Pediatric Lymphoma Diagnosis: Role of FNAC, Biopsy, Immunohistochemistry and Molecular Diagnostics

Peripheral lymphadenopathy in the pediatric age group is screened using fine needle aspiration cytology (FNAC). Cases found to have features suspicious for lymphoma on FNAC need to undergo biopsy with immunohistochemistry for characterization and typing. In pediatric age group, peripheral lymph nodes are common in Hodgkin’s lymphoma for which biopsy is needed for subtyping. Distinction of classical Hodgkin’s lymphoma of lymphocyte rich type from nodular lymphocyte predominant Hodgkin’s lymphoma needs biopsy evaluation and a panel of immunostains. T lymphoblastic lymphomas and Burkitt’s lymphoma are the common types of non Hodgkin’s lymphoma seen in the pediatric age group. All lymphomas require a biopsy evaluation with immunohistochemistry and analysis of molecular genetic markers for proper characterization and selection of optimal treatment which are discussed in detail in this review.     

MALT lymphoma in children: a report from the NHL-BFM Study Group

Marginal zone lymphomas of MALT type comprise a considerable group of indolent B-cell non-Hodgkin lymphoma (NHL) in adult patients. In childhood, however, these tumors are extremely rare, as nearly all pediatric patients have aggressive NHL. Among 2,703 children and adolescents registered into the prospective multicenter NHL-BFM treatment studies since 1986, only 4 patients (0.1%) displayed features of MALT lymphoma. These tumors were localized in the stomach, breast, lower lid, and conjunctiva, respectively and they were associated with H. pylori infection in two patients. All children are alive but long-term follow-up will be mandatory to assess the behavior of MALT lymphoma in this age group.     

Epigenetic changes in the DAP-kinase CpG island in pediatric lymphoma

BACKGROUND: Hypermethylation of CpG islands in the promoter region of death-associated protein kinase (DAP-kinase) coupled with the loss of gamma-interferon-induced apoptosis have been reported in B-cell malignancies suggesting a role in pathogenesis or prognosis. Along with B-cell malignancies, pediatric lymphomas also include T-cell non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma, and Hodgkin disease, each with unique prognoses. The purpose of this study was to elucidate epigenetic changes in the DAP-kinase promoter region of pediatric cases to determine associations with aberrant hypermethylation. PROCEDURES: Thirty-nine cases of different lymphoid pathology [10 Burkitt lymphoma, 1 B-cell NHL; 7 T-cell lymphoblastic lymphoma; 4 anaplastic large cell lymphoma (LCL); 2 B-cell LCL; 14 nodular sclerosing Hodgkin disease (NSHD); and 1 B-cell acute lymphoblastic leukemia (ALL)] had methylation-specific polymerase chain reaction performed on bisulfite-treated DNA, which distinguishes the methylation status of the promoter region, and DAP-kinase mRNA expression assays performed on available specimens. RESULTS: In normal lymphocytes, the CpG islands in the promoter region were unmethylated, as were the T-cell lymphoblastic lymphoma and anaplastic LCL. In contrast, 100% of the Burkitt lymphoma (10/10) and B-cell ALL (1/1) were hypermethylated. Of the specimens with mRNA available, 7/8 Burkitt lymphoma had no DAP-kinase mRNA expression compared to normal expression in 3/3 and 4/4 T-cell lymphoblastic lymphoma and NSHD, respectively. CONCLUSIONS: In these pediatric lymphoid tumors, hypermethylation of the DAP-kinase promoter region with associated loss of DAP-kinase gene expression was associated with B-cell malignancies and thus may be important in the development and/or provide a prognostic tool in B- cell lymphomas.     

Immunohistochemical analyses of phosphatases in childhood B-cell lymphoma: lower expression of PTEN and HePTP and higher number of positive cells for nuclear SHP2 in B-cell lymphoma cases compared to controls

Although many pediatric B-cell lymphoma patients are being cured today, much is still unknown about the pathogenesis of this disease. Protein tyrosine phosphatases are involved in the control of survival, growth, and differentiation of cells. The authors have analyzed 26 pediatric B-cell lymphoma cases for the expression of a panel of phosphatases and report a statistically significant lower expression intensity of PTEN and HePTP and higher nuclear SHP2 expression in B-cell lymphoma cases compared to lymphoid tissue. Knowledge about the expression of key regulatory proteins in pediatric B-cell lymphomas is necessary for revealing the complex molecular background of this disease.     

