Non-Hodgkin Lymphoma in Children
John T. Sandlund, Jr.
Mihaela Onciu
INTRODUCTION
There have been significant clinical and laboratory advances over the last 25 years in our understanding of the non-Hodgkin lymphomas (NHLs) of childhood. These include the refinement of diagnosis and classification of clinically relevant histologic subtypes, the elucidation of various pathogenic mechanisms, and most importantly, improvements in therapy and supportive care which have resulted in improved event-free and overall survival rates. Increased attention to the reduction and elimination of late effects of therapy such as infertility, cardiotoxicity, and second cancers is another important hallmark of clinical research over recent years. These advances and future directions will be discussed in this chapter.
Malignant lymphomas, which comprise both Hodgkin lymphoma and NHL, are the third most common type of childhood cancer after acute lymphoblastic leukemia (ALL) and brain tumors.1, 2, 3, 4, 5, 6, 7 Among children <18 years of age, there is a slight predominance of Hodgkin lymphoma, whereas the reverse is true among those <15 years of age.3, 6
It is important to note the distinction between the NHLs of adults and children.8, 9, 10 Children typically present with diffuse extranodal disease in contrast to adults, among whom primary nodal disease is more common. Additionally, the pediatric NHLs are typically high grade tumors,9 in contrast to the low- and intermediate-grade tumors which are predominant among adults. Age-related differences in the immune system and associated susceptibility to malignant transformation are possible contributing factors to these observed differences in histologic subtype.7
EPIDEMIOLOGY
There are at least 500 cases of newly diagnosed pediatric NHL in the United States each year.3, 4, 5Although there is no clear peak age, the median age in one single institution review was 10 years (range, 7 months to 19 years).10 This disease occurs uncommonly in very young children (i.e., <3 years of age).2, 10 NHL is two to three times more common in boys than in girls, and more common in black children than in white children.2, 7 The reasons for these differences have yet to be elucidated.
There are geographical differences with respect to frequency and distribution of histologic subtypes of NHL in children.11 For example, although NHL is very common in equatorial Africa, it is very rare in Japan.12 Among the NHL cases observed in equatorial Africa, Burkitt lymphoma (BL) is the most common type observed. BL is also the most frequent histologic subtype encountered in northeastern Brazil and in some areas of the Middle East.13 In contrast, lymphoblastic lymphoma (LBL) is the predominant histologic subtype in southern India.13
BL is also of interest with respect to the geographical (i.e., endemic versus sporadic) variances that exist with respect to both clinical and biologic features.14 Those tumors, which arise in children from equatorial Africa (“endemic subtype”), are characterized clinically by frequent involvement of jaw, abdomen, paraspinal area, and orbit, and by a younger age at diagnosis.14, 15, 16 Those Burkitt tumors which arise in children from Western Europe and the United States (“sporadic subtype”), are in contrast characterized by frequent involvement of the abdomen, nasopharynx, and bone marrow and an older age at diagnosis.14, 15, 16 The breakpoint in the c-myc proto-oncogene and in the IG heavy chain (IGH) genes in BLs has also been reported to vary with respect to geography: in sporadic cases the breakpoints tend to occur within the MYC gene and the switch region of IGH gene, as compared to upstream of MYC and the VDJ region of IGH in endemic cases.14, 17
An infectious agent was suspected to play a role in the pathogenesis of BL in equatorial Africa after it was noticed that the malaria belt overlapped with the lymphoma belt. Subsequently, EBV was shown to be associated with BL in this part of the world (i.e., equatorial Africa).14, 16 The association of EBV with BL has been shown, however, to vary with geography. EBV association occurs in approximately 85% of endemic cases, in contrast to the 15% association in Western Europe and the United States.14, 16 An intermediate degree of EBV association has been observed in other parts of the world, such as northeastern Brazil.18 Although the evidence for a direct role for EBV in BL pathogenesis is relatively lacking, the circumstantial evidence is compelling. It was initially hypothesized that EBV, a B-cell mitogen, increases the target pool of cells that would be susceptible to a malignant transformation.14 This hypothesis is supported by the observation that the expression of the recombination activating gene (RAG) can be induced by EBV, and therefore potentially increases the chance that a chromosomal translocation may occur during IG gene rearrangement.19
