in the characterization of hematologic malignancies.

[edit] SPECIFIC DISEASES

[edit] Myeloproliferative Disorders

The myeloproliferative disorders represent an abnormal proliferation of relatively mature-appearing cells of the erythrocyte, megakaryocytic, and/or myeloid lineage, although the abnormality resides in the earliest stem cell. Although the cells in excess may appear at least superficially normal on morphologic examination, they may be functionally abnormal. The myeloproliferative disorders are usually classified based on the primary cell in excess, although all lineages are affected.^[2] Clinical features of these disorders are summarized in Table 119-1.

Table 119-1 Clinical Features of Myeloproliferative Disorders

✢Platelet defects may induce occult gastrointestinal blood loss, producing an artifactually normal or decreased hematocrit and morphologic changes consistent with iron deficiency.

†Gross chromosomal translocation may occasionally be absent, but genetic rearrangements involving the bcr locus on chromosome 22 and c-abl locus on chromosome 9 should be detectable on Southern Blot analysis.

An excessive proliferation of myeloid cells and granulocytes characterizes chronic myelocytic leukemia (CML). The primary differential diagnosis of mature granulocytosis is between CML and a benign leukemoid reaction. Patients with a leukemoid reaction will frequently have a history of infection or other inciting process, will lack splenomegaly, and will have an elevated leukocyte alkaline phosphatase (LAP) score. Patients with CML, in contrast, have low LAP scores and lack signs or symptoms of a clear inciting event. CML is confirmed by bone marrow examination, with identification of a characteristic reciprocal genetic translocation involving the bcr locus on chromosome 22 and c-abl locus on chromosome 9 that frequently produces the abnormal Philadelphia chromosome.

CML typically presents as an indolent disorder, with patients remaining in the chronic phase for several years before it transforms in time to acute leukemia. Marrow or stem cell transplantation is the treatment of choice in younger patients, with well-matched donors inducing “cures” in 60% to 80%. Interferon treatment is an important alternative, with frequent responses and some long-term remissions. Prior interferon therapy may compromise the success of transplantation, especially from unrelated donors, so should be used judiciously in potential transplant candidates. Hydroxyurea can temporarily control cell counts and symptoms, and may be a less toxic approach for older patients.^[2]

Polycythemia vera is a disorder manifested primarily as a proliferation of red blood cells. Patients may be diagnosed on the basis of an abnormal CBC or present with thrombosis due either to vascular sludging associated with the polycythemia or related to associated quantitative or qualitative platelet defects; gastrointestinal hemorrhage from qualitative platelet defects; or pruritus.

The specific diagnosis of polycythemia vera is historically based on the determination of an elevated red blood cell mass and evaluation for other indicators including splenomegaly and associated leukocytosis or thrombocytosis. The history and physical examination, measurement of arterial oxygen saturation, and determination of carboxyhemoglobin can exclude reactive polycythemias caused by chronic obstructive pulmonary disease, congenital or other cardiopulmonary disease, inheritance of a hemoglobin with abnormal oxygen affinity, or elevated carboxyhemoglobin levels due to smoking. Direct assay of circulating erythropoietin levels is becoming a useful adjunctive procedure as erythropoietin levels are elevated in reactive polycythemias but depressed in polycythemia vera. Neoplasms of the kidneys or liver may occasionally produce erythropoietin autonomously, inducing a secondary polycythemia, and should be sought in patients with unexplained elevations of erythropoietin.