IMMUNOHISTOCHEMICAL ANALYSES OF PHOSPHATASES IN CHILDHOOD B-CELL LYMPHOMA: Lower Expression of PTEN and HePTP and Higher Number of Positive Cells for Nuclear SHP2 in B-Cell Lymphoma Cases Compared to Controls

Although many pediatric B-cell lymphoma patients are being cured today, much is still unknown about the pathogenesis of this disease. Protein tyrosine phosphatases are involved in the control of survival, growth, and differentiation of cells. The authors have analyzed 26 pediatric B-cell lymphoma cases for the expression of a panel of phosphatases and report a statistically significant lower expression intensity of PTEN and HePTP and higher nuclear SHP2 expression in B-cell lymphoma cases compared to lymphoid tissue. Knowledge about the expression of key regulatory proteins in pediatric B-cell lymphomas is necessary for revealing the complex molecular background of this disease.     

Pediatric Anaplastic Lymphoma Kinase-Positive Large B-cell Lymphoma: A Case Report and Review of the Literature

ABSTRACT We present a case of pediatric anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK-positive LBCL) with a cervical, mesentery, and pelvis cavity mass. Histologic examination of the cervical mass revealed that the lesion was composed of diffuse large immunoblastic-like or plasmablastic-like tumor cells with a sinusoidal growth pattern. The tumor cells were strongly immunoreactive for ALK; revealed a granular cytoplasmic distribution; and were diffusely positive for CD45, CD4, CD138, epithelial membrane antigen, and multiple myeloma oncogene-1 but negative for CD20 and CD79a. The patient underwent 5 courses of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposid and obtained a remarkable clinical response with regression of mesentery and pelvis cavity mass. We suggest that this distinct subtype of large B-cell lymphoma should belong to the spectrum of pediatric lymphomas and that radiologic examination should be performed to inspect the progression of disease even if the patients experienced complete remission at initial chemotherapy.     

TREATMENT OF PEDIATRIC B-CELL NON-HODGKIN'S LYMPHOMAS AT THE MOTOL HOSPITAL IN PRAGUE, CZECH REPUBLIC: Results Based on the NHL BFM 90 Protocols

Malignant non-Hodgkin's lymphomas (NHL) of childhood and adolescence are a heterogeneous group of diseases originating from the lymphoid cells. Unlike adults with non-Hodgkin's lymphoma, children typically have extranodal disseminated disease of high grade (Burkitt's lymphoma, large cell lymphoma, or lymphoblastic lymphoma). This study was conducted to determine the feasibility of treating children in the Czech Republic with B-cell non-Hodgkin's lymphomas according to very intensive protocols based on the German Berlin Frankfurt Munster (BFM) NHL 90 study. Treatments are divided in the BFM studies according to "B" and "non-B" immunophenotypes. The authors report only those treated according to the BFM B-cell protocol. From 1991 through 1997 eighty-two patients less than 18 years with NHL were admitted to the department. Seventy-three of them were classified as B-cell lymphoma and 54 were thus eligible for the BFM B-cell treatment. The entire group consisted of 38 males and 16 females (ratio 2.38). Median age was 11.6 years. Twelve had stage I disease, 3 stage II, 30 stage III, and 9 stage IV lymphoma. There were 21 patients with Burkitt's lymphoma, 29 with large cell lymphoma, of which 5 were patients with MALT lymphoma. In 3 cases B-cell NHL was not further classified and one child had a mediastinal B lymphoma. Patients were further stratified according to clinical stage and lactate dehydrogenase (LDH) level. Therapy consisted of a prephase and short (2, 4, or 6 courses), intensive 5-day therapy with 6 drugs. The probability of event-free survival (pEFS) for the entire group was 74% and overall survival at 5 years was 80%. There was a significantly better outcome for children classified as stage I. No difference was observed between the EFS of stage III and IV patients. Four patients died from treatment-related complications in complete remission. Treatment results were not identical between NHL subtypes, with large cell lymphoma patients doing significantly better (pEFS 90%, p=.008). The use of protocols based on BFM 90 study was feasible at this center. The treatment results are approximately 10% lower than those reported by BFM investigators, but comparable to results from other centers.     

MALT Lymphoma in Children: Case Report and Review of the Literature

Mucosa-associated lymphoid tissue (MALT) lymphoma predominantly occurs in adults, and is rare in children. We report a case of MALT lymphoma involving minor salivary gland of the lip in an otherwise healthy 12-year-old boy. This is the second case report of MALT lymphoma of minor salivary gland in an immunocompetent child. Of 24 cases of MALT lymphomas in children reported in the English literature, parotid MALT lymphomas in human immunodeficiency virus (HIV) patients and H. pylori infection-associated gastric MALT lymphomas are the most common. As in adult cases, most MALT lymphomas in the pediatric age group are localized and follow an indolent clinical course, respond well to therapy, and have an excellent outcome.     