Children with certain immunodeficiency conditions are at increased risk for the development of NHL.2, 7 Examples of specific populations at risk include those with congenital immunodeficiency disorders such as ataxia-telangiectasia (A-T),20 X-linked lymphoproliferative syndrome (XLP), and Wiskott-Aldrich syndrome. It is important that these underlying conditions be recognized in children who present with NHL, so that appropriately designed therapy can be delivered. For example, in children with A-T, involved field irradiation and the use of radiomimetics such as bleomycin should be avoided, and the judicious use of x-rays is advised. Children with A-T are also at increased risk for the development of severe late onset hemorrhagic cystitis following the administration of alkylating agents such as cyclophosphamide and ifosfamide; therefore, vigorous hydration and administration of the uroprotectant mesna are recommended whenever these agents are delivered. Boys with XLP are at increased risk for the development of both B-cell lymphomas and fatal infectious mononucleosis, and are potential candidates for allogeneic bone marrow transplantation. Therefore, the diagnosis of XLP should be considered in any boy who presents with a B-cell lymphoma and whose brother has had either B-cell lymphoma or fatal infectious mononucleosis, or in any male who has had two primary B-cell lymphomas. There is also an increased risk for the development of NHL among children with acquired immunodeficiency conditions.21 Specific populations at risk include those with the acquired immunodeficiency syndrome (AIDS) and those on immunosuppressive therapy following bone marrow or organ transplantation.
PATHOLOGIC SPECIMEN EVALUATION
Most of the NHLs of childhood are very rapidly growing neoplasms. It is therefore imperative that the diagnosis be established as soon as possible so that appropriate therapy can be started. The diagnosis typically requires a comprehensive characterization of the tumor, including histologic, flow cytometric, cytogenetic,
and molecular genetic studies. Ideally, larger fragments of tissue should be obtained by open biopsy of an involved site, but percutaneous image-guided needle biopsy has been increasingly used for diagnosis in the pediatric age group with good results.22 Bilateral bone marrow aspirates and biopsies should be considered before open biopsy, since this may allow the diagnosis to be established without a more invasive open biopsy. In patients who are not candidates for general anesthesia, such as those with a large anterior mediastinal mass, the diagnosis may be established by examination of pleural fluid obtained by thoracentesis or by parasternal core biopsy of the mass using local anesthesia with an anesthesiologist in attendance.23
and molecular genetic studies. Ideally, larger fragments of tissue should be obtained by open biopsy of an involved site, but percutaneous image-guided needle biopsy has been increasingly used for diagnosis in the pediatric age group with good results.22 Bilateral bone marrow aspirates and biopsies should be considered before open biopsy, since this may allow the diagnosis to be established without a more invasive open biopsy. In patients who are not candidates for general anesthesia, such as those with a large anterior mediastinal mass, the diagnosis may be established by examination of pleural fluid obtained by thoracentesis or by parasternal core biopsy of the mass using local anesthesia with an anesthesiologist in attendance.23
CLASSIFICATION
The most recent World Health Organization (WHO) Classification of Tumors of Haematopoietic and Lymphoid Tissues24 designates NHLs, including those predominant in the pediatric age group, according to their clinical, morphologic, immunophenotypic, and genetic features, and also acknowledges difficulties in differentiating some of the clinically significant subtypes of B-cell lymphoma by introducing some borderline (“gray-zone”) categories to encompass these issues. Table 89.1 summarizes the pediatric NHLs according to the WHO Classification 2008. Table 89.2 summarizes the main diagnostic immunophenotypic features of the most common subtypes of NHL encountered in this age group.