Unlike chronic myelogenous leukemia, polycythemia vera has a very low tendency toward transformation into acute leukemia and many patients enjoy relatively long survival. Treatment goals are directed at reduction of the effects of hyperviscosity with improved vascular flow as well as reductions in the risk of hemorrhage and thrombosis. Simple phlebotomy is the mainstay of therapy, but may be paradoxically associated with an increased thrombotic risk during the initial months of treatment. Elderly patients who cannot tolerate phlebotomy may be treated pharmacologically or with radioactive phosphorus to suppress red cell production, although such treatment raises the risk of leukemic transformation.^[2]

Essential thrombocytosis is a less frequent syndrome associated with a predominant proliferation of platelets. Patients may present with either hemorrhage or thrombosis due to quantitative and qualitative platelet abnormalities, or may be diagnosed incidentally on routine CBC. Essential thrombocytosis must be differentiated from reactive thrombocytosis due to inflammation, iron deficiency anemia, or thrombocytosis postsplenectomy. Reactive thrombocytoses rarely achieve levels greater then 10⁹ platelets per mcl.

The approach to patients with thrombocytosis is largely empiric. Any patient with an unexplained, persistent platelet count elevation above 600,000 per mcl and hemorrhage or thrombosis should be considered for therapy. Platelet apheresis is acutely effective and may immediately alleviate the symptoms of essential thrombocytosis. Aspirin has historically been avoided in the treatment of thrombocytosis associated with myeloproliferative disorders, but low-dose therapy may be useful, particularly in occasional patients who have severe or recurrent thromboses. Survival with essential thrombocytosis is variable: some patients are highly resistant to therapy, suffering multiple and severe thrombotic or bleeding complications that lead to their premature death, whereas others enjoy long, symptom-free survival. Anagrelide, hydroxyurea, or interferon therapy may be used to suppress excessive platelet production.

Myelofibrosis with myeloid metaplasia may present primarily or as an end stage of other myeloproliferative disorders. Patients present with marked splenomegaly and hepatomegaly and have variable, but often decreased, circulating cell counts and a leukoerythroblastic peripheral smear with teardrop red blood cells, nucleated red blood cells, and immature myeloid cells. Myelofibrosis with myeloid metaplasia probably represents a proliferation of megakaryocytes with a secondary release of a factor or factors that stimulate fibroblast proliferation within the marrow, which “displaces” hematopoiesis to extramedullary sites producing both the characteristic organomegaly and the changes seen on peripheral smear. Treatment of myelofibrosis is disappointing, with only occasional, transient responses, and short survival. Patients with massive splenic enlargement may benefit from splenectomy or splenic irradiation.^[2]

[edit] Myelodysplastic Syndromes

The terms myelodysplastic and myeloproliferative are often confused. Whereas myeloproliferative disorders demonstrate proliferation of morphologically relatively normal-appearing cells, the myelodysplastic syndromes present an inherently different problem of abnormal maturation with typical cytopenias rather than cellular excess in the peripheral blood. As with the myeloproliferative disorders, the myelodysplastic syndromes originate in the transformation of a very early hematopoietic stem cell and typically have effects in multiple cell lineages. Because of the high frequency of acute leukemic evolution, these disorders are often referred to as preleukemic.

The median age of patients affected with myelodysplastic syndromes is 60 to 70 years old, although younger patients may occasionally present with similar abnormalities, particularly 5 to 10 years after intensive chemotherapy or radiotherapy for other malignant disorders. Presenting signs may be fatigue or weakness related to anemias, bleeding related to thrombocytopenia, and more infectious complications related to leukopenia. CBC and differential will frequently reveal cytopenias, and morphologic changes may include poorly granulated or hyposegmented neutrophils and hypochromic red cells, frequently with moderate to marked anisocytosis and poikilocytosis. Because of the marked maturation abnormalities, developing hematologic cells are incapable of normally completing their maturation sequence and thus accumulate in increased numbers within the marrow. Reflecting the preleukemic nature of this disorder, myeloblasts are often increased in number. Chromosome abnormalities are frequent with these syndromes, particularly those involving chromosomes 5, 7, 8, 17, and 21, and chromosomal analysis of marrow samples has become a mainstay of diagnosis.^[4]Box 119-3 summarizes the myelodysplastic syndromes.

