Malignant Lymphomas in Childhood

Introduction

It is an ongoing discussion whether LBL and ALL are two clinical presentations of the same disease or two different diseases. Patients with a mass and fewer than 25% bone marrow lymphoblasts are designated as LBL, whereas patients with at least 25% bone marrow involvement have ALL. In contrast to ALL, more than 75% of LBL demonstrate a precursor T-cell immunophenotype (T-LBL), with the remainder showing a precursor B-cell immunophenotype (pB-LBL).

Epidemiology

LBL constitutes 22% to 28% of childhood NHL. There is a 2:1 male predominance for LBL, but the incidence of LBL remains constant across the pediatric age group for both boys and girls.

Pathobiology

LBL arises from precursor T- or B-lymphoblasts at varying stages of differentiation. Morphology is similar to that of ALL, with lymphoblasts of small or medium size and with scant cytoplasm, round or convoluted nuclei, fine chromatin, and indistinct or small nucleoli. Immunophenotyping shows terminal deoxynucleotidyl transferase (TdT) positivity. T-LBL is usually positive for CD7 and surface or cytoplasmic CD3, with variable expression of CD2, CD5, CD1a, CD4, and CD8. Stains for TdT, CD3, MPO, and a B-cell marker like pax5 or CD79a are recommended parts of a resource-saving diagnostic staining panel. CD10 expression is more frequent in T-LBL (40%) than T-ALL (less than 10%), possibly related to the maturational stage, with T-ALL more frequently demonstrating an immature phenotype. B-lineage markers are positive in B-LBL. Similar to ALL, cases with mixed phenotypes are reported but interestingly not associated with inferior outcome. Unlike ALL, there are no known cytogenetic prognostic factors for LBL. Recurrent cytogenetic anomalies are seen in about half of childhood T-ALL but have not been well-defined in T-LBL. Literature is scarce regarding typical chromosomal aberrations for T-LBL. The commonest chromosomal translocations for both T-LBL and T-ALL involve the T-cell receptor ( TCR ) gene loci at chromosome 14q11 or 7q34. Certain molecular genetic alterations were analyzed in relevant patient series of pediatric T-LBL including NOTCH1 , FBXW7, PTEN alterations, PIM1 variants, alterations of chromosome 9p containing CDKN2A/CDKN2B loci, and chromosome 6q. A recent targeted sequencing study of a relevant series of pediatric T-LBL confirmed NOTCH1 as the putative driver for T-LBL resulting in an activated NOTCH/PI3K-AKT signaling axis. In addition, alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. The mutational status of KMT2D was identified as a prognostic marker. The ongoing international clinical trial LBL 2018 (NCT04043494) introduced a new stratification system taking into account the mutational status of NOTCH1 and FBXW7 . In parallel, the trial will allow prospective systematic validation of the prognostic relevance of individual markers or marker combinations to be translated into future trials.

Clinical Manifestations

The clinical features at presentation vary with primary site and extent of disease spread. Almost all patients with T-LBL frequently present with an anterior mediastinal mass that may cause respiratory symptoms, airway compromise, dysphagia, or superior vena cava syndrome (see Fig. 88.1D ). Pleural effusions are common (75%), and lymphadenopathy above the diaphragm is frequent. Bone, skin, bone marrow, central nervous system (CNS), abdominal organs, other lymph nodes, and occasionally testes may also be involved. Children with B-LBL are less likely to present with a mediastinal mass, but there is a higher frequency of cutaneous, soft tissue, or bone involvement with pB-LBL. CNS involvement at diagnosis is seen in 4% to 5% of patients with LBL.

Differential Diagnosis

LBL is distinguished from ALL by having less than 25% bone marrow involvement defined by cytomorphology of bone marrow smears and from myeloid malignancies being positive for TdT and T- or B-cell markers and negative for myeloperoxidase and additional myeloid markers. T-LBL and B-LBL are differentiated by flow cytometry or immunohistochemistry. In cases of insufficient biopsy material or incomplete diagnostic staining, LBL is sometimes misdiagnosed (e.g., as Ewing sarcoma or other small-, round-, blue-cell tumors).

Prognosis (Staging)

After obtaining malignant effusion or tissue diagnosis, staging is performed with imaging (ultrasound of the abdomen, lymph nodes and testes, and magnetic resonance imaging or computed tomography of involved sites), bilateral bone marrow evaluation, and lumbar puncture. Bone scans are only done if clinically indicated. Childhood NHL, including LBL, is most commonly staged using the Murphy classification previously and now by the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) ( Table 88.2 and 88.3 ).

With current therapies based on ALL protocols, LBL has a long-term survival greater than 90% in low-stage disease and greater than 80% in advanced-stage disease ( Table 88.4 ). The Children’s Oncology Group demonstrated that minimal disseminated disease at diagnosis has prognostic value, as indicated by flow cytometric evidence of tumor cells in bone marrow. The prognostic impact of minimal disseminated disease at diagnosis and minimal residual disease is under evaluation. On NHL-BFM trials, adolescent females with T- LBL had poorer outcomes than adolescent males despite similar presenting characteristics. One adult study for T-cell ALL has demonstrated poorer outcomes in females than males, but a prognostic impact of gender has not been found in other pediatric or adult studies for LBL. While adolescent age itself has not been established as a poor prognostic factor as it has for ALL, adult outcomes for LBL are inferior to pediatric outcomes.

