Acute lymphoblastic leukemia and lymphoblastic lymphoma encompass different clinical presentations of similar disease entities that are defined by the unbridled proliferation of immature lymphoid cells referred to as lymphoblasts. Acute lymphoblastic leukemia presents in the bone marrow and the peripheral blood, whereas lymphoblastic lymphoma presents as a mass within the bone or soft tissues. These different clinical manifestations relate in part to the origin of the tumor. B-cell tumors almost always arise in the bone marrow (where B cells develop) and present as "leukemias," whereas T-cell tumors often arise in the thymus (where T cells develop) and present as lymphomatous masses. For simplicity we will discuss these two forms of the disease together under the rubric of acute lymphoblastic leukemia/lymphoblastic lymphoma, or ALL.
ALL is the most common cancer of children. There are about 2500 to 3000 new cases of pediatric ALL in the United States per year. The disease also occurs throughout life in adults but makes up a much smaller fraction of the cancer burden in this segment of the population. The factors leading to the pathogenic mutations that drive ALL development are unknown. It most commonly appears sporadically in previously healthy, normal children. There are two major ALL subdivisions, ALL of B-cell origin (B-ALL) and ALL of T-cell origin (T-ALL). These two types of ALL are morphologically identical but differ in terms of their clinical characteristics, immunophenotype, and genetics.
B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOBLASTIC LYMPHOMA
B-ALL is the most common type of ALL, comprising roughly 85% of cases. The peak incidence is about age 3 years, which closely coincides with the time of peak bone marrow production of B cells during life. Groups that are at relatively increased risk include children of White or Hispanic origin as well as those with Down syndrome (trisomy 21).
The most common clinical features in B-ALL are related to the replacement of the marrow by lymphoblasts and the resulting pancytopenia. The patient usually presents acutely with several weeks of fatigue or listlessness due to increasing anemia, often accompanied by easy bruising due to thrombocytopenia. Neutropenia may lead to infection, producing fever and sometimes localizing signs. Inspection of the peripheral blood film reveals the presence of lymphoblasts, which may be few or numerous, as well as anemia, thrombocytopenia, and granulocytopenia of variable severity. Unusual patients with lymphomatous presentations may complain of pain in a single long bone or come to attention due to involvement of the skin. B-ALL tends to spread via the meninges to the central nervous system and also may involve other immunologically privileged sites such as the ovary and testis. Splenomegaly, hepatomegaly, and lymphadenopathy may also be present due to tumor infiltration, but these features are usually not prominent.
The diagnosis can be strongly suspected based on morphologic inspection of the blood or the marrow. By definition, the diagnosis in those with leukemic presentations requires that lymphoblasts, cells with fine chromatin, small nucleoli, and scant agranular cytoplasm (Fig. 21-2), comprise at least 25% of the marrow cellularity. However, definitive diagnosis requires immunophenotyping, which is usually carried out by flow cytometry. The tumors cells are positive for terminal deoxynucleotidyl transferase (TdT, an enzyme that is expressed only in immature B and T cells) and certain B-lineage proteins such as CD19, and negative for surface immunoglobulin, which appears only on mature B cells (Fig. 21-3). In unusual lymphomatous presentations, the neoplastic nature of the process is obvious from the effacement of normal tissue by sheets of lymphoblasts, and the diagnosis is usually established by performance of immunohistochemistry on tissue sections. The principal diagnostic difficulties arise in children with severe viral infections, in which the immune response may increase the production of normal precursor B cells in the bone marrow while suppressing hematopoiesis, sometimes resulting in modest granulocytopenia. It is usually not difficult to distinguish such processes from B-ALL because reactive populations of lymphoblasts include cells from all stages of early B-cell development and never replace the marrow. In contrast, neoplastic lymphoblasts tend to have a uniform immunophenotype representing one or another stage of early B-cell development.
B-cell acute lymphoblastic leukemia, bone marrow aspirate smear. All of the nucleated cells are lymphoblasts with irregular nuclei, coarse chromatin, and scant amounts of agranular blue cytoplasm.