[edit] Chronic Lymphocytic Leukemia

The proliferating cell of chronic lymphocytic leukemia (CLL) is a mature-appearing lymphocyte that is morphologically indistinguishable from its normal counterpart. The morbidity of CLL is rarely attributable directly to the malignant cell. Patients with CLL can tolerate white blood cell counts exceeding 1 million per mcl without leukostasis or other major direct sequelae. Rather, patients ultimately die either from cytopenias resulting from marrow replacement or, more frequently, from infectious complications resulting from disordered lymphocyte development or function. In contrast to the acute leukemias and to chronic myelocytic leukemia, survival in patients with CLL is frequently prolonged and may not be dramatically different from that age-matched controls in patients presenting at a relatively low stage.

Patients are typically over 60 years of age and are frequently discovered incidentally based on the differential obtained with a routine CBC. They may occasionally present with mild symptoms of peripheral lymphadenopathy, splenomegaly, fatigue related to anemia, or infectious complications. Demonstration of a monoclonal circulating B cell clone in excess of 5×10⁹ cells/L expressing the CD5 antigen makes a diagnosis of CLL. Although marrow evaluation is no longer required for diagnosis, establishment of the pattern of marrow involvement as nodular or diffuse provides important prognostic information.^[5] Additionally, where cytopenias are present, marrow evaluation may help distinguish their etiology as due to loss of marrow production vs. immune destruction.

In the absence of marked cytopenias, excessive adenopathy or organomegaly, or major symptoms of fatigue or infection, a simple policy of “watchful waiting” may be the most effective initial therapy. Once specific therapy is required, the traditional approach has been to combine an oral alkylator with prednisone in pulse or continuous therapy. More recently, fludarabine has been found to produce dramatic responses and is favored by some as initial therapy, particularly for patients with good performance status. The vast majority of patients with CLL are elderly and not good candidates for allogeneic bone marrow transplantation. The occasional younger patient presenting with this disease should be considered for such therapy because it offers the potential for a permanent cure, although the complication rate is high; investigational autologous stem cell transplantation approaches are currently in development.^[5]

[edit] Acute Leukemias

Acute leukemia can be considered a maturation arrest of an immature hematopoietic progenitor that rapidly proliferates and displaces normal elements within the marrow and peripheral blood. Classification schemes were historically based on morphologic and immunohistochemical criteria and divided the acute leukemias into lymphoblastic and nonlymphoblastic categories, depending on the presumed cell of origin. Monoclonal antibodies detecting specific cell surface markers have provided a more rapid and precise means of separating the various types of acute leukemia. Where possible, leukemias are increasingly classified on the basis of specific chromosomal or oncogene rearrangements.^[6][4][7] Classification schemes and treatment outlines for acute lymphoblastic and nonlymphocytic leukemia are summarized in Boxes 119-4 and 119-5.

Acute leukemias are rapidly fatal if not successfully treated, most often due to infections related to granulocytopenia or bleeding related to thrombocytopenia. Occasional individuals presenting with hyperleukocytosis, particularly of immature blasts, may develop leukostasis reactions in the pulmonary or cerebral circulations and require immediate leukapheresis. Patients with acute promyelocytic leukemia or the monocytic variants may present with DIC, necessitating factor transfusion and platelet support in the face of active bleeding. Immediate all trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia has substantially reduced the risk and morbidity of DIC, and significantly improved the prognosis of that disorder.^[7]

Patients with acute leukemias have high levels of spontaneous cell turnover, which increases after the institution of therapy. The sudden transfer of the intracellular contents and cellular breakdown products to the extravascular space can cause life-threatening elevations of uric acid, potassium, and phosphate in the so-called tumor lysis syndrome. Thus patients presenting with acute leukemia should be routinely initiated on fluid support and allopurinol therapy in anticipation of rapid application of definitive chemotherapy. Many patients may already be cytopenic, and aggressive antibiotic and transfusion support may need to be initiated even before a final diagnosis has been made.

