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Pediatric Non–Hodgkin Lymphomas


Sherrie Perkins
University of Utah
Salt Lake City, UT


Non-Hodgkin's lymphoma (NHL) makes up approximately 7% of all pediatric cancers diagnosed in the US (750-800 cases diagnosed/year), comprising 3% of tumors in children younger than 5 and 8-9% of tumors in children between 5-20 years of age. The numbers of NHL diagnosed in children under the age of 15 has remained relatively constant over the past 20 years, but the rates in adolescents 15 and older has risen steadily. Males are affected 2 to 3 times more frequently than females, and white children have approximately twice the rate of lymphoma as do African Americans, with Hispanics having an intermediate incidence of disease between whites and African Americans. There is also an increased incidence of NHL in children with inherited or acquired autoimmune disorders, including HIV, Wiscott-Aldrich syndrome, severe combined immune deficiency, ataxia-telangiectasia, common variable immunodeficiency or those on immune suppression drugs following solid organ transplant.

NHL in the pediatric age group differs from adult lymphomas both in the distribution of subtypes of lymphoma and clinical presentation as well as in response to therapy. Pediatric lymphomas are almost exclusively clinically aggressive lymphomas with indolent tumors, such as follicular lymphomas being distinctly unusual. Precursor (lymphoblastic) lymphomas are common in children, comprising almost 30% of pediatric NHL, compared to <5% of adult NHL. Pediatric NHL also differs from adult disease in that nearly half of the NHL are of T-cell phenotype (including both precursor and mature T-cell phenotypes), unlike adults where T-cell phenotype is seen in <10% of cases. Extranodal disease is much more common in children than in adults, and high stage (Stage III or IV) disease with involvement of bone marrow or the CNS is also much more common.

There are four main subtypes of pediatric NHL that are recognized by the WHO Classification that make up >95% of NHL in patients less than 20 years of age. These include precursor B and T-cell lymphomas (lymphoblastic lymphoma), Burkitt and atypical Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and CD30 positive anaplastic large cell lymphoma (ALCL). All are treated by systemic multi-agent chemotherapy with choice of drugs and duration of treatment dictated by the histologic subtype. Current therapies have cure rates of better than 85% for most patients with limited (Stage I or II) disease. Radiotherapy has limited use, usually as treatment for acute respiratory distress, superior vena cava syndrome or active CNS involvement. Because of the excellent response to therapy, surgery also has limited use, and is mainly employed for diagnosis or relief from symptoms of rapidly growing tumors (i.e. bowel obstruction or intussusceptions in Burkitt lymphoma). Because of the rapid growth of many of the tumors, pediatric patients are susceptible to tumor lysis syndrome or acute obstructive symptoms.

Precursor T and B-cell lymphomas (lymphoblastic lymphomas) make up about 30% of pediatric NHL, and 90% are of precursor T-cell origin. The precursor T-cell lymphomas will show variable expression of T-cell surface antigens with frequent expression of CD1a and TdT as well as co-expression of CD4 and CD8. CD3 is often expressed in the cytoplasm rather than the cell surface. CD10 expression is seen in one third to one half of cases, and aberrant expression of myeloid or B-cell antigens may be seen. Clonal T-cell receptor (TCR) gene rearrangements may be seen in some, but not all cases. About one third of cases will show cytogenetic abnormalities involving either the alpha or delta locus of the TCR and one quarter will have abnormalities or deletions of the TAL-1 locus at (9q). The definition of lymphoblastic lymphoma is somewhat arbitrary in the precursor cell lymphoproliferative processes, with a cut off of <25% bone marrow lymphoblasts defining lymphoma and >25% blasts considered as acute lymphoblastic leukemia (ALL). The most common clinical presentation of T-lymphoblastic lymphoma is a mediastinal or supradiaphragmatic mass with or without pleural effusions and variable cervical lymphadenopathy. Other, extranodal sites may also be involved. Respiratory compromise secondary to airway compression is a common complication of the rapidly growing mediastinal mass. About 10% of lymphoblastic lymphomas are precursor B-cell origin (expressing CD19, CD24, CD10, CD79a and TdT), and these are more likely to present in skin, soft tissue, bone, tonsils or in peripheral lymph nodes (often solitary), and appear to not progress to full-blown ALL in most cases. Treatment of lymphoblastic lymphoma is currently based on leukemia-type regimes with long term (12-24 month) duration of therapy with up to ten different agents including high dose methotrexate, vincristine, daunorubicin asparaginase and prophylactic cranial radiation. This approach has lead to 85-90% EFS in high stage disease. Limited stage disease is also treated with systemic leukemic type regimes with similar outcomes. Earlier approaches of treatment with more conventional NHL therapies led to frequent relapses, often as ALL. CNS prophylaxis is needed, even in limited stage disease, to achieve an EFS of 85%.