Flow cytometric findings, B-acute lymphoblastic leukemia (B-ALL). The cells are positive for CD19 (a marker expressed on all B-lineage cells), terminal deoxynucleotidyl transferase (a marker expressed by precursor B and T cells), and CD34 (a hematopoietic stem cell marker present on immature cells) and are negative for kappa and lambda immunoglobulin light chains (which are expressed by mature B cells) and the myeloid marker CD33. This combination of markers is diagnostic of a tumor of precursor B cells.
Subtyping of B-ALL is based on cytogenetics, and particular cytogenetic abnormalities are strongly predictive of clinical outcome; for these reasons, cytogenetic studies should be obtained in all patients with ALL. The most common abnormalities, the involved genes, and their clinical correlates are listed in Table 21-2. Of note, B-ALL associated with BCR-ABL fusion genes, rearrangements of the MLL gene, or hypodiploidy are associated with poor outcomes with conventional therapies. Outcomes are also worse for patients under 1 or over 10 years. This is partly due to age-dependent differences in the frequency of particular cytogenetic abnormalities (Table 21-2). High white cell counts are also associated with worse outcomes, possibly because they identify patients with unusually high tumor burdens. Overall, B-ALL in children has an excellent prognosis, with complete remissions being obtained in >95% and cures in 75% to 85% of patients. In adults the outcome is more guarded, with cures being obtained in a minority of patients.
TABLE 21-2Major Cytogenetic Subtypes of B-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma ||Download (.pdf) TABLE 21-2 Major Cytogenetic Subtypes of B-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
|Cytogenetic Abnormality ||Involved Genes ||Mechanism of Activity ||Frequency ||Prognosis |
|t(12;21) ||TEL-AML1 ||Chimeric transcription factor that interferes with AML1 function ||25% in children; rare in adults ||Excellent |
|Hyperdiploidy (>50 and <66 chromosomes) ||Unknown ||Unknown ||25% in children; rare in adults ||Excellent |
|Hypodiploidy (<45 chromosomes) ||Unknown ||Unknown ||1%-5%, children and adults ||Poor |
|t(9;22) ||BCR-ABL ||Constitutively active tyrosine kinase ||3% in children, 25% in adults ||Poor |
|t(11q23;v) ||MLL and many other genes ||Chimeric transcription factor that alters MLL function ||Most common subtype in infants; rare in older children ||Poor |
T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOBLASTIC LYMPHOMA
T-ALL makes up roughly 15% of ALL. The peak incidence is at about age 15 years, which coincides roughly with the age at which the thymus reaches its greatest size. For unknown reasons, there is a 2:1 male predominance. About two-thirds of T-ALL present as mediastinal lymphomas associated with large masses centered in the thymus, the organ that gives birth to normal T cells. The enlarging tumor mass often compresses structures such as the major airways and blood vessels, producing cough, shortness of breath, and superior vena cava syndrome, which is characterized by swelling and redness of the face and upper extremities due to blockage of venous return to the heart. The remaining third of cases present with predominantly bone marrow involvement and a leukemic picture identical to that seen with most B-ALL. T-ALL shows a somewhat greater tendency than B-ALL to produce organomegaly and lymphadenopathy, and like B-ALL, often spreads to the central nervous system.
The diagnosis is based on morphologic demonstration of lymphoblasts effacing tissues such as the thymus or bone marrow (Fig. 21-4). As in B-ALL, immunophenotyping is essential to confirm the diagnosis. T-ALL expresses terminal deoxynucleotidyl transferase and variable combinations of T-lineage antigens such as CD1a, CD3, CD4, and CD8 (Fig. 21-5). Unlike in B-ALL, cytogenetics has not proved helpful in predicting patient outcome. In addition to very common activating mutations in NOTCH1, other genetic mechanisms that induce T-ALL include chromosomal rearrangements or other aberrations that lead to increased expression of several other transcription factors, including TAL1, LMO1, and LMO2. Many of these dysregulated factors appear to interfere with the activity of E2A, a transcription factor that is required for proper B- and T-cell development. Activating mutations in tyrosine kinases are being sought but appear to be uncommon, and the identity of the class 1 mutations in most T-ALLs is uncertain. T-ALL also very commonly has loss-of-function mutations in CDKN2A, a complex locus on chromosome 9q that encodes two tumor suppressors, ARF, which inhibits p53, and p16, which inhibits several kinases that promote cell division.