Definitive treatment of acute leukemia requires aggressive chemotherapy, usually in a tertiary care center. Consolidating allogeneic bone marrow transplantation in first complete remission may be associated with long-term disease-free survival rates approaching 50% among appropriately selected patients, although newer protocols with autologous transplant or even high-dose ara-C without stem cell support as consolidation produce increasingly similar results, particularly in individuals with “good risk” cytogenetics.^[6][4]

[edit] Hodgkin's Disease

Hodgkin's disease probably represents a more diverse group of disorders than previously recognized. The Reed-Sternberg cell is the putative malignant cell without whose presence it is difficult or impossible to establish a diagnosis of Hodgkin's disease. The precise origin of this cell remains a subject of debate, and indeed it is possible that it may have different lineage derivations in the different subtypes of Hodgkin's disease.

Hodgkin's disease has a bimodal age distribution, with peaks in the second and third decades and then again in the sixth and seventh decades of life. Typical presentation is with cervical or axillary adenopathy or the detection of a medial mediastinal mass on chest x-ray. Patients may also frequently present with associated symptoms of fevers, night sweats, weight loss, or pruritus. The diagnosis is established by characteristic lymph node histology. Based on that histology, patients may be subcategorized as having lymphocyte-predominant, mixed cellularity, or lymphocyte-depleted disease. A separate category of Hodgkin's disease is the so-called nodular-sclerosing Hodgkin's in which bands of sclerosis are noted dividing the affected node into lobules; this has a somewhat better prognosis. The histologic classification is summarized in Box 119-6.

Spread is usually by lymphatic or hematogenous routes to contiguous lymphoid groups. Staging is largely based on physical examination; CT scans of the chest, abdomen, and pelvis; and bone marrow examination (Table 119-2). Lymphangiograms are used less often, while gallium scans are a newer and increasingly useful adjunct. Splenectomy is rarely performed now for staging.

Table 119-2 Staging Classification of Hodgkin's Disease (Modified Ann Arbor)

The more economic staging approaches, and in particular elimination of splenectomy, represent both an improvement in noninvasive diagnostic modalities and a shift in the basic paradigm of treatment for Hodgkin's disease. Although limited stage disease, especially IA and IIA, has been a traditional target for radiotherapy alone, there is increasing sentiment for the use of chemotherapy in essentially all patients with Hodgkin's disease. With newer combination chemotherapy regimens such as ABVD associated with better tolerance and less long-term side effects, most oncologists now advocate that limited stage disease be treated either with a truncated chemotherapy regimen combined with involved field radiation, or even with chemotherapy alone.

Advanced stage disease is still treated with full course chemotherapy, with adjunctive radiotherapy included for patients with bulky mediastinal disease or poorly resolving disease elsewhere. Long-term disease-free survival rates appear to be improved both for advanced and limited stage Hodgkin's disease with the more universal application of chemotherapy. Bone marrow transplantation may be useful in the treatment of relapsed disease.^[8]

There is an unfortunate increase in late secondary leukemias or solid malignancies complicating treatment for Hodgkin's disease, especially with older nitrogen mustard– based regimens and extensive irradiation ports. Secondary malignancies are also seen after stem cell transplantation. Patients must be closely counseled that even successful therapy will carry this risk, and appropriate screening measures should be instituted after successful primary therapy. This especially focuses on breast cancer screening for young women treated for Hodgkin's disease. Cardiovascular disease is also significantly increased after mediastinal irradiation for Hodgkin's disease.

[edit] Non-Hodgkin's Lymphoma

Non-Hodgkin's lymphomas are predominantly of B cell origin and typically present as adenopathy or an abdominal mass. Non-Hodgkin's lymphomas are classified based on morphology, immunophenotype, genetic features, and clinical characteristics. A recent revision of the classification system is summarized in Box 119-6 and anticipates the ultimate dissemination of a World Health Organization classification system to be published in the near future. Lymphomas were previously grouped into three broad clinical categories:indolent, intermediate, and highly aggressive. Better characterization of the clinical features of individual diagnostic categories shows a more heterogeneous outcome, and suggests that prognosis and treatment should be more individualized.