Primary Mediastinal Large Cell Lymphoma in Children: A Report from the Childrens Cancer Group

Malignant lymphomas arising in the mediastinum account for approximately 60% of all mediastinal tumors in children; two-thirds are non-Hodgkin's lymphomas and one-third represent Hodgkin's disease. In contrast to adults, in children mediastinal non-Hodgkin's lymphomas are usually synonymous with lymphoblastic lymphoma, and nonlymphoblastic lymphomas are rare. We describe nine children with primary mediastinal large cell lymphoma who were treated with the Children's Cancer Group protocol CCG-503, a randomized phase III protocol for disseminated nonlymphoblastic lymphoma. Histologic subclassification revealed three immunoblastic lymphomas, three multilobated large cell lymphomas, one with clear cell features, and two large noncleaved cell lymphomas. Sclerosis, of variable degrees, was seen in all tumors. Immunophenotyping revealed all tumors to be of B cell lineage. Thymic epithelial cells could be demonstrated, utilizing antibody to keratin, in two of nine patients, suggesting that some of the tumors are of thymic origin. None of the patients had central nervous system or bone marrow involvement. It appears that primary mediastinal nonlymphoblastic lymphomas in children, although much less common, are similar to those seen in adults. These tumors must be differentiated from lymphoblastic lymphoma and Hodgkin's disease, as the therapeutic approach may depend on histologic subtype. Primary mediastinal large cell lymphoma in children appears curable with aggressive treatment in the majority of patients.     

Bilateral conjunctival extranodal marginal zone B-cell lymphoma

Extranodal marginal zone B-cell lymphomas (EMZLs), while relatively common in adults, are rare entities in the pediatric population. A subclass of the typically aggressive non-Hodgkin lymphomas, the few reported pediatric cases indicate that, as in adults, these tumors tend to be indolent. We present a case of EMZL arising in the conjunctivae in a 9-year-old male with bilateral disease. The patient was treated with surgical excision alone and has remained disease-free 6 years after the operation.     

Ki-1 positive (anaplastic, large cell) lymphoma (case reports and review).

Ki-1 positive (anaplastic, large cell) lymphoma is a subgroup of non-Hodgkin lymphomas identified recently by Ki-1 (or BER-H2) (CD 30) monoclonal antibody. The clinicopathological features of two such pediatric cases of lymph node origin described here, and also the available literature emphasize the heterogenous nature of Ki-1 positive lymphomas, in almost every respect. Nevertheless, the Ki-1 antibody serves as an important diagnostic tool to differentiate lymphomas from other anaplastic, large malignancies.     

Unexpected finding of laparoscopic appendectomy: appendix MALT lymphoma in children

Mucosa-associated lymphoid tissue (MALT) lymphomas comprise a group of indolent B-cell non-Hodgkin lymphomas (NHL), which are rare in pediatric age. The clinical presentation of MALT lymphomas varies according to the location of the lymphoma. We report on a case of MALT lymphoma involving the appendix in a 6-year-old girl. A 6-year-old girl was referred to our institution in May 2005 with a diagnosis of appendicitis. The abdominal ultrasound showed slight effusion in the pelvic fossa. The patient underwent laparoscopic appendectomy using the three-trocar technique. The appendix appeared moderately hyperaemic with slight enlargement of the two-thirds of the distal portion. The postoperative course was uneventful and the girl was discharged on day 1 without any complication. The morphological and immunohistochemical examination showed typical findings of low-grade MALT lymphoma (positivity for CD20, no immunostaing for CD5 and CD10, positivity for anti-λ light chain and low positivity for Ki-67). Further extensive examinations (abdominal MRI, gastroscopy, colonscopy and capsule endoscopy of the ileum) revealed that the lymphoma was limited to the distal two-third of the appendix (stage IA) and was not associated with any specific infection. At a recent follow-up the patients appeared to be doing well. Appendiceal MALToma is a rather uncommon pathology and, to our knowledge, there is only one report of appendiceal intussusception associated with appendiceal maltoma. According to our experience, low-grade MALToma can be managed by simple appendectomy. The histological examination should be the rule whenever an appendectomy is performed in children.     

Morphological and Phenotypic Features in Pediatric Large Cell Lymphoma and Their Correlation with ALK Expression and the t(2;5)(p23;q35) Translocation