T-lymphoblastic lymphoma, thymus. The tissue is effaced by a population of lymphoblasts with oval nuclei, speckled chromatin, and scant cytoplasm. Mitotic figures are present.
Flow cytometric findings, T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) by flow cytometry. Staining with a panel of antibodies reveals a population of cells that uniformly expresses the T-cell marker CD3 and is partially positive for terminal deoxynucleotidyl transferase, a marker of precursor B and T cells. In contrast, the cells are negative for the pan-B- cell marker CD19. These findings are consistent with a proliferation composed of immature T-cell progenitors.
In the past, T-ALL was considered to have a poorer prognosis than B-ALL, but with newer chemotherapy regimens, this difference no longer holds. Overall, 75% to 80% of T-ALL patients in the pediatric age group are cured, whereas the cure rates in adults are in the 40% to 50% range.
ALLs, regardless of molecular subtype, are very aggressive tumors with high growth rates and a proclivity to infiltrate many different organs. Unless effective therapy is given, patients succumb to the disease in weeks to a few months, usually due to complications related to bone marrow failure. Currently, childhood B-ALL and T-ALL are treated with an identical regimen that has several phases. The initial goal is to induce remission and clear the central nervous system of any infiltrating lymphoblasts. This is achieved with high doses of intravenous and intrathecal1 chemotherapy, sometimes with cranial irradiation as well. Several studies have shown that complete clearance of the tumor at the end of induction (4 weeks), as assessed by either very sensitive flow cytometry or PCR-based assays, predicts whether patients will remain in remission, independent of other risk factors. Remission is then consolidated with multiple rounds of high-dose chemotherapy, which is followed with daily low-dose maintenance chemotherapy for up to another 2 to 2.5 years. Young adults also respond well to this very intensive pediatric treatment regimen. It remains to be seen whether use of intensive regimens in selected older adults will also be beneficial.
Along with therapy directed toward the malignant blast cell, supportive measures to prevent complications that are caused or exacerbated by chemotherapy are essential components of treatment. These consist of:
Transfusions of both red cells and platelets, to reverse cytopenias stemming from leukemia and chemotherapy-induced myelosuppression.
Careful monitoring for signs and symptoms of infection. In the setting of neutropenia, fever is often the only sign of bacterial or fungal infections, which can be rapidly fatal. Febrile patients require immediate culturing of blood and other body fluids followed by prompt treatment with broad-spectrum antimicrobial agents.
Meticulous attention to fluid, electrolyte, and acid-base balances. Highly proliferative lymphoblasts are rapidly killed and lysed by chemotherapy, releasing large amounts of metabolites and electrolytes such as uric acid, potassium, and phosphate. These substances must be carefully monitored, and appropriate measures must be taken to prevent toxic buildup during treatment. For example, uric acid released into the blood and filtered by the kidney may precipitate in the renal tubules, leading to acute renal failure. This complication can be prevented by allopurinol, a drug that blocks the conversion of the soluble purines hypoxanthine and xanthine to poorly soluble uric acid.
Psychological support and encouragement for both the patient and the family. It is essential that caregivers provide clear and unambiguous information, allay fears, and foster hope throughout the arduous and prolonged period from the time of diagnosis through the completion of therapy.
Unconventional therapies are needed for ALL patients with cytogenetic abnormalities that predict a poor prognosis, and for those who either fail to go into remission, or recur during therapy or after therapy is completed. These alternative approaches include intensified chemotherapy and bone marrow transplantation, which is the treatment of choice for patients with B-ALL associated with BCR-ABL fusion genes or MLL gene rearrangements. Imatinib and dasatinib, tyrosine kinase inhibitors that are effective in chronic myelogenous leukemia and other myeloproliferative disorders, also have been used in patients with BCR-ABL-positive B-ALL. Most tumors respond well to tyrosine kinase inhibitors initially but recur within a few months. Analysis of recurrent tumors usually shows the presence of BCR-ABL mutations that confer resistance to these inhibitors, indicating that the growth of the tumor still depends on signals generated by BCR-ABL. Recent studies have shown that administration of tyrosine kinase inhibitors in combination with conventional chemotherapy agents produces sustained remissions in most patients with BCR-ABL-positive B-ALL, and it appears that at least some of these patients may be cured.