Approximately 20% of lymphomas are B cell follicular lymphomas constituting the bulk of the category previously referred to as indolent lymphomas, and typically present in older patients. Affected nodes are composed of relatively small, well-differentiated cells organized in a nodular pattern. Genetic analysis usually demonstrates the t(14:18) translocation with overexpression of bcl-2. Although slow growing, this group of lymphomas often present at an advanced stage because of the insidious symptoms associated with them. The indolent nature of these neoplasms usually results in relatively prolonged survival that may approach that of age-matched controls in selected patients.

Diffuse large B cell lymphoma constitutes 30% of Non-Hodgkin's lymphoma. Left untreated, the natural history of this aggressive subtype is more rapid, resulting in death within a short period of time, although a significant proportion of patients can be cured with chemotherapy. Lymphoblastic lymphoma, a T cell disorder, and the B cell–derived Burkitt's lymphoma are acute leukemia-like disorders whose onset tends to be explosive, with a high predilection toward involvement of the central nervous system (CNS) or other “sanctuary sites.” Their course rapidly progresses to death unless successfully treated.

Several new diagnostic categories have been developed to account for entities with unique genetic or clinical characteristics. Mucosal-associated lymphoid tumors (MALT) are frequently present in extranodal tissues and pursue a typically indolent course. Gastrointestinal presentations may be associated with Helicobacter pylori infection and remit with antibiotic therapy directed against that organism. Mantle cell lymphomas are B cell neoplasms previously grouped with the indolent lymphomas. They are typically associated with the t(11:14) translocation and overexpression of cyclin D1. Mantle cell lymphoma has an aggressive and relatively inexorable clinical course that is resistant to standard-dose chemotherapy. Anaplastic large cell lymphoma is a histologically aggressive–appearing T cell malignancy that overexpresses CD30 (Ki-1) but seems to respond quite well to standard lymphoma chemotherapy, particularly the variant associated with the t(2:5) translocation.^[8][9]

Non-Hodgkin's lymphomas have historically been staged in a manner analogous to that of Hodgkin's disease, although the lack of orderly spread and more unitary treatment approaches make that form of staging less useful in this context. The International Prognostic Index classification system, based on age, a more general distinction of localized vs. advanced disease, extent of extranodal involvement, performance status, and a biologic assessment of disease as reflected by serum LDH, has emerged as a more useful predictor of prognosis and guide to therapy,^[10] superseding the previous histologic distinction of indolent, intermediate, and aggressive.

Treatment is most dependent on histologic subtype, stage, and status of the patient. Patients who present with apparently localized follicular lymphoma after full staging may enjoy prolonged disease-free survival after regional irradiation. For the advanced stage follicular lymphomas, therapy is historically minimalistic and often delayed until necessary to treat symptoms.

Monoclonal antibody–based therapies targeted against the CD20 molecule expressed on the surface of many of these lymphomas have provided an interesting new treatment option. Monoclonal antibody treatment combined with aggressive chemotherapy produces very high response rates, although the effect on long-term survival has yet to be fully determined. The occasional low grade–lymphoma patient who presents at a young age or with very good performance status may benefit from autologous or allogeneic bone marrow transplantation, although the toxicities are potentially significant and cure rates disappointing.

In the treatment of the large B cell lymphomas, a recently completed large cooperative group trial indicated no difference between more involved, and toxic, regimens and the standard combination of Cytoxan, Adriamycin, vincristine, and prednisone (CHOP), which has re-emerged as primary therapy. Patients with limited stage disease are often treated with three cycles of CHOP followed by involved field irradiation; more advanced disease is treated with six to eight cycles of chemotherapy. Monoclonal antibody therapy and stem cell transplantation may be useful to treat relapse.

