Non-hodgkin lymphoma in children and adolescents

1

Describe the epidemiology of non-Hodgkin lymphoma in children and adolescents.

Non-Hodgkin lymphoma (NHL) is a heterogeneous category that includes a wide diversity of malignancies derived from lymphocytic cell origin. Although the World Health Organization (WHO) classification of lymphoid neoplasms includes more than 50 distinct diagnostic entities, many of them are extremely rare in the pediatric population. Five lymphomas account for more than 90% of all pediatric NHL diagnoses ( Table 39.1 ). Burkitt lymphoma (BL) is the most common, followed by T-cell lymphoblastic lymphoma (T-LBL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), and primary mediastinal B-cell lymphoma (PMBL). There are unique geographic distinctions in the epidemiology of childhood NHL; endemic BL is the most common overall childhood cancer in equatorial regions of sub-Saharan Africa where Plasmodium falciparum infection is holoendemic, whereas East Asia and Central and South America have a higher incidence of the rare Epstein-Barr virus (EBV)-associated T and natural killer (NK)-cell lymphomas and lymphoproliferative disorders.

NHL is the fourth most common cancer of childhood and fifth most common in adolescence, occurring more often in males in both groups. Risk of developing NHL is well-established in patients with underlying immune deficiency, including inherited cell-mediated and humoral immunodeficiency syndromes, disorders of cell repair, and acquired immunodeficiency in the form of human immunodeficiency virus (HIV) infection or post-transplant immune suppression. Pathogenesis in the setting of immune deficiency is often attributed to viral infection with EBV and human herpesvirus-8 (HHV-8). Nonetheless, cases of pediatric NHL in the setting of underlying immune deficiency or dysregulation represent a small proportion of overall diagnoses, and the vast majority of lymphomas occur de novo.

2

Provide an overview of the classification of NHL in the pediatric population.

The WHO classification categorizes NHL based on the cell compartment of origin as B versus T/NK cell ( Table 39.2 ). The majority of pediatric NHL arise from mature lymphocytes. Mature B-cell NHL is most common, including BL, DLBCL, and PMBL. Several histologic variants of DLBCL have recently been defined and are typically grouped with BL/DLBCL. ALCL is the most common mature T-cell NHL of childhood, whereas other mature B/T/NK-cell NHLs are categorized as rare. Lymphoblastic lymphoma arises in precursor lymphocytes and represents approximately 25% of NHLs in children. Contrary to patterns in lymphoblastic leukemia, T-LBL accounts for the majority (~ 75%) of lymphoblastic lymphomas compared with B-cell LBL.

3

What are some considerations specific to the adolescent/young adult population?

The high incidence of NHL in adolescents and young adults (AYA) emphasizes its epidemiological importance. Some important issues pertaining specifically to the AYA population include:

• Although BL is common in pediatric oncology and treated with intensive multiagent chemotherapy, such regimens are poorly tolerated by the rare older adult with BL. Nevertheless, considering the superior survival advantage associated with pediatric mature B-NHL regimens and its tolerability in younger adults, there is rationale for incorporating pediatric-based therapeutic strategies for young adults with BL.

• Some of the rare NHLs that infrequently occur in children (e.g., nonanaplastic mature T/NK-cell NHL) do not have an established pediatric-specific treatment paradigm; therefore extrapolation from adult oncology guidelines may be necessary to offer evidence-based strategies for the rare pediatric patients.

• The biology of DLBCL occurring in the pediatric population appears distinct from that described in adults. On the other hand, there seems to be substantial overlap between the biology of childhood versus adult BL. It remains to be proven whether NHL occurring in younger patients represents a distinct biological phenomenon or if extrapolation from the molecular mechanisms established in adult disease may apply and enlighten the development of targeted therapies for children.

• Strong consideration must be taken for pediatric and AYA patients regarding the potential late effects of chemotherapy, immunotherapy, and radiation therapy. This includes a comprehensive review of fertility preservation.

4

Which staging system is used for pediatric NHL?

The St. Jude NHL staging classification was developed by Sharon Murphy over 35 years ago and is the most widely accepted tool to define disease extent in pediatric NHL ( Table 39.3 ) . Nevertheless, there has been significant advancement in the evaluation, treatment, and prognosis of pediatric NHL since the St. Jude staging system was first proposed. A revised international pediatric NHL staging system (IPNHLSS) attempts to incorporate technological advances in molecular diagnostic methods, the detection of minimal disseminated disease, and advanced imaging technologies. Some pragmatic distinctions of the pediatric NHL staging system include the following: Stage IV is limited to central nervous system (CNS) or bone marrow involvement, whereas clinical presentation with nonresected abdominal disease or mediastinal mass is automatically stage III, even if disease involvement is restricted to one side of the diaphragm.

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