Lymphoblastic Lymphoma (T and B Lymphoblastic Lymphoma/Leukemia)
ALL and LBL are neoplasms of precursor B-cells or T-cells, characterized by immature (blastic) morphology and immunophenotype. At the pathologic and clinical levels, ALL and LBL appear to represent an overlapping continuum, with the distinction between these two processes being largely quantitative and arbitrary: cases involving at least 25% of the marrow cellularity are managed as ALL, while cases with less or no marrow involvement, are designated as LBL.25, 26, 27 More recent studies have identified important differences in gene expression profiles, adhesion molecule expression, and molecular pathways of T-ALL and T-LBL that explain at least partially their distinct dissemination patterns.28, 29, 30 T-LBL is the more common subtype and involves most often the mediastinum, lymph nodes, skin, bone, or soft tissues, and less commonly kidney, lung, or orbit. By contrast, the less common B-LBL more often presents in the lymph nodes, skin, bone, soft tissues, or breast, with mediastinal presentation being very uncommon.31, 32, 33, 34, 35 The most frequent location of skin lesions in children is the scalp.34, 35
TABLE 89.1 SUBTYPES OF NON-HODGKIN LYMPHOMA ENCOUNTERED IN CHILDREN ACCORDING TO THE WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION (2008) | ||||||||||||||||||||||||||||||||||||||||||||
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Histologically, B- and T-LBLs show a diffuse growth pattern, with extensive replacement of the underlying normal tissue architecture by sheets of blastic cells. The malignant lymphoblasts are small to intermediate in size, with scant to moderate amounts of basophilic cytoplasm, finely dispersed nuclear chromatin, and small indistinct nucleoli (see Fig. 89.1). In some cases the nuclei may have markedly irregular or convoluted outlines, a feature more common in T-LBL. Mitotic figures may be numerous in some cases, correlating with the presence of a “starry sky” appearance imparted by scattered pale macrophages containing apoptotic nuclear debris. BL should be considered in the differential diagnosis of such cases.
Immunophenotypically, approximately 90% of LBLs are of T lineage and the remaining 10% of B lineage.36, 37, 38, 39, 40 Most T-LBLs resemble cortical thymocytes, a feature that may lead to difficulties in the differential diagnosis with thymoma and residual normal thymus in biopsy samples obtained from mediastinal and cervical lesions. They typically express CD1a, CD10, weak CD79a, BCL2, CD99, and the pan-T-cell antigens CD2, CD3 (mostly cytoplasmic), CD5, and CD7, although these markers may under- or overexpressed when compared to their normal counterparts. Similar to thymocytes, T-LBLs are often CD4+ and CD8+ and usually terminal deoxynucleotidyl transferase (TdT) positive, a marker that can be used to distinguish this neoplastic process from mature T-cell lymphomas.41, 46 Other immature T-cell markers, including CD34 and HLA-DR are also coexpressed in these cases. A more frequent expression of T-cell receptor αβ than γδ has been reported in T-cell LBL as compared to precursor T-cell ALL.47 Some LBLs may aberrantly express myeloid-associated antigens.37, 48, 49 Of note, CD45 expression, often used to differentiate blasts by flow cytometry, ranges from dim (“blast-like”) to strong (“mature lymphocyte-like”) in T-ALL/LBL. A subset of T-LBLs resemble late thymocytes. In these cases TdT expression may be absent. They also express strong surface CD3, lack expression of CD1a, CD10, CD34, and HLA-DR, and are CD4+ or CD8+, rendering distinction from mature T-NHL very difficult, especially in small needle biopsy samples. The mediastinal localization and blastic cell morphology are very helpful in such cases.
B-LBLs typically resemble normal progenitor B-cells found primarily in the bone marrow and in lower numbers in blood, lymph nodes, and tonsils.46, 50, 51 They express CD10, TdT, CD99, the B lineage antigens PAX-5 and CD79a, and may be negative or only weakly positive for the mature B-cell marker CD20. The neoplastic cells most often lack expression of surface IG and light chain restriction. Most often they express cytoplasmic µ heavy chain without detectable κ or λ IG light chains.38, 52, 53 Rare cases of B-LBL may express surface IG with light chain restriction, associated with strong CD20 expression and without detectable TdT; in such cases BL should be considered in the differential diagnosis.39, 54 Of note, a significant proportion of pediatric B-ALL/LBL lack expression of CD45 (leukocyte common antigen), a marker often used to identify hematopoietic neoplasms in tissue
sections. This feature, combined with the frequent expression of CD99 by these neoplasms may lead to an erroneous diagnosis of Ewing sarcoma, another CD99+ pediatric neoplasm with blastic morphology, unless other markers (e.g., PAX5, TdT) are included in the diagnostic immunohistochemistry panels.
sections. This feature, combined with the frequent expression of CD99 by these neoplasms may lead to an erroneous diagnosis of Ewing sarcoma, another CD99+ pediatric neoplasm with blastic morphology, unless other markers (e.g., PAX5, TdT) are included in the diagnostic immunohistochemistry panels.
