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1030 Part VII Hematologic Malignancies

TABLE Initial Evaluation of a Patient With Acute Several metabolic abnormalities are present at the time of diagnosis
66.1 Lymphoblastic Leukemia and frequently reflect tumor burden. For example, LDH levels are
frequently elevated, and almost 50% of the patients have levels
• Complete history (including family history) between 300 and 1000 U/L. Elevated serum levels of calcium, potas-
• Physical examination sium, and phosphorous have been noted. More importantly, elevated
• CBC with differential serum uric acid levels are frequently present and reflect tumor burden.
• Comprehensive metabolic profile, including LFTs Hyperuricemia needs to be carefully monitored and aggressively
• LDH, uric acid corrected to avoid renal failure, especially at the time of starting
• Coagulation profile induction therapy.
• BM aspiration and biopsy (morphology, immunohistochemistry, flow
cytometry, molecular and cytogenetic analysis)
• HLA typing of the patient (if a potential aSCT candidate) MORPHOLOGY
• Lumbar puncture
• Chest radiography or CT imaging of the chest Romanowsky-based stains such as Wright Giemsa and Giemsa
aSCT, Allogeneic stem cell transplantation; BM, bone marrow; CBC, complete provide the greatest cytoplasmic detail for evaluation of cytomorphol-
blood count; CT, computed tomography; HLA, human leukocyte antigen; LDH, ogy of the cells in the peripheral blood smear, BM aspirate smear,
lactate dehydrogenase; LFT, liver function test. and touch imprints (Fig. 66.1). Most frequently, lymphoblasts are
small to intermediate in size and have scant, agranular cytoplasm. B
lymphoblasts are morphologically indistinguishable from T lympho-
blasts, and this distinction relies on immunophenotyping. The nuclei
blood if lymphoblasts are present) to the molecular oncology diag- are usually round, with uniformly dispersed “smudgy” chromatin and
nostic laboratory to evaluate for the presence of the BCR-ABL fusion inconspicuous nucleoli (see Fig. 66.1C). However, variations in
transcript using reverse-transcriptase polymerase chain reaction morphology are common, and larger cells with abundant bluish gray
because these patients will receive frontline therapy that includes a cytoplasm, larger, somewhat irregular nuclei, and variably prominent
tyrosine kinase inhibitor (TKI). nucleoli can be frequently seen (see Fig. 66.1D). Even though the
A lumbar puncture should be performed at diagnosis to determine nuclear chromatin of these cells can be fine, it is never as finely dis-
CNS involvement. In the event of increased risk of bleeding caused persed as in a myeloblast. At the other end of the morphologic
by severe thrombocytopenia or risk of cerebrospinal fluid contamina- spectrum are smaller cells with uniformly condensed, mature
tion caused by high peripheral blood blasts, the lumbar puncture lymphocyte-like chromatin (see Fig. 66.1E), and distinction from
should be performed by an experienced operator. It is prudent to mature B-cell malignancies relies on immunophenotyping. Coarse
administer intrathecal chemotherapy at the time of the diagnostic azurophilic granules (see Fig. 66.1F) can be seen in a subset of blasts
lumbar puncture after obtaining the necessary samples. in 5% to 8% of childhood ALLs and even more frequently in adult
ALL patients. These have been reported in association with Philadel-
+
phia chromosome-positive (Ph ) ALL and in ALL in Down syndrome
APPROACH TO DIAGNOSIS patients. The granules are coarser than the granules seen in myelo-
blasts and are invariably myeloperoxidase negative (see later discussion
While evaluation of morphology and immunophenotype are suffi- of cytochemistry). Morphologic distinction between the L1 and L2
cient for making the diagnosis, current risk stratification relies on category recommended in the French–American–British (FAB) clas-
additional cytogenetic and molecular genetic information. Data from sification has proven to be poorly reproducible and of little prognostic
these tests is therefore an important adjunct to the initial diagnostic value. It has been abandoned in the current World Health Organiza-
work up. tion (WHO) classification.
Initial laboratory evaluation starts with a CBC and morphologic Cytoplasmic vacuolation (see Fig. 66.1H) can be seen in as many
evaluation of a Giemsa-stained peripheral blood smear. An abnormal- as 28% of childhood ALL patients. These lymphoblasts can be dis-
ity of at least one of the CBC parameters is detected in more than tinguished from leukemic presentation of BL (see later discussion)
90% of ALL patients at the time of diagnosis. Anemia and throm- based on other morphologic features such as a smaller cell size, lack
bocytopenia are common. The anemia is usually a normochromic, of deep blue cytoplasm, and less coarse chromatin. However, when
normocytic anemia accompanied by reticulocytopenia. The hemoglo- morphology is confounding, the distinction relies on immunophe-
bin levels range from 30−174 g/L, and almost 50% of the patients notyping of the malignant cells. In contrast to BL cells, ALL blasts
have hemoglobin levels below 100 g/L. The median platelet count at are precursor B cells that express terminal deoxynucleotidyl transferase
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presentation is approximately 55–60 × 10 /L, and almost 60% to (TdT) and lack surface immunoglobulin (Ig) expression (see later
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70% of patients have platelet counts below 100 × 10 /L. Although discussion).
the total white blood cell (WBC) count may be low, normal or ele- The trephine biopsy sections show hypercellular BM (Fig. 66.2).
vated, neutropenia is commonly present. In a Cancer and Leukemia The sections are evaluated after staining with hematoxylin and eosin.
Group B (CALGB) study, the median WBC count at presentation The BM is usually packed with a relatively uniform population of
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was 19.3 × 10 /L. Almost one-third of the patients are likely to small round blasts with round to oval nuclei. Less frequently, the
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present with WBC count greater than 30 × 10 /L. Blasts account for blasts can be more pleomorphic, with indented, convoluted, and
a variable proportion of the circulating WBCs, and the percent blast variably sized nuclei. The chromatin is described as being finely
population can range from 0% to 100%. A leukoerythroblastic dispersed or stippled and the nucleoli are usually not conspicuous.
picture can sometimes be seen. In an extreme form, immature Brisk mitotic activity is almost always present. The effacement of the
myeloid precursors and myeloblasts constitute the vast majority of BM space is almost complete and uniform at the time of initial
cells in the peripheral blood. This should be kept in mind when presentation. Minimal residual hematopoiesis is present; in most
attempting to make a diagnosis exclusively from peripheral blood. instances this is represented by a few megakaryocytes and some
Eosinophilia as a presentation of ALL is extremely uncommon and erythropoiesis. Normocellular or even hypocellular BMs at presenta-
is seen in association with specific chromosomal abnormalities, tion have been described but are uncommon. Rarely, the initial
including t(5;14)(q31;q32) or, even less frequently, with 8p11- presentation of ALL can be with an aplastic or markedly hypocellular
associated ALL. Eosinophilia associated with t(5;14) is reactive and BM. Making the diagnosis in this hypocellular context can be par-
due to overexpression of interleukin-3 on chromosome 5 driven by ticularly challenging because of a paucity of material available for
the immunoglobulin H (IgH) promoter on chromosome 14. The supporting studies such as cytogenetics and immunophenotyping.
eosinophilia can be extremely pronounced and mask the blast popula- BM biopsy can show partial or complete necrosis (see Fig. 66.2C).
tion in this subset of patients. When extensive necrosis is present, making a diagnosis can be