Burkitt lymphoma (BL) and atypical Burkitt lymphoma account for about 40% of pediatric NHL. Most of the cases appear to be of the sporadic type and lack evidence of the EBV genome (<30% of cases). These are mature B-cell neoplasms expressing CD19, CD20, CD22 and CD79a with cell surface IgM and light chains and somatic mutation of the Ig genes. BL frequently presents as extranodal disease involving gut, ovary and bones. Presentation of abdominal disease often presents with abdominal pain, nausea, vomiting and other signs of acute bowel obstruction. BL has a high incidence of CNS and bone marrow involvement, which may be seen in up to 20% of cases. CNS disease may present as cranial nerve palsies, seizures or cord compression. Bone marrow involvement often presents as cytopenias and a leukemic form of Burkitt lymphoma (previously designated as ALL L3) may be seen. Atypical Burkitt's lymphoma (also termed Burkitt-like lymphoma or high grade B-cell lymphoma) is more likely to present as peripheral node disease, and lacks morphologic features of classic BL such as a prominent starry sky pattern and cytologic homogeneity. Pathologic identification of atypical Burkitt lymphoma remains problematic with poor intra-observer agreement, as many of the features of increased cytologic pleomorphism may be difficult to distinguish without optimal fixation and slide preparation. Burkitt lymphoma has a very high mitotic rate (99-100% by MIB-1 or Ki-67 immunostaining), accounting for the typical acute clinical presentations. It has been proposed that Burkitt and atypical Burkitt lymphoma be defined on the basis of cytogenetic/molecular findings that include a c-myc translocation. Previous studies of Burkitt-like lymphomas in adult populations have seen combinations of c-myc and bcl-2 translocations. Cytogenetics of Burkitt-like cases in pediatric trials find a much higher number of c-myc translocations with bcl-2 translocations being very rare, suggesting that the disease is more closely related to BL in the pediatric population. Additional cytogenetic abnormalities, including duplication of 1q21-32 and deletion of 13q are also very common. Treatment of Burkitt and atypical Burkitt lymphomas is by a very intense but short duration therapeutic approach. Most regimes currently used last for 4-6 months and show 85-95% EFS even in high stage disease. Poorer outcome is seen with leukemic disease, but still is near 75% (compared to 20% in 1977!). CNS disease, with current therapeutic regimes, does not impart independent adverse prognosis.

DLBCL makes up approximately 20% of pediatric NHL and is more common in adolescents and older children. In the pediatric group, DLBCL is more likely to present as higher stage disease, with up to 70% presenting with Stage III disease, often involving mediastinum or abdomen (although abdominal disease is not as frequently seen as with the Burkitt lymphomas). Extranodal disease in tonsils, testes and other organs is also common. Stage IV disease (involving CNS or marrow is rare (<5%). DLBCL will have a mature B-cell phenotype with expression of CD20 and cell surface immunoglobulin (with exception of some primary mediastinal large B-cell lymphomas). Other subtypes of DLBCL seen in adults, such as T-cell rich large B-cell lymphoma or mediastinal large B-cell lymphoma, are also seen in children. DLBCL is not associated with any specific cytogenetic abnormalities, although >80% will display cytogenetic abnormalities, which are often complex. Detection of the t(14;18)(q32;q21) that characterizes many adult DLBCL has not been described in pediatric DLBCL or pediatric follicular lymphomas, although the t(8;14) seen in BL is well described in pediatric cases that have classic morphologic features of DLBCL. Although the extensive molecular analysis that has been done on adult DLBCL has not been carried out on pediatric cases, extensive immunophenotypic analysis has suggested that nearly all of the pediatric cases display a germinal center phenotype (positive for bcl-2, bcl-6 and/or CD-10, and lacking expression of MUM-1 and/or CD138). Treatment of pediatric DLBCL with intense, short multiagent chemotherapy lasting between 6 weeks to 6 months with 90-100% 5 year EFS in limited (Stage I-II) and 80-95% 3year EFS in advanced stage disease. Therapeutic approaches include therapy that is directed towards mature B-cell disease (both DLBCL and Burkitt lymphoma) or therapy designed specifically for large cell disease (both B and T-cell phenotypes) has been used.

