Cellular Classification of Childhood NHL
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.[1-3] The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage and T-lineage or natural killer [NK] cell lineage) and (2) differentiation (i.e., precursor vs. mature).
On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into the following three therapeutically relevant categories:
- Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma).
- Lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma).
- Anaplastic large cell lymphoma (mature 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. Posttransplant lymphoproliferative diseases are classified according to WHO nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic. While the majority of posttransplant lymphoproliferative diseases are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.
Other types of lymphoma, such as peripheral T-cell lymphoma, T/NK lymphomas, cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma), are more commonly seen in adults and occur rarely in children. Refer to the following PDQ summaries 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 are the most current NHL classifications utilized and are shown below. 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. For the most part, the remaining categories do not pertain to pediatric NHL and are not shown.
|Category (WHO Classification/ Updated REAL)||Category (Working Formulation)||Immuno-phenotype||Clinical Presentation||Chromosome Translocation||Genes Affected|
|CNS = central nervous system; ML = malignant lymphoma; REAL = Revised European-American Lymphoma; WHO = World Health Organization.|
|aAdapted from Percy et al.|
|Burkitt and Burkitt-like lymphomas||ML small noncleaved cell||Mature B cell||Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS||t(8;14)(q24;q32), t(2;8)(p11;q24), t(8;22)(q24;q11)||C-MYC, IGH, IGK, IGL|
|Diffuse large B-cell lymphoma||ML large cell||Mature B cell; maybe CD30+||Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal||No consistent cytogenetic abnormality identified|
|Lymphoblastic lymphoma, precursor T-cell leukemia, or precursor B-cell lymphoma||Lymphoblastic convoluted and non-convoluted||Pre-T cell||Mediastinal, bone marrow||MTS1/p16ink4a; Deletion TAL1 t(1;14)(p34;q11), t(11;14)(p13;q11)||TAL1, TCRAO, RHOMB1, HOX11|
|Pre-B cell||Skin, bone, mediastinal|
|Anaplastic large cell lymphoma, systemic||ML immunoblastic or ML large||CD30+ (Ki-1+)||Variable, but systemic symptoms often prominent||t(2;5)(p23;q35); less common variant translocations involving ALK||ALK, NPM|
|T cell or null cell|
|Anaplastic large cell lymphoma, cutaneous||CD30+ (Ki-usually)||Skin only; single or multiple lesions||Lacks t(2;5)|
Burkitt and Burkitt-like lymphoma/leukemia
Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 30% of childhood NHL and exhibits consistent, aggressive clinical behavior.[2,3,7] The overall incidence of Burkitt lymphoma is 2.5 cases per million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,8] The most common primary sites of disease are the abdomen and the lymph nodes, especially of the head and neck region.[3,8] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS).
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). 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 oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.
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 because of features that are consistent with diffuse large B-cell lymphoma. 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 ≥99%). Studies have demonstrated that the vast majority of Burkitt-like or “atypical Burkitt” lymphomas have a gene expression signature similar to Burkitt lymphoma. Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma.[10,11] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.[12-15]
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2,3,16] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,17,18] The WHO classification system does not recommend morphologic subclassification based on morphologic variants (e.g., immunoblastic, centroblastic) of diffuse large B-cell lymphoma. Pediatric diffuse large B-cell lymphoma 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.[16,17,20]
About 20% of pediatric diffuse large B-cell lymphoma presents as primary mediastinal disease (primary mediastinal B-cell lymphoma). This presentation is more common in older children and adolescents and has been associated with an inferior outcome compared with other pediatric diffuse large B-cell lymphoma.[13,14,17,21-23] In a study of adolescents with stage III primary mediastinal large B-cell lymphoma treated with FAB/LMB-96 (NCT00002757) therapy, the 5-year event-free survival (EFS) was 66%, versus 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[Level of evidence: 2A] However, a single-arm study in adults showed excellent disease-free survival utilizing the DA-EPOCH-R regimen (dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab; usually six cycles) with filgrastim and no radiation therapy. The 5-year EFS was 93% and overall survival (OS) was 97%.[Level of evidence: 2A] At 10 years poststudy, there was no evidence of cardiac toxicity. This is currently being tested in pediatric clinical trials.
Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [22,23] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[26,27] Primary mediastinal B-cell lymphoma also has a distinctive gene expression profile in comparison with other diffuse large B-cell lymphoma, suggesting a close relationship of primary mediastinal B-cell lymphoma with Hodgkin lymphoma.[28,29]
With the exception of primary mediastinal B-cell lymphoma, diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults. The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[18,30,31] Unlike adult diffuse large B-cell lymphoma 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 diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation. As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma. A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.
Lymphoblastic lymphoma comprises approximately 20% of childhood NHL.[2,3,17] 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.[3,33] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma.
As many as 75% of patients with lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as 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 less than observed in Burkitt lymphoma. Low-stage lymphoblastic lymphoma may occur in lymph nodes, bone, testes, or subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered low-stage 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
Anaplastic large cell lymphoma accounts for approximately 10% of childhood NHL. While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or NK-cell surface antigen expression) does occur. The WHO classification system classifies anaplastic large cell lymphoma as a peripheral T-cell lymphoma. Many view ALK-positive anaplastic large cell lymphoma differently than other peripheral T-cell lymphoma because prognosis tends to be superior to other forms of peripheral T-cell lymphoma. All anaplastic large cell lymphoma cases are CD30-positive and more than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are comprised of variant ALK translocations. Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations. There is no correlation between outcome and ALK translocation type. In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).
Clinically, systemic anaplastic large cell lymphoma 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. Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis. There is a subgroup of anaplastic large cell lymphoma 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 patients have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this anaplastic large cell lymphoma subgroup may require more aggressive therapy.[39,40]
Lymphoproliferative disease associated with immunodeficiency in children
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]). Epstein-Barr virus (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. HIV-associated NHL can be broadly grouped into three subcategories: (1) systemic (nodal and extranodal), (2) primary CNS lymphoma, and (3) body cavity–based lymphoma, also referred to as primary effusion lymphoma. Approximately 80% of all NHL in HIV patients is considered to be systemic. Primary effusion lymphoma, 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. Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[43,44] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma, and diffuse large B-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.
NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology. Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed. Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.
PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant. The WHO has classified PTLD into the following three subtypes:
- Early lesions – Early lesions show germinal center expansion, but tissue architecture remains normal.
- Polymorphic PTLD – Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions.
- Monomorphic PTLD – Histologies observed in the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma 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. Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype. 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 (low stage or high stage), which are often extranodal (frequently in the allograft). Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which almost always results in death despite therapy.
Rare NHL occurring in children
Low- or intermediate-grade mature B-cell lymphomas, such as small lymphocytic lymphoma, MALT lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma, are rarely seen in children. The most recent WHO classification has identified pediatric follicular lymphoma and pediatric nodal marginal zone lymphoma as unique entities.
Pediatric follicular lymphoma is a disease that differs from the adult counterpart genetically and clinically. The genetic hallmark of adult follicular lymphoma, the translocation of t(14;18)(q32;q21) involving BCL2, is typically not detectable in pediatric follicular lymphoma.[50-52] Molecular alterations observed in pediatric follicular lymphoma include translocations of the immunoglobulin locus and IRF4, losses of regions of chromosome 1p, and mutations of TNFSFR14 on chromosome 1p.[32,53]
Pediatric follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, is more likely to be localized disease, and has an EFS of approximately 94%. In contrast, adult follicular lymphoma usually presents as disseminated disease with a relatively low proliferation rate.[50,51,55] Cervical lymph nodes and tonsils are common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid.[50-52,55-57] The outcome of pediatric follicular lymphoma is excellent, and in contrast to adult follicular lymphoma, the clinical course is not dominated by relapses.[50,52,55,56] One study suggested that for children with stage I disease who had a complete resection, a “watch and wait” approach without chemotherapy may be indicated. Patients with higher-stage disease also had a favorable outcome with low- and intermediate-intensity chemotherapy with 94% EFS and 100% OS, with a 2-year median follow-up. It appears that BCL2-rearrangement negativity and high proliferative index predict favorable disease. In pediatric follicular lymphoma, a high-grade component (i.e., grade 3) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children.[50,52,55]
Other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as low-stage (stage I or II) disease, and pediatric gastric MALT lymphomas are associated with Helicobacter pylori and require no more than local therapy involving curative surgery and/or radiation therapy. Conjunctival MALT lymphomas are often associated with chlamydial psittaci infections. Intralesional interferon-alpha for conjunctival MALT lymphoma has been described.
Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary CNS lymphoma. 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 primary CNS lymphoma (OS, 70%–80%) may be superior to that of adults with primary CNS lymphoma. These reports suggest that long-term survival can be achieved without cranial irradiation.[61-65] Most children have diffuse large B-cell lymphoma or anaplastic large cell lymphoma. Therapy with high-dose intravenous methotrexate and cytosine arabinoside is most successful and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.[62,64] There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result. This apparently good outcome needs to be confirmed, especially since similar results have not been observed in adults. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for nonacquired immunodeficiency syndrome–related primary CNS lymphoma.)
Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children. Mature T-cell/NK-cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., TdT negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor (TCR) genes, either alpha/beta and/or gamma/delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma-not otherwise specified, although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported.[67-69] Mycosis fungoides has rarely been reported in children and adolescents. A Japanese study described extranodal NK/T-cell lymphoma, nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma, nasal type is generally EBV-positive, and 60% of the cases observed in Japanese children were EBV-positive. Though very rare, hepatosplenic T-cell lymphoma is associated with children and adolescents who have Crohn disease and have been on immunosuppressive therapy; this lymphoma has been fatal in all cases.
Optimal therapy for peripheral T-cell lymphoma is unclear, even for adult patients. There have been three retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The United Kingdom Children's Cancer Study Group (UKCCSG) reported on 25 children diagnosed over a 20-year period with peripheral T-cell lymphoma, with an approximate 50% 5-year survival rate. The UKCCSG also observed that the use of acute lymphoblastic leukemia (ALL)–like therapy, instead of NHL therapy, produced a superior outcome. The Children's Oncology Group (COG) reported 20 patients older than 8 years treated on Pediatric Oncology Group NHL trials. Eight of ten patients with low-stage disease achieved long-term disease-free survival compared to only four of ten patients with high-stage disease. A study of Japanese children with peripheral T-cell lymphoma (N = 21) reported a 5-year OS rate of 85.2%. Treatment for peripheral T-cell lymphoma was not consistent in this study and included chemotherapy (n = 18), radiation (n = 2), and autologous (n = 2) and allogeneic (n = 9) stem cell transplantation.
An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas and cutaneous gamma-delta T-cell lymphomas in a series of 15 patients from three institutions.
In an attempt to learn more about the clinical and pathologic features of these types of NHL seen rarely in children, the COG has opened a registry study (COG-ANHL04B1). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.
- Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008.
- Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 35-50. Also available online. Last accessed April 03, 2014.
- Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996. [PUBMED Abstract]
- Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 157-66.
- Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999. [PUBMED Abstract]
- Swerdlow SH, Webber SA, Chadburn A: Post-transplant lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 343-9.
- Leoncini L, Raphael M, Stein H: Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 262-4.
- Mbulaiteye SM, Biggar RJ, Bhatia K, et al.: Sporadic childhood Burkitt lymphoma incidence in the United States during 1992-2005. Pediatr Blood Cancer 53 (3): 366-70, 2009. [PUBMED Abstract]
- Kluin PM, Harris NL, Stein H: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 265-6.
- Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008. [PUBMED Abstract]
- Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006. [PUBMED Abstract]
- Sevilla DW, Gong JZ, Goodman BK, et al.: Clinicopathologic findings in high-grade B-cell lymphomas with typical Burkitt morphologic features but lacking the MYC translocation. Am J Clin Pathol 128 (6): 981-91, 2007. [PUBMED Abstract]
- Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]
- Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007. [PUBMED Abstract]
- Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007. [PUBMED Abstract]
- Reiter A, Klapper W: Recent advances in the understanding and management of diffuse large B-cell lymphoma in children. Br J Haematol 142 (3): 329-47, 2008. [PUBMED Abstract]
- Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005. [PUBMED Abstract]
- Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006. [PUBMED Abstract]
- Stein H, Warnke RA, Chan WC: Diffuse large B-cell lymphoma (DLBCL), NOS. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 233-7.