TABLE 89.2 IMMUNOPHENOTYPIC FEATURES OF THE MOST COMMON PEDIATRIC NON-HODGKIN LYMPHOMAS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Cytogenetic studies of pediatric LBLs are few and include small numbers of patients (Table 89.3).55, 56, 57 Additionally, some reports of the cytogenetic or molecular genetics of LBL include cases of ALL with extra-medullary spread. T-LBL and T-ALL share similar chromosomal abnormalities. Chromosome abnormalities of the T cell receptor are relatively common and include chromosome abnormalities at 7q34-36, 7p15, and 14q11.56, 57 The t(9;17) translocation appears more commonly in T-LBL than T-ALL.56, 57 These patients often present with a mediastinal mass and have an aggressive disease course. The t(8;13)(p11;q11-14) has been described in rare cases of precursor T-LBL that present with myeloid hyperplasia and eosinophilia.58, 59, 60
The t(10;11) (p13-14;q14-21) is an uncommon but recurring translocation associated with T-ALL, and T-LBL, where it correlates with expression of the γ/δ T-cell receptor by the neoplastic cells.61, 62, 63 Cytogenetic abnormalities have not been shown to be of prognostic significance in LBL. At the molecular level, B-LBLs and T-LBLs contain IG (IG) and T-cell receptor gene (TCR) rearrangements, respectively. The latter should not be used for lineage determination, as B-LBLs (like B-ALL) often contain TCR rearrangements, and T-LBLs may also harbor IG gene rearrangements.
 FIGURE 89.1. Lymphoblastic lymphoma. Sheets of small lymphoid cells with fairly uniform chromatin without clearing and scant cytoplasm are present. They show little variation in size and many show mitotic activity. |
Burkitt Lymphoma
The WHO Classification replaced “small noncleaved cell lymphoma” of the older NCI Working Formulation with BL (Table 89.1),9, 64, 65 and also combined under the same category the ALL-L3 of the French-American-British classification, which corresponded to cases of high-stage BL with leukemic dissemination.
BL is a mature B-cell lymphoma which resembles highly proliferative B-cells present in the follicular germinal center (GC). The biology of this lymphoma is characterized by translocations involving the MYC gene and leading to its overexpression and the typical high proliferation rate. Notably, however, MYC gene rearrangements are not unique to this subtype of mature B-cell lymphoma. Clinically, as described above (see section “Epidemiology”) there are three recognized variants of BL: endemic, sporadic, and immunodeficiency-associated, which appear to correlate with distinct profiles of clinical presentation, association with EBV, molecular lesions, and cytogenetic abnormalities. Histologically, BL may present as one of three patterns with no prognostic significance (classic, atypical, and plasmacytoid), previously recognized as disease variants and currently merged under the unique designation of BL. Regardless of the histologic variant, BL is characterized by a diffuse growth pattern that typically replaces extensively the normal underlying tissue architecture. Occasionally, BL cells may also be seen “colonizing” preexisting GCs adjacent to the main tumor or present in the lymph nodes, draining an area involved by diffuse BL. Frequent mitotic and apoptotic cells are present and reflect this lymphoma’s high proliferative rate and apoptotic index,
respectively. Tingible body macrophages interspersed among the neoplastic cells impart a characteristic low-power microscopic “starry sky” appearance. The proliferation index, measured by immunohistochemical nuclear expression for Ki-67, typically approaches 100% of the tumor cells and is a requirement for the diagnosis of BL, regardless of the morphologic subtype, as an acceptable surrogate for the demonstration of MYC gene rearrangements. In the classic BL variant the neoplastic cells are monomorphous, medium-sized (“small noncleaved”) with moderate amounts of basophilic cytoplasm (see Fig. 89.2).64, 65 The cells have round nuclei, clumped or condensed chromatin with clear parachromatin, and one to three nucleoli. When seen in Wrightstained cytologic preparations, BL cells have a characteristically deeply basophilic cytoplasm with prominent clear cytoplasmic vacuoles. In the atypical variant, the neoplastic cells are more pleomorphic, including large cells with centroblastic appearance and often prominent central nucleoli. The plasmacytoid BL cells, which are seen mostly in association with immunodeficiency, are more monomorphous, predominantly large, with eccentric nucleus, prominent nucleolus, and more abundant, IG-positive cytoplasm. BL cells retrieved from malignant pleural effusions often are larger and more pleomorphic than their tissue or blood counterparts.