Although Burkitt's and lymphoblastic lymphomas may be very chemotherapy responsive, their aggressive growth and extensive nature make them more challenging to treat than the aggressive lymphomas. A fulminant treatment-related tumor lysis syndrome may precipitate renal failure, cardiac arrhythmias, or other serious sequelae. Younger patients with good initial organ function and performance status may enjoy good survival after treatment with intensive but relatively short course therapy with aggressive CNS prophylaxis patterned after successful pediatric protocols.^[8][9]

[edit] Myeloma and Related Plasma Cell Disorders

Myeloma is a disease of plasma cells, the terminally differentiated, immunoglobulin-secreting B cell. The classic presentation of myeloma is that of “punched-out” lytic lesions of the major marrow-containing bones, including the skull, proximal long bones, and axial skeleton, along with a monoclonal immunoglobulin spike detectable in the peripheral blood or urine. Plasmacytoma is a histologically similar plasma cell lesion presenting as a soft tissue mass.

Myeloma should be suspected in cases of pathologic fracture, unexplained anemia, unexplained renal failure, unexplained hypercalcemia, or unexpectedly severe osteoporosis, or with the detection of a monoclonal protein. Diagnosis is made by serum protein electrophoresis combined with marrow evaluation. Treatment includes chemotherapy and radiotherapy to skeletal lesions. Long-term survival is achievable with marrow transplantation in selected individuals.

Patients with low levels of monoclonal protein, less than 10% plasma cells in the marrow, and no other stigmata of myeloma such as lytic lesions or renal failure are labeled as having a “monoclonal gammopathy of unknown significance.” Most such patients are elderly at diagnosis and more often die of unrelated causes, although long-term survivors may evolve frank myeloma. Watchful waiting may be the most appropriate initial intervention.

[edit] STEM CELL TRANSPLANTATION

Bone marrow and stem cell transplantation are increasingly important therapies used in the treatment of hematologic malignancies. The general features of stem cell transplantation are summarized in Box 119-7.

Autologous transplant approaches are primarily a mechanism for chemotherapy dose escalation. The established role for autologous transplant is in the treatment of relapsed lymphoma, where a significant proportion of patients enjoy long-term disease-free survival. Selected patients with myeloma and acute nonlymphoblastic leukemia may also benefit from an autologous approach. The most common application of autologous transplant is in breast cancer, but its efficacy remains controversial. Ongoing clinical trials will hopefully better define the role of transplant there, although initial review suggests no dramatic improvement in survival.

Allogeneic transplant is an important option in the treatment of advanced malignant and nonmalignant bone marrow disorders. Chemotherapy and radiation dose escalation explain only a portion of the effects of allogeneic transplant; more important may be the replacement of marrow function from a new source, particularly the introduction of the donor immune system. Although this new immune functionality produces the primary danger of allogeneic transplant, graft-versus-host disease, the altered immune reactivity against residual malignant clones may explain their ultimate disappearance. Indeed, several centers are actively investigating the ability to introduce allogeneic transplants after much more modest preparative regimens, with interesting preliminary results. For patients who do not have appropriate sibling donors, unrelated donors or, especially for the pediatric population, cord blood transplantation may be an important alternative.^[11]

A final word regarding cord blood banking is in order. The rapid evolution and increasing application of stem cell transplantation has spawned a number of proprietary enterprises that will indefinitely bank cord blood collected at birth for possible autologous or other family use at a later date. Potential parents find themselves in an emotional dilemma when promotional materials from these companies suggest that they may harm the prospects for their child if they do not bank the cord blood.

Although many individuals are indeed destined to contract a malignancy at some point in their lives, the subset who would actually benefit from autologous transplant is only a small fraction of those who have cancer. The expense of banking, the small likelihood of the later use of the cells, the increasing availability of alternate-treatment means, and the unknown durability of the technologies of storage make a recommendation of cord blood banking seem ill-advised in all but the very affluent for whom the investment in this procedure will not divert much-needed funds from more fruitful uses.

[edit] REFERENCES