- Lones MA, Perkins SL, Sposto R, et al.: Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 18 (22): 3845-53, 2000. [PUBMED Abstract]
- Seidemann K, Tiemann M, Lauterbach I, et al.: Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group. J Clin Oncol 21 (9): 1782-9, 2003. [PUBMED Abstract]
- Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005. [PUBMED Abstract]
- Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011. [PUBMED Abstract]
- Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013. [PUBMED Abstract]
- Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013. [PUBMED Abstract]
- Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005. [PUBMED Abstract]
- Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005. [PUBMED Abstract]
- Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003. [PUBMED Abstract]
- Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003. [PUBMED Abstract]
- Miles RR, Raphael M, McCarthy K, et al.: Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 51 (3): 369-74, 2008. [PUBMED Abstract]
- Gualco G, Weiss LM, Harrington WJ Jr, et al.: Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33 (12): 1815-22, 2009. [PUBMED Abstract]
- Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011. [PUBMED Abstract]
- Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000. [PUBMED Abstract]
- Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008. [PUBMED Abstract]
- Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001. [PUBMED Abstract]
- Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000. [PUBMED Abstract]
- Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011. [PUBMED Abstract]
- Sevilla DW, Choi JK, Gong JZ: Mediastinal adenopathy, lung infiltrates, and hemophagocytosis: unusual manifestation of pediatric anaplastic large cell lymphoma: report of two cases. Am J Clin Pathol 127 (3): 458-64, 2007. [PUBMED Abstract]
- Onciu M, Behm FG, Raimondi SC, et al.: ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Report of three cases and review of the literature. Am J Clin Pathol 120 (4): 617-25, 2003. [PUBMED Abstract]
- Grewal JS, Smith LB, Winegarden JD 3rd, et al.: Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. Ann Hematol 86 (7): 499-508, 2007. [PUBMED Abstract]
- McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996. [PUBMED Abstract]
- Jaffe ES: Primary body cavity-based AIDS-related lymphomas. Evolution of a new disease entity. Am J Clin Pathol 105 (2): 141-3, 1996. [PUBMED Abstract]
- Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001. [PUBMED Abstract]
- Godot C, Patte C, Blanche S, et al.: Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era. J Pediatr Hematol Oncol 34 (7): e282-8, 2012. [PUBMED Abstract]
- Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006. [PUBMED Abstract]
- Fedorova A, Mlyavaya T, Alexeichik A, et al.: Successful treatment of the HIV-associated Burkitt lymphoma in a three-year-old child. Pediatr Blood Cancer 47 (1): 92-3, 2006. [PUBMED Abstract]
- Loren AW, Porter DL, Stadtmauer EA, et al.: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31 (3): 145-55, 2003. [PUBMED Abstract]
- Chadburn A, Cesarman E, Liu YF, et al.: Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms. Cancer 75 (11): 2747-56, 1995. [PUBMED Abstract]
- Collins MH, Montone KT, Leahey AM, et al.: Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 107 (6): E89, 2001. [PUBMED Abstract]
- Louissaint A Jr, Ackerman AM, Dias-Santagata D, et al.: Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement. Blood 120 (12): 2395-404, 2012. [PUBMED Abstract]
- Liu Q, Salaverria I, Pittaluga S, et al.: Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. Am J Surg Pathol 37 (3): 333-43, 2013. [PUBMED Abstract]
- Lorsbach RB, Shay-Seymore D, Moore J, et al.: Clinicopathologic analysis of follicular lymphoma occurring in children. Blood 99 (6): 1959-64, 2002. [PUBMED Abstract]