respectively. Tingible body macrophages interspersed among the neoplastic cells impart a characteristic low-power microscopic “starry sky” appearance. The proliferation index, measured by immunohistochemical nuclear expression for Ki-67, typically approaches 100% of the tumor cells and is a requirement for the diagnosis of BL, regardless of the morphologic subtype, as an acceptable surrogate for the demonstration of MYC gene rearrangements. In the classic BL variant the neoplastic cells are monomorphous, medium-sized (“small noncleaved”) with moderate amounts of basophilic cytoplasm (see Fig. 89.2).64, 65 The cells have round nuclei, clumped or condensed chromatin with clear parachromatin, and one to three nucleoli. When seen in Wrightstained cytologic preparations, BL cells have a characteristically deeply basophilic cytoplasm with prominent clear cytoplasmic vacuoles. In the atypical variant, the neoplastic cells are more pleomorphic, including large cells with centroblastic appearance and often prominent central nucleoli. The plasmacytoid BL cells, which are seen mostly in association with immunodeficiency, are more monomorphous, predominantly large, with eccentric nucleus, prominent nucleolus, and more abundant, IG-positive cytoplasm. BL cells retrieved from malignant pleural effusions often are larger and more pleomorphic than their tissue or blood counterparts.
TABLE 89.3 CLINICAL AND BIOLOGIC CHARACTERISTICS OF NON-HODGKIN LYMPHOMA IN CHILDREN | ||||||||||||||||||||||||||||||||||||
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 FIGURE 89.2. Burkitt lymphoma. Sheets of medium-sized lymphocytes are present with fine chromatin and multiple nucleoli. In addition, there are scattered large histiocytes containing debris. These histiocytes give the “starry sky” appearance to the histology of BL. |
Immunophenotypically, BLs have a mature GC-like profile. They express CD10, CD19, strong uniform CD20, CD22, CD79a, PAX5, BCL-6, and surface IG (IgM, or less commonly IgA or IgG), with IG light chain κ or λ restriction (Table 89.2).66 They are typically negative for BCL2, CD34, and TDT. The latter two antigens are useful in the differential diagnosis with B-LBL, which is most often positive for these markers. CD21, the receptor for complement fragment Cd3 and the Epstein-Barr virus, is more frequently detected in the endemic than sporadic form.
Cytogenetically, all cases of BL harbor one of three chromosomal translocations which rearrange the MYC oncogene locus to regions controlled by regulatory components of the IGH or light chain (IGK or IGL) genes, leading to constitutionally overexpressed MYC in the neoplastic B-cells (Table 89.3). These translocations include t(8;14)(q24;q32)/MYC-IGH (80% to 90% of the cases), t(2;8)(q11;q32)/IGL-MYC, and t(8;22)(q23;q11)/MYC-IGK. The translocations associated with BL are relatively easily detected by classical cytogenetic methods and more recently by fluorescent in situ hybridization of interphase nuclei.67 In addition to these classic translocations, a significant proportion of pediatric BLs also contain other nonspecific but recurrent cytogenetic abnormalities, some of which may correlate with prognosis, at least in cases with high-stage presentation.68
Diffuse Large B-cell Lymphoma
Diffuse Large B-Cell Lymphoma (DLBCL) is a mature B-cell neoplasm composed predominantly of large cells (i.e., nuclear size equal to or exceeding that of macrophage nuclei), with a diffuse growth pattern, and with a proliferation index typically less than that required for a diagnosis of BL (typically 90% or less). The neoplastic cells may have a predominantly centroblastic (>80% in children),69 immunoblastic (<10% in children),69 or anaplastic appearance, defining three morphologic variants with no known prognostic implications (see Fig. 89.3).65 Tumors rich in T-lymphocytes and histocytes are defined as a distinct entity in the most recent WHO Classification as T-cell/histocyte-rich large B-cell lymphoma.
