Childhood Cancer Genomics (PDQ®) 3/8 —Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version

Non-Hodgkin Lymphoma

In This Section

• Mature B-cell Lymphoma
  • Burkitt and Burkitt-like lymphoma
  • Diffuse large B-cell lymphoma
  • Primary mediastinal B-cell lymphoma
• Lymphoblastic Lymphoma
• Anaplastic Large Cell Lymphoma
• Pediatric-type Follicular Lymphoma

Mature B-cell Lymphoma

The mature B-cell lymphomas include Burkitt and Burkitt-like lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.

Burkitt and Burkitt-like lymphoma

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).[1]

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 MYConcogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[2-4] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[5]

While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.

• Activating mutations in the transcription factor TCF3 and inactivating mutations in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[6-9]
• Mutations in TP53 are observed in one-third to one-half of cases.[6,8]
• Mutations in cyclin D3 (CCND3) are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[6,8]
• Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to increase MYC stability.[6,10]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[11]

Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.[12]

Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkittlymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia.[13,14] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[13,15]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Diffuse large B-cell lymphoma

The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[16]

Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

• 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.[5,17,18] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[19]
• Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.[17]
• 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/leukemia.[13,15]
• In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[15,20]
• A subset of pediatric diffuse large B-cell lymphoma cases was 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 in 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.[21] Large B-cell lymphoma with IRF4 rearrangement was added as a distinct entity in the 2016 revision of the WHO classification of lymphoid neoplasms.[22]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Primary mediastinal B-cell lymphoma

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification.[23] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.

Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:

• Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[23]
• Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.

Primary mediastinal B-cell lymphoma has a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[24,25] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.

• Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes PD-L1 (PDL1) and PD-L2 (PDCD1LG2), and the genomic alterations lead to increased expression of these checkpoint proteins.[26-28]
• Genomic alterations in CIITA, which is the master transcriptional regulator of MHC class II expression, are common in primary mediastinal B-cell lymphoma and lead to loss of MHC class II expression. Loss of MHC class II expression provides another mechanism of immune escape for primary mediastinal B-cell lymphoma.[29]
• Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.[30]
  • The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes Janus kinase 2 (JAK2), which activates the signal transducer and activator of transcription (STAT) pathway.[31,32]
  • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% of primary mediastinal B-cell lymphoma by either mutation or gene deletion.[33,34]
  • The interleukin-4 receptor gene (IL4R) shows activating mutations in approximately 20% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.[30]
• Copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL, also occur in primary mediastinal B-cell lymphoma.[31,32]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Lymphoblastic Lymphoma

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[2,35]

As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16.[36,37]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Anaplastic Large Cell Lymphoma

While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[22]

All anaplastic large cell lymphoma cases are CD30-positive. 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 composed of variant ALK translocations.[38] 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, as shown in Table 2.[39]

Table 2. Variant ALK Translocation and Associated Partner Chromosome Location and Frequencya

Gene Fusion	Partner Chromosome Location	Frequency of Gene Fusion
aAdapted from Tsuyama et al.[39]
NPM-ALK	5q36.1	~80%
TPM3-ALK	1p23	~15%
ALO17-ALK	17q25.3	Rare
ATIC-ALK	2q35	Rare
CLTC-ALK	17q23	Rare
MSN-ALK	Xp11.1	Rare
MYH9-ALK	22q13.1	Rare
TFG-ALK	3q12.2	Rare
TPM4-ALK	19p13	Rare
TRAF1-ALK	9q33.2	Rare

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[40] Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease.[41] In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[42-44]

In a European 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).[43] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.[44]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Pediatric-type Follicular Lymphoma

Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2rearrangements; BCL6 and MYC rearrangements are also not present. The TNFSFR14mutations are common in pediatric-type follicular lymphoma, and they appear to occur with similar frequency in adult follicular lymphoma.[45,46] However, MAP2K1 mutations, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphomas. Other genes (e.g., MAPK1 and RRAS) have been found to be mutated in cases without MAP2K1 mutations, suggesting that the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[47,48] Translocations of the immunoglobulin locus and IRF4 and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[21,45]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

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