- Launay E, Pangault C, Bertrand P, et al.: High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 26 (3): 559-62, 2012. [PUBMED Abstract]
- Attarbaschi A, Beishuizen A, Mann G, et al.: Children and adolescents with follicular lymphoma have an excellent prognosis with either limited chemotherapy or with a "Watch and wait" strategy after complete resection. Ann Hematol 92 (11): 1537-41, 2013. [PUBMED Abstract]
- Oschlies I, Salaverria I, Mahn F, et al.: Pediatric follicular lymphoma--a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkin's Lymphoma--Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials. Haematologica 95 (2): 253-9, 2010. [PUBMED Abstract]
- Lones MA, Raphael M, McCarthy K, et al.: Primary follicular lymphoma of the testis in children and adolescents. J Pediatr Hematol Oncol 34 (1): 68-71, 2012. [PUBMED Abstract]
- Agrawal R, Wang J: Pediatric follicular lymphoma: a rare clinicopathologic entity. Arch Pathol Lab Med 133 (1): 142-6, 2009. [PUBMED Abstract]
- Claviez A, Meyer U, Dominick C, et al.: MALT lymphoma in children: a report from the NHL-BFM Study Group. Pediatr Blood Cancer 47 (2): 210-4, 2006. [PUBMED Abstract]
- Stefanovic A, Lossos IS: Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114 (3): 501-10, 2009. [PUBMED Abstract]
- Holds J, Buchanan A, Hanson R: Intralesional interferon-α for the treatment of bilateral conjunctival mucosa-associated lymphoid tissue lymphoma. Pediatr Blood Cancer 59 (1): 176-8, 2012. [PUBMED Abstract]
- Abla O, Sandlund JT, Sung L, et al.: A case series of pediatric primary central nervous system lymphoma: favorable outcome without cranial irradiation. Pediatr Blood Cancer 47 (7): 880-5, 2006. [PUBMED Abstract]
- Abla O, Weitzman S: Primary central nervous system lymphoma in children. Neurosurg Focus 21 (5): E8, 2006. [PUBMED Abstract]
- Shah AC, Kelly DR, Nabors LB, et al.: Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients. Pediatr Blood Cancer 55 (6): 1227-30, 2010. [PUBMED Abstract]
- Abla O, Weitzman S, Blay JY, et al.: Primary CNS lymphoma in children and adolescents: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG). Clin Cancer Res 17 (2): 346-52, 2011. [PUBMED Abstract]
- Yoon JH, Kang HJ, Kim H, et al.: Successful treatment of primary central nervous system lymphoma without irradiation in children: single center experience. J Korean Med Sci 27 (11): 1378-84, 2012. [PUBMED Abstract]
- Akyuz C, Aydin GB, Cila A, et al.: Successful use of intraventricular and intravenous rituximab therapy for refractory primary CNS lymphoma in a child. Leuk Lymphoma 48 (6): 1253-5, 2007. [PUBMED Abstract]
- Windsor R, Stiller C, Webb D: Peripheral T-cell lymphoma in childhood: population-based experience in the United Kingdom over 20 years. Pediatr Blood Cancer 50 (4): 784-7, 2008. [PUBMED Abstract]
- Hutchison RE, Laver JH, Chang M, et al.: Non-anaplastic peripheral t-cell lymphoma in childhood and adolescence: a Children's Oncology Group study. Pediatr Blood Cancer 51 (1): 29-33, 2008. [PUBMED Abstract]
- Wang ZY, Li YX, Wang WH, et al.: Primary radiotherapy showed favorable outcome in treating extranodal nasal-type NK/T-cell lymphoma in children and adolescents. Blood 114 (23): 4771-6, 2009. [PUBMED Abstract]
- Kim ST, Sim HJ, Jeon YS, et al.: Clinicopathological features and T-cell receptor gene rearrangement findings of mycosis fungoides in patients younger than age 20 years. J Dermatol 36 (7): 392-402, 2009. [PUBMED Abstract]
- Kobayashi R, Yamato K, Tanaka F, et al.: Retrospective analysis of non-anaplastic peripheral T-cell lymphoma in pediatric patients in Japan. Pediatr Blood Cancer 54 (2): 212-5, 2010. [PUBMED Abstract]
- Rosh JR, Gross T, Mamula P, et al.: Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm Bowel Dis 13 (8): 1024-30, 2007. [PUBMED Abstract]
- Mehta N, Wayne AS, Kim YH, et al.: Bexarotene is active against subcutaneous panniculitis-like T-cell lymphoma in adult and pediatric populations. Clin Lymphoma Myeloma Leuk 12 (1): 20-5, 2012. [PUBMED Abstract]