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1336 Part VII Hematologic Malignancies

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and the treatment is identical in children. Outcomes for pediatric
DLBCL are superior to those for adults, with 5-year overall survival
(OS) of 90% for current therapies. Adolescent girls fared worse
28
than adolescent boys with DLBCL on NHL-BFM protocols.
BCL2 expression is not an unfavorable prognostic factor in children
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with DLBCL, in contrast to adults with DLBCL. Prognosis is
poorer for children and adolescents with PMBCL (5-year EFS of
65% to 75%). 48,75 In the setting of PMBCL, LDH of 500 U/L
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or more has a worse prognosis. For adult patients with PMBCL,
favorable outcome was reported using a dose-adjusted EPOCH-
rituximab regimen with continuous infusions of etoposide, doxo-
rubicin, vincristine, and bolus administrations of cyclophosphamide
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and prednisone. In a small pediatric series, similar excellent
results were observed, but they require systematic prospective
validation. 78
Therapy
In children, all mature B-cell lymphomas are usually treated similarly Fig. 84.2 HISTOLOGIC AND IMMUNOPHENOTYPIC FEATURES
with good results. Despite biologic and clinical differences, BL OF ANAPLASTIC LARGE-CELL LYMPHOMA. The section shows ana-
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therapy is effective in DLBCL (Table 84.6). Risk-adapted therapy plastic cells including a “wreath cell” and a staining pattern with bright CD30
with LMB (SFOP) or B-NHL (BFM) backbones consists of short, (Ki-1) positivity (top right) and anaplastic lymphoma kinase (ALK) positivity
dose-intense courses of chemotherapy including steroids, vincristine, (bottom right). The nuclear and cytoplasmic staining by ALK would predict
high-dose methotrexate, cyclophosphamide, doxorubicin, cytarabine, that the case has the t(2;5) translocation.
etoposide, and intrathecal chemotherapy. 42,57,60,79 As described for BL,
risk-adapted therapy based on FAB/LMB-96 and NHL-BFM 95 are
also the current standard of care for childhood DLBCL. 57,59,60 Ritux-
imab can improve adult outcomes for DLBCL when added to CHOP on chromosome 2p23. The hybrid protein produced from the
or CHOP-like therapy, but the benefit has not been proven in translocation links the amino terminus of NPM with the catalytic
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children. 80–82 Adult data suggest that rituximab may allow diminished domain of ALK. Deregulated expression of the truncated ALK may
use of agents with serious acute or late toxicities, warranting further contribute to malignant transformation. The chimeric NPM-ALK
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study. Having evolved from BL regimens, DLBCL treatment has protein is clearly oncogenic, perhaps through triggering of antiapop-
traditionally included intrathecal chemotherapy for CNS prophylaxis. totic signals via phosphatidylinositol 3-kinase/Akt, although second-
Because the risk of CNS involvement is lower for DLBCL than for ary molecular events may be required for lymphomagenesis.
BL, it is unclear if CNS-directed therapy should be as intensive. 24,68 Immunologic and molecular biologic studies reveal that most
+
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Local radiation has no role in frontline DLBCL therapy. As men- cases of Ki-1 ALCL are derived from activated T cells, although
tioned above, the optimal treatment strategy for PMBCL has not non-T, non-B cell (null cell) cases, and more rarely B cell cases,
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been established yet, but might be influenced by the preliminary occur. On the basis of extended testing for T-cell antigens and
favorable results with DA-R-EPOCH. examination of the configuration of T-cell receptor genes, many
“null” cell cases are, in fact, T-lineage neoplasms, although a minority
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may be derived from NK cells. The diagnosis of ALCL can be
Anaplastic Large Cell Lymphoma difficult, and many cases are initially misdiagnosed as Hodgkin
disease. Molecular techniques (reverse-transcriptase polymerase chain
Epidemiology reaction [RT-PCR]) to detect the fusion gene produced of the t(2;5)
in many cases of ALCL confirms the diagnosis. Variant translocations
Most childhood NHLs previously classified as large-cell lymphomas where ALK is involved with other partner genes on other chromo-
fall into the category of ALCL in the REAL and WHO classifications. somes limit the application of RT-PCR for diagnosis. However, the
This entity was first described in 1985 as a clinicopathologic variant t(2;5) results in the expression of the NPM-ALK fusion protein,
of large-cell lymphoma with a predilection for young patients. 83 whereas the variant translocations result in upregulation of ALK. The
ALK1 monoclonal antibody recognizing the formalin-resistant
Pathobiology epitope of both the NPM-ALK chimeric protein and normal ALK
ALCL are characterized by the proliferation of large, pleomorphic thus serves as a useful diagnostic reagent for identifying cases of
cells with one or more prominent nucleoli (Fig. 84.2). The cells ALCL. It should be noted that the distribution of ALK staining
preferentially involve lymph node sinuses and extranodal sites varies, depending on the translocation. Further, ALK expression is a
(notably skin, bone, and soft tissue), where they grow in a cohesive feature of inflammatory myofibroblastic tumors; however, confusion
pattern. The cells express epithelial membrane antigen and CD30 with ALCL can be minimized by testing for other hematopoietic
(Ki-1) antigen, a 120-kDa membrane-bound molecule that is a markers, and the distinction is not usually difficult for experienced
member of the tumor necrosis factor receptor superfamily, previously pathologists.
found in association with Hodgkin disease. A soluble (88-kDa) form
of the CD30 molecule is found at high levels in the serum of nearly Clinical Manifestations
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all patients with ALCL. Marked elevation of soluble CD30 levels ALCL is rare, accounting for approximately 8% to 13% of childhood
in patients with ALCL correlates with higher risk of relapse, and NHLs and roughly 30% to 40% of the pediatric large-cell lympho-
soluble CD30 levels correlate with clinical disease status, returning mas. Approximately one-third of the cases present with localized
to normal with attainment of complete remission and increasing with disease, whereas the majority have advanced disease at presentation,
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disease recurrence. although BM and CNS involvement is uncommon. A rare leukemic
The ALCL are associated with chromosomal rearrangements presentation of ALCL possibly associated with the small-cell variant
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involving the long arm of chromosome 5 at position q35. In most of ALCL has been described. Systemic symptoms (fevers, weight
cases, this translocation includes material from chromosome 2p23 loss) are frequently present in advanced-stage disease. Cutaneous
[t(2;5)(p23;q35)], resulting in the fusion of the nucleophosmin (spontaneously regressing) lesions sometimes accompany disease at
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(NPM) nucleolar phosphoprotein gene on chromosome 5q35 to other sites, but skin involvement is not universal. A variety of pre-
anaplastic lymphoma kinase (ALK), a tyrosine kinase gene senting sites—both nodal and extranodal—can occur, including the