 FIGURE 89.3. Diffuse large B cell lymphoma. Sheets of variably sized large cells with prominent nucleoli and chromatin clearing. There is variation in cell size, in contrast to the more uniform cells of BL. |
Immunophenotypically, DLBCLs express one or more pan-B-associated markers CD19, CD20, CD22, CD79a, and PAX5. Surface or cytoplasmic IG are expressed by 50% or more cases. Some cases may express CD5, CD10, BCL2, BCL6, IRF4/MUM1, and CD30 (Table 89.3). Gene expression profiling and immunohistochemical studies have defined subgroups with distinct biology in DLBCL. These groups do not currently determine therapy in children. The GC-like group, which is predominant in children69 is characterized by a CD10+/-, BCL6+/-, IRF4/MUM1-immunophenotype, while the non-GC subtype is CD10–, BCL6+/- and IRF4/MUM1+. Rare cases of anaplastic lymphoma kinase (ALK)-expressing DLBCL with plasmablastic features can be found among DLBCL of children.70, 71, 72 These have been included under the designation of ALK-positive large B-cell lymphoma in the WHO Classification 2008.24
Cytogenetics of DLBCL often include complex karyotypes with recurrent, but nonspecific abnormalities. While in adults many of the GC-like cases contain the t(14;18) characteristic for follicular lymphoma (FL), this is not the case in pediatrics, perhaps due to the unique biology of FL in this age group (see below).69 The rare ALK-positive cases may harbor the t(2;5) or t(2;17), resulting in ALK gene overexpression.70, 71, 72
Primary Mediastinal (Thymic) Large B-cell Lymphoma
Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is an uncommon subtype of diffuse large B-cell lymphoma (<10% of large cell lymphomas in children) thought to arise from nonrecirculating thymic medullary B-cells.65, 73, 74, 75, 76, 77, 78 The latter feature may explain the biologic behavior of this tumor, which never involves the bone marrow (prerequisite feature for a diagnosis of PMBL and exclusion of DLBCL with secondary mediastinal involvement). Patients present with signs and symptoms of a large mediastinal mass, frequently with extension into adjacent structures including lung, pericardium, chest wall, and superior vena cava. Extrathoracic extension at diagnosis is uncommon but with disease progression can include kidneys, brain, soft tissue, skin, and adrenal glands. In the pediatric age group, the presence of extrathoracic disease at presentation is an adverse prognostic feature.76
Histologically, PMBL is characterized by a diffuse growth pattern and is composed of tumor cells that may range from mediumsized to large. They may have a centroblast-like appearance, may show lobated, “flower-like” nuclear outlines, or may have an anaplastic, Reed-Sternberg-like appearance. Often, they have abundant pale cytoplasm, with a “clear cell” appearance. The neoplastic cells are typically surrounded by thin to thick, dense fibrotic bands. Small benign-appearing lymphocytes and eosinophils may be present and add to the difficulty in differentiating PMBL from Hodgkin lymphoma.