Anaplastic large cell lymphoma (ALCL) comprises approximately 10% of pediatric NHL in the US, but appears to have a higher incidence in some European cohorts. ALCL in the pediatric population is most often high stage (III or IV) systemic disease, with 40-60% of children having involvement of extranodal sites such as bone, soft tissue and skin as well as nodal disease. All morphologic subtypes, including the common type and lymphohistiocytic, and small cell variants are seen. ALCL is typically mature T-cell disease by immunophenotyic analysis or demonstration of clonal TCR gene rearrangements. All will express CD30, and in contrast to adults where ALK overexpression may be seen in 50-60% of cases, >95% of pediatric cases will demonstrate evidence of ALK over-expression by immunohistochemistry or FISH analysis. As with adults, a wide variety of translocation partners involving the ALK locus are seen in the pediatric age group and, to date, there has been no association with response or therapeutic outcome. ALCL varies from many of the other types of pediatric NHL in that patients are susceptible to late relapses, often occurring 4-8 years after initial diagnosis. Treatment approaches have varied from NHL based CHOP type regimes to regimes directed more specifically at T-cell disease using doxorubicin, prednisone and vincristine (APO) over a 5-36 month period. Both approaches give short-term response rates of 75%. However EFS at 5 years falls to 50-60% in many studies, due to late relapses. Poor prognostic factors include extensive organ or skin involvement and B-symptoms. Relapses may be aggressive (waxing and waning disease) or rapidly aggressive disease. Salvage therapy includes bone marrow transplantation or second line NHL therapies with 40-50% 3-year survivals.

Although lymphoblastic lymphoma, Burkitt and atypical Burkitt lymphoma, DLBCL and ALCL make up >90% of pediatric tumors, a small number of other lymphomas have been seen in children. These include low-grade tumors such as follicular lymphomas and marginal zone lymphomas as well as rare aggressive peripheral T-cell lymphomas (exclusive of ALCL), gamma delta hepatosplenic lymphoma, mycosis fungoides and NK cell neoplasms. Follicular lymphoma is probably the most commonly seen of these rare NHLs, and appears to be distinctly different from adult follicular center cell lymphomas in that it is commonly low stage (often Stage I) or extranodal (testes) disease and are often predominantly large cell processes. These tumors may also have different pathogenetic mechanisms, as many do not over-express bcl-2 by immunohistochemistry and lack the characteristic t(14;18) seen in adult follicular center cell tumors. Many of the marginal zone type lymphomas in the pediatric population occur in immunosuppressed patients. Due to the small numbers of pediatric patients, a clear treatment approach for these diseases has not been established, and many are treated with adult based therapies or with immune based therapies (such as use of Rituximab for less aggressive B-cell disease). The prognosis in these young patients remains unknown.

The prognosis for children with NHL has improved markedly in the past 20 years and most patients have excellent outcomes with short-intensive therapies with mature B-cell neoplasms and long-term therapy with precursor lesions. Challenges in improving outcome with treatment of ALCL, finding effective salvage therapies for the small numbers of patients that fail therapy in other entities and in minimizing toxic side effects due to the intensive treatment regimes remain. Late effects, such as sterility, cardiomyopathy and secondary tumors are still seen in some patients and because of the predicted long life spans of many of the patients remain problematic. Use of less toxic or alternative therapies, such as immune-based therapies (very rarely used in children in contrast to adults) or better prognostic risk identification to allow minimization of therapy for some patients are challenges remaining in therapy of pediatric NHL.

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