Cellular Classification and Clinical Presentation
        Burkitt and Burkitt-like lymphoma/leukemia
        Diffuse large B-cell lymphoma
        Lymphoblastic lymphoma
        Anaplastic large cell lymphoma
        Lymphoproliferative disease associated with immunodeficiency in children
         Rare non-Hodgkin lymphoma occurring in children

Cellular Classification and Clinical Presentation

In children, non-Hodgkin lymphoma (NHL) is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, almost all NHL that occurs in children is high grade.[1,2] Classification of NHL in childhood and adolescence has historically been based on clinical behavior and response to treatment. A study by the Children’s Cancer Group demonstrated that the outcome for lymphoblastic NHL was superior with longer leukemia-like therapy consisting of induction, consolidation, and maintenance, while nonlymphoblastic NHL (Burkitt and large cell) had superior outcome with short, intensive, pulsed therapy.[3] In general, these treatment principles still apply.

The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage, T-lineage, or natural killer [NK] cell lineage); and (2) differentiation (i.e., precursor versus mature/peripheral).[1] On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into three therapeutically relevant categories: (1) B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma [DLBCL]); (2) lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma); and (3) anaplastic large cell lymphoma (T-cell or null-cell lymphomas). NHL associated with immunodeficiency generally has a mature B-cell phenotype and is more often of large cell than Burkitt histology.[2] Posttransplant lymphoproliferative diseases (PTLDs) are classified according to standard NHL nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic.[1]

Other types of lymphomas are more commonly seen in adults and occur rarely in children. (Refer to the PDQ summaries on the treatment of Adult Non-Hodgkin Lymphoma, Primary CNS Lymphoma, and Mycosis Fungoides and the Sézary Syndrome for more information.)

Each type of childhood NHL is associated with distinctive molecular biological characteristics, which are outlined in the following table. The Revised European-American Lymphoma (REAL) classification and the WHO classification [1] are the most current NHL classifications utilized and are shown below.[2] The Working Formulation is also listed for reference. The WHO Classification applies the principles of the REAL classification and focuses on the specific type of lymphoma for therapy purposes. The remainder of the categories, for the most part, do not pertain to pediatric NHL and are not shown.

Burkitt and Burkitt-like lymphoma/leukemia accounts for about 50% of childhood NHL and exhibits consistent, aggressive clinical behavior.[2,4,5] The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase (TdT). These malignant cells usually express surface immunoglobulin, most bearing surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD20, CD22) are usually present, and almost all childhood Burkitt/Burkitt-like lymphoma/leukemia express CALLA (CD10). About 25% contain Epstein-Barr virus (EBV) genomes. Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc gene to immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, the gene involved in cellular proliferation. Pediatric Burkitt lymphoma patients whose tumors also contain cytogenetic abnormalities of 13q and 22q have a markedly poor survival on current chemotherapy protocols.[2,6]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma consists of uniform, small, noncleaved cells, whereas Burkitt-like lymphoma is a highly disputed diagnosis among pathologists owing to features that are consistent with DLBCL.[1,2] A study assessing gene expression profiles compared to pathologic diagnosis by an expert panel demonstrated that the gene expression profile agreed with the pathologic review, with 19 of 20 Burkitt-like cases being molecularly similar to Burkitt lymphoma. Of 20 cases of pathologically called DLBCL, however, seven cases had gene expression profiles consistent with Burkitt lymphoma.[2,7] Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the WHO has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., Ki-67[+] of at least 99%).[1] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.[8]

The two most common primary sites of disease are the abdomen and head and neck region.[9] Other sites of involvement include testes, bone, peripheral lymph nodes, skin, bone marrow, and central nervous system (CNS).

DLBCL is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL. DLBCL occurs more frequently during the second decade of life than during the first decade.[4,5,10] While classification systems have described morphologic variants (e.g., immunoblastic, centroblastic) of DLBCL, the WHO classification system for hematological malignancies does not recommend morphologic subclassification.[1] Pediatric DLBCL may present clinically similar to Burkitt or Burkitt-like lymphoma, though it is more often localized and less often involves the bone marrow or CNS.[5,11]

Nonmediastinal DLBCL in children and adolescents differs biologically from DLBCL in adults. Pediatric DLBCL belongs primarily to the germinal center B-cell type, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells.[10] Unlike adult DLBCL of the germinal center B-cell type, in which the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene is commonly observed, pediatric DLBCL rarely demonstrates the t(14;18) translocation.[2,10] Outcomes for children with DLBCL are more favorable than those observed in adults, with overall 5-year event-free survival rates of approximately 90% in children.[12-15]

About 20% of pediatric DLBCL presents as primary mediastinal disease (primary mediastinal B-cell lymphoma [PMBCL]). This presentation is more common in older children and adolescents and is associated with an inferior outcome compared with other pediatric DLBCL.[5,11,14,16,17] PMBCL is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [17] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[18,19] PMBCL also has a distinctive gene expression profile in comparison with other DLBCL, suggesting a close relationship of PMBCL with Hodgkin lymphoma.[20,21]

Lymphoblastic lymphoma makes up approximately 20% of childhood NHL.[4,5] Lymphoblastic lymphomas are usually positive for TdT, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[22] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma.