Therapy

Two potentially life-threatening situations requiring urgent intervention must be considered in children with LBL: (1) mediastinal tumor with airway obstruction or superior vena cava syndrome, and (2) tumor lysis syndrome. Due to the cardiac and respiratory risks of anesthesia or sedation in children with a large mediastinal mass, the least invasive procedure should be chosen to establish a diagnosis. In children with relevant pleural effusion, pleural puncture and morphologic combined with immunologic diagnostics by flow cytometry allow adequate diagnosis. In children with peripheral lymphadenopathy, lymph node biopsy under local anesthesia may be possible. In children who cannot tolerate a procedure, pretreatment with steroids may be necessary to stabilize the patient. Since pretreatment may diminish the ability to accurately diagnose a patient, a tissue diagnosis should be obtained as soon as it is possible to do so safely. Tumor lysis syndrome is characterized by metabolic consequences of the breakdown of lymphoma cells, causing renal failure if severe. Hyperuricemia, hyperkalemia, and hyperphosphatemia must be aggressively managed by hyperhydration, rasburicase and/or allopurinol, and close monitoring. Children with NHL can also present with epidural masses and associated neurologic deficits caused by spinal cord compression. If the diagnosis is known, chemotherapy should be started as soon as possible. If the diagnosis is not known, or if there is a sluggish response to chemotherapy, low-dose radiation therapy may be considered in consultation with a radiation oncologist.

ALL treatment strategies achieved favorable outcomes in LBL and are accepted as standard treatments as (e.g., the Berlin-Frankfurt-Münster [BFM]) combination chemotherapy with induction, consolidation, and maintenance phases lasting a total of 24 months with 90% 5-year event-free survival (EFS). Even patients with stage III and IV LBL had good outcomes on ALL-type therapy. This ALL-like therapy has now become standard for LBL (see Table 88.4 ). CNS prophylaxis is needed for LBL, but chemotherapy prophylaxis has not proven inferior to prophylactic cranial irradiation in CNS-negative patients, even with advanced-stage disease. Additionally, recent studies did not demonstrate a survival advantage of high-dose methotrexate for T-LBL. Unfortunately, outcome is still poor for patients suffering LBL relapse.

Introduction

Burkitt lymphoma (BL) was first described by Dennis Burkitt in the 1950s in Uganda. First thought to be endemic to equatorial Africa, it was subsequently observed in Europe and North America. The WHO classification recognizes three variants: (1) sporadic BL, occurring throughout the world and more common in children, adolescents, and young adults; (2) endemic BL, occurring primarily in sub-Saharan Africa and New Guinea, with some unique clinical features but morphologically identical to sporadic BL; and (3) immunodeficiency-associated BL, observed primarily in HIV patients and less commonly in the setting of other immunodeficiencies. Burkitt-like lymphoma with 11q aberration is introduced as a provisional lymphoma entity in the 2017 revision of the WHO classification. When there is marrow involvement of more than 25%, it is designated Burkitt leukemia (FAB L3 leukemia) but is treated similarly to BL.

Epidemiology

Sporadic BL constitutes approximately 50% of childhood NHL and is much more common in boys than girls (ratio 4:1), with a peak incidence between 5 and 14 years of age. Endemic BL associated with Epstein-Barr virus (EBV) in more than 85% of cases accounts for approximately half of all childhood cancers in equatorial Africa. In contrast, sporadic BL is most common in the United States and Europe and is associated with EBV in only 10% to 15% of cases.

Pathobiology

BL is composed of monomorphic, small, noncleaved cells with round nuclei, clumped chromatin, and basophilic cytoplasm. A high uniform proliferation index is seen, with the Ki-67 positivity approaching 100%. The classic “starry sky” appearance of BL seen under low power microscopy is caused by tingible body macrophages scattered among malignant cells. BL cells show mature B-cell features and usually express surface immunoglobulins. B-cell markers such as CD19, CD20, and CD22 are usually present, and the majority express CD10 (common acute lymphoblastic leukemia antigen, CALLA). BL is negative for TdT and in most cases for B-cell lymphoma (BCL)-2. CD21, the EBV receptor, is more commonly seen in endemic BL than in sporadic BL.

Characteristic chromosomal translocations suggest that BL develops from genetic aberrations during somatic hypermutation or attempted immunoglobulin class switching. These translocations, usually t(8;14) or infrequently t(8;22) or t(2;8), juxtapose the c- myc gene (involved in cellular proliferation) with immunoglobulin locus regulatory elements, resulting in c- myc overexpression. In sporadic cases, the predominant chromosome 8 breakpoints usually occur within the c- myc gene, whereas they are upstream of the gene in endemic cases. For the rare event of c-myc -negative BL, characteristic aberrations of chromosome 11q characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter were reported. Other cytogenetic abnormalities, such as gain of 7q and deletion of 13q, are uncommon. Recently published large-scale next-generation sequencing studies unveiled sets of recurrently mutated genes in tumor cells of pediatric and adult B-NHL patients and introduced functionally related inhibitor of DNA 3 ( ID3) , transcription factor 3 ( TCF3) , and cyclin D3 ( CCND3) as potential drivers of BL lymphomagenesis.