Immunophenotypically, PMBL cells express CD45 and B-cell-associated antigens PAX5, CD19, CD20, CD22, and CD79a (Table 89.2), characteristically lack IG, and very often show variable degrees of CD30 expression,79 as well as CD23 and IRF4/MUM1 positivity. Expression of CD10, BCL-6, and BCL2 is less common. Although not unique to PMBL, the expression of the myelin and lymphocyte protein (MAL) may be useful in differentiating it from other mature B-cell and post-thymic T-cell lymphomas.80
Molecular studies uniformly reveal clonal IG gene rearrangements even if IG expression is not demonstrable by immunologic techniques. The lymphoma cells show mutated IG V region genes consistent with post-germinal center B-cells.81, 82 Uncommonly, evidence of clonal EBV genome may be present in the tumor cells. The relatively few cytogenetic studies reported show aneuploid tumor cells, often with gains of chromosome 9p or Xq.83, 84 The tumor cells may overexpress REL or MAL in a minority of cases.85 BCL6, TP53, CDKN2A alterations and MYC rearrangements may be present.83, 84, 85, 86, 87
Unclassifiable Large B-cell Lymphomas
The most recent WHO Classification has recognized the existence of some borderline B-cell lymphomas, where complete morphologic, immunophenotypic, and genetic characterization does not allow a clear distinction between clinically significant categories of aggressive B-cell NHL or between DLBCL and classical Hodgkin lymphoma. This recognition has led to the definition of two heterogeneous disease categories that are not to be applied for cases where sufficient information is not available for a definitive distinction. These rare cases do occur in the pediatric age group and, at the present time, it appears that they are best managed as aggressive B-cell lymphomas in these patients.
B-cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-cell Lymphoma and Burkitt Lymphoma
This is a heterogeneous category of mature B-cell lymphomas, often with morphologic features of both DLBCL and BL, but with intermediate biologic features: cases of DLBCL with a gene expression profile similar to BL, many of which harbor dual translocations involving MYC and BCL2 (“double-hit lymphomas”), correlating with a particularly poor outcome; cases of DLBCL with high proliferation rate and immunophenotype resembling BL, but lacking a detectable MYC translocation; or cases with morphology typical for BL, but atypical immunophenotype or genetic features. Some of these cases would have been classified as “Burkitt-like lymphoma” in previous classification systems.
B-cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-cell Lymphoma and Classical Hodgkin Lymphoma
This category has been introduced mainly to reflect a distinct group of B-cell lymphomas occurring in the mediastinum and showing features intermediate between PMBL and classical Hodgkin lymphoma (“gray-zone lymphomas”).88 However, lymphomas with similar features have also been described in peripheral lymph nodes. Gene expression profiling studies
have suggested related molecular signatures for PMBL and classical Hodgkin lymphoma,89, 90, 91 offering a possible explanation for these phenotypically intermediate categories, although specific genomic studies of gray-zone lymphomas have not been reported.
have suggested related molecular signatures for PMBL and classical Hodgkin lymphoma,89, 90, 91 offering a possible explanation for these phenotypically intermediate categories, although specific genomic studies of gray-zone lymphomas have not been reported.
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphomas (ALCLs) are mature T lineage lymphomas characterized by anaplastic morphology (large “hallmark” neoplastic cells with abundant cytoplasm, pleomorphic, often horseshoe-shaped nuclei) and strong uniform expression of CD30. The most recent WHO Classification has recognized two distinct biologic entities sharing these features: ALK-positive ALCL and ALK-negative ALCL. The vast majority of pediatric ALCLs are ALK-positive and therefore, the latter disease subtype will be referred to exclusively in the remainder of this chapter. In children, ALCL tends to involve lymph nodes and extranodal sites including skin, soft tissues, lungs, and bones.92 Approximately 20% to 25% of patients have bone marrow involvement at diagnosis that may not be obvious without ancillary studies.93 Histologically, ALK expression by these lymphomas has allowed recognition of a wide spectrum of morphologic variants. These range from classical (common) cases, where the anaplastic cells predominate, growing in diffuse sheets (see Fig. 89.4) or within sinusoidal lymph node space; to the small cell variant,65, 94 where the anaplastic cells are a minor component, admixed with predominantly small neoplastic cells; and the lymphohistiocytic variant,95, 96 containing a minority of “hallmark” cells surrounded by a reactive lymphohistiocytic population that forms the bulk of the tumor. The monomorphic variant, more common in children (author’s unpublished observation) consists of sheets of monotonous immunoblastic cells with a high mitotic rate and “starry sky” appearance, mimicking BL. Rare cases have a sarcomatoid appearance, consisting of spindled CD3+/ALK+/CD30+ neoplastic cells. Although none of these variants appears to have prognostic implications, the small cell variant appears to be associated more often with systemic dissemination and leukemic peripheral blood involvement at presentation.97, 103