Nearly 75% of patients with lymphoblastic lymphoma have an anterior mediastinal mass and may present with symptoms of dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck. Pleural effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, CNS, abdominal organs (but rarely bowel), and occasionally other sites such as lymphoid tissue of Waldeyer ring and testes. Abdominal involvement is rare compared with Burkitt lymphoma. Localized lymphoblastic lymphoma may occur in lymph nodes, bone, and subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered localized disease.

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have leukemia, and those with fewer than 25% marrow blasts are considered to have lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Anaplastic large cell lymphoma (ALCL) accounts for approximately 10% of childhood NHL.[5] While the predominant immunophenotype of ALCL is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or NK-cell surface antigen expression) does occur. More than 90% of ALCL cases are CD30-positive and have the translocation t(2;5)(p23;q35) leading to the expression of the fusion protein NPM/ALK, though variant ALK translocations have been reported.[23] Clinically, ALCL has a broad range of presentations, including involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the CNS and bone marrow is uncommon. However, in a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcriptase-polymerase chain reaction (RT-PCR) from NPM-ALK, were found in approximately 50% of patients and correlated with clinical stage;[24] marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. ALCL is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. There is a subgroup of ALCL with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly. Most of these cases have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this ALCL subgroup may require more aggressive therapy.[25,26] Patients with ALCL may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis, but have mediastinal or other adenopathy that, when biopsied, is diagnostic of ALCL.[27]

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect, secondary to human immunodeficiency virus (HIV) infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). EBV is associated with most of these tumors, but some tumors are not associated with any infectious agent.

NHL associated with HIV is usually aggressive, with most cases occurring in extralymphatic sites.[28] HIV-associated NHL can be broadly grouped into three subcategories: systemic (nodal and extranodal), primary CNS lymphoma (PCNSL), and body cavity–based lymphoma, also referred to as primary effusion lymphoma (PEL). Approximately 80% of all NHL in HIV patients is considered to be systemic.[28] PEL, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[29] Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for PCNSL cases.[30] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum including PEL, PCSNL, mucosa-associated lymphoid tissue (MALT),[31] Burkitt lymphoma,[32] and diffuse large cell lymphoma. NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[28]

NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology. Mature T-cell and anaplastic large cell lymphoma have been observed.[33] Children with primary immunodeficiency and NHL are more likely to have disseminated disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.[33]

PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV,[34] but EBV-negative PTLD can be seen following solid organ transplant. The WHO has classified PTLD into three subtypes: early lesions, polymorphic PTLD, and monomorphic PTLD.[1] Early lesions show germinal center expansion but tissue architecture remains normal. Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions. Histologies observed in the monomorphic subtype are similar to those observed in NHL, with DLBCL being the most common histology, followed by Burkitt lymphoma, with myeloma or plasmacytoma occurring rarely. The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphous and monomorphous histologies may be present in a patient, even within the same lesion of PTLD.[35] Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype.[1] EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (localized or diffuse), which are often extranodal (frequently in the allograft).[36] Although less common, PTLD may present as a rapidly progressive, disseminated disease that clinically resembles septic shock, which almost always results in death despite therapy.[37]

Mature T-cell and NK-cell NHL are much less common in children than in adults. Mature B-cell lymphomas such as small lymphocytic, MALT, mantle cell lymphoma, myeloma, or follicular cell lymphoma are also rarely seen in children. It is unclear whether these histologies observed in children are the same diseases as those seen in adults.[38] For example, follicular lymphoma observed in children express bcl-2 only in a small number of cases.[39] However, other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as localized disease and are associated with H. pylori and require no more than local therapy of surgery and/or radiation therapy to cure.[38]

Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary cutaneous lymphomas and PCNSLs. Due to small numbers, it is difficult to ascertain if the disease observed in children is the same as in adults and, therefore, it is difficult to determine optimal therapy. Reports suggest that the outcome of pediatric patients with PCNSL may be superior to that of adults with PCNSL. These reports suggest that long-term survival can be achieved without cranial irradiation.[40,41] One report showed that most of the children had DLBCL or ALCL. Results of this study showed that therapy with high-dose intravenous methotrexate and cytosine arabinoside was most successful and that intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.[41] There is a case report of repeated doses of rituxumab, both intravenous and intraventricular, being administered to a 14 year old boy with refractory primary CNS lymphoma, with an excellent result.[42] This apparently good outcome needs to be confirmed especially since similar results have not been observed in adults.

In an attempt to learn more about the clinical and pathologic features of these types of NHL seen rarely in children, the Children’s Oncology Group has opened a registry study. This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome to therapy.

References

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