Immunophenotypically, ALCLs express one or more T-cell-associated antigens including CD2, CD3, CD4, CD7, CD43, or CD45RO (Table 89.2).65, 104 T-cell antigens CD5 and CD8 are usually negative. Some cases lack demonstrable T-cell antigens but have evidence of TCR gene rearrangements.65 Most ALCLs express cytoplasmic cytotoxic cell-associated proteins TIA-1, granzyme B, or perforin. A membranous and Golgi pattern of CD30 expression is characteristic of the neoplastic cells of ALCL.105, 107 The most intense reactivity to CD30 antibodies is seen in the large cells, whereas the smaller cells are weakly positive or more often negative. Most ALCLs are positive for the EMA (epithelial membrane antigen) with a pattern similar to CD30.108 Myeloid-associated antigens (CD13, CD15, CD33) are often expressed by neoplastic cells, especially when analyzed by flow cytometry.109 Expression of myeloid markers CD13 and CD33 appears to differentiate ALK+ ALCL from ALK- ALCL.110
 FIGURE 89.4. Anaplastic large cell lymphoma. Heterogeneous population of large lymphocytes is present with clearing of the nuclear chromatin and moderately abundant pink cytoplasm. Some cells have irregular and horseshoe-shaped nuclei (“hallmark” cells). |
Cytogenetically, the t(2;5)(p23;q35)/NPM-ALK translocation is demonstrable in over 75% of ALK+ ALCLs (Table 89.3).111, 112 Several other translocations involving the ALK gene have been described, including t(1;2)(q25;p23), t(2;3)(p23;q21), inv(2) (p23q35), t(2;22), t(2;17)(p23;q11), and t(2;19)(p23;p13).97, 113, 114, 115 All of these translocations lead to cytoplasmic overexpression and activation/phosphorylation of the ALK gene product as a result of dimerization of the gene partner-associated proteins. The NPM-ALK fusion is unique in that it is associated with both nuclear and cytoplasmic expression of ALK, due to the unique nuclear localization properties of NPM (nucleophosmin). As a result ALCLs associated with this translocation show nuclear and cytoplasmic ALK expression, while all other tumors show cytoplasmic ALK only, allowing immunohistochemical staining for ALK to predict the underlying genetic lesion in these lymphomas.
Of note, ALK expression is not unique to ALCL, but has also been demonstrated in a large subset of inflammatory myofibroblastic tumors, a predominantly pediatric mesenchymal neoplasm that also harbors translocations involving ALK; as well as in other pediatric tumors, where alternative mechanisms of overexpression may be operative.116, 117, 118 Therefore, careful immunophenotypic characterization of ALK+ neoplasms should be performed to confirm the diagnosis of ALCL.
Uncommon Pediatric Lymphomas
While the lymphoblastic and large cell lymphomas detailed above represent the vast majority of pediatric NHLs, a small but significant proportion of lymphomas occurring in this age group consists of low-grade B-cell lymphomas and some subtypes of peripheral T-cell lymphoma (see Table 89.1). The diagnosis of these rare lymphomas in children is often delayed or initially interpreted as a reactive process or as one of the more common pediatric lymphomas.
Some of these neoplasms (including FL and marginal zone lymphoma [MZL]) appear to constitute distinct clinicopathologic entities in this age group and will be detailed below. Other rare lymphomas of children and adolescents include hepatosplenic T-cell lymphoma, mycosis fungoides,119, 120, 121, 122, 123, 124, 125, 126 panniculitis-like T-cell lymphoma,127, 128, 129 HTLV-1-associated leukemia/lymphoma,130, 131, 132 and natural killer (NK) lymphoma.129, 133, 134, 135 For the most part, the clinical and biologic features of these lymphomas in children resemble their adult counterparts. A detailed presentation of all of these lymphoma subtypes is beyond the scope of this chapter. Only hepatosplenic lymphoma will be discussed below, with an emphasis on the frequent bone marrow involvement at presentation and the importance in differential diagnosis with the more common pediatric leukemias.
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