Anaplastic large cell lymphoma (ALCL) was proposed as a clinicopathologic entity over 14 years ago, but has been somewhat controversial due to the variability of its defining features and variable occurrence in different age-groups. To evaluate this entity in a pediatric population, 36 cases of childhood large cell lymphoma were evaluated for abnormalities of the anaplastic lymphoma kinase (ALK) gene that has been associated with ALCL morphology and immunophenotype. ALK abnormalities were evaluated by assay for the t(2;5)(p23;q35) translocation by RT-PCR and/or expression of NPM-ALK fusion protein by immunohistochemistry. Results showed 17 patients to have evidence of ALK gene expression. All of these children (mean age, 9.3 years) had tumors that were of T-cell phenotype (with the exception of a single case of null phenotype) and that expressed CD30. In contrast, 19 children with no evidence of ALK expression were older (mean, 12.7 years), and the majority (12/19) had tumors of B-cell phenotype. CD30 was also diffusely expressed in 8 of these 19 tumors. The difference in mean age between the two groups was statistically significant (P= 0.015). In three cases tested for both ALK and the t(2;5), ALK protein was detected in the absence of the t(2;5) translocation but no cases showed the reverse pattern, consistent with ALK fusion to genes other than NPM or activation of the ALK gene by another mechanism. These findings provide further support that ALK-positive ALCL is a distinct pathologic entity among pediatric large cell lymphomas primarily characterized by expression of T-cell markers, CD30, and EMA, and by a younger mean age. Received November 8, 1999; accepted September 11, 2000.     

小儿原发性胃肠道非霍奇金淋巴瘤的临床病理分析

目的探讨小儿原发性胃肠道非霍奇金淋巴瘤（primary gastrointestinallymphoma,PGIL）的临床病理特征及免疫表型。方法对10例小儿PGIL采用sP法行CD45、CD3、CD3e、CD5、CD10、CD15、CD20、CD30、CD45R01CD56、CD68,CD99、Bcl-2、Bcl-6、ALK、CyelinD1、Mum-1、MPO、PAX-5、TdT、TIA-1、Ki-67及细胞角蛋白（CK）免疫组织化学染色,运用原位杂交检测Epstein—Barr病毒编码的早期RNA（EBER）,按2008年WHO淋巴造血系统肿瘤分类标准进行分类。结果①10例瘤细胞均表达CIM5、Ki-67,无一例表达CK;10例均经病理、免疫组化及原位杂交检测等确诊为不同类型PGIL;②临床表现为腹痛、腹泻、腹部包块、发热、贫血和消瘦等。发生在小肠5例、回盲部2例、结肠1例、直肠2例。6例为溃疡型,4例为隆起型;③B细胞性NHL7例,其中伯基特淋巴瘤5例,B淋巴母细胞性淋巴瘤1例,弥漫性大B细胞淋巴瘤1例;T细胞NHL3例,其中NK／T细胞淋巴瘤1例,肠病相关T细胞淋巴瘤1例,ALK阳性间变性大细胞淋巴瘤1例。结论小儿PGIL临床症状无特异性,以B细胞淋巴瘤多见,T细胞淋巴瘤少见,预后差,须与其他胃肠道恶性肿瘤相鉴别。     

Nijmegen Breakage Syndrome-associated T-cell-rich B-cell Lymphoma: Case Report

In 1981 Weemaes et al. first described the Nijmegen breakage syndrome (NBS), a rare autosomal recessive disorder characterized by stunted growth, microcephaly, immunodeficiency, spontaneous chromosome instability, and a peculiar predisposition to cancer development. Most NBS-related malignancies are lymphomas, but their pathologic features have rarely been specified. We report here the case of a northern Italian 8-year-old child who, 2 years after the diagnosis of NBS, developed a diffuse large B-cell lymphoma (T cell–rich B-cell lymphoma variant). The histological and immunobiological features of the lymphoma population are analyzed and discussed in detail. Received March 29, 1999; accepted June 18, 1999.     

Early and reliable diagnosis of non-Hodgkin lymphoma in childhood and adolescence: contribution of cytomorphology and flow cytometric immunophenotyping

Non-Hodgkin lymphoma (NHL) represents one of the most rapidly growing malignancies in childhood and adolescence. About 80% of patients now are cured with adequate treatment. Serious complications at presentation due to tumor lysis syndrome or local tumor effects are commonly observed. Thus, a rapid diagnosis with the least invasive procedure enabling the initiation of early and specific therapy is necessary to diminish early fatality or persistent impairment. In 56 centrally registered patients with NHL, cytomorphologic analyses (FAB criteria) of May-Grünwald-Giemsa-stained touch imprints or malignant effusions and flow cytometric immunophenotyping (EGIL criteria) of fresh cell suspensions with a standardized panel of monoclonal antibodies were performed. The authors identified 23 patients with Burkitt lymphoma by the combination of FAB L3 morphology and a mature B-cell phenotype and 22 patients with lymphoblastic lymphoma by FAB L1/L2 morphology and a T-/B-cell precursor phenotype. They also found 11 patients with large cell lymphomas, 3 of them with anaplastic large cell lymphoma (T-cell phenotype; NPM/ALK-positive). In the remaining 8 patients diffuse large B-cell lymphoma was suspected by the combined use of cytologic and immunophenotypic findings (mature B-cell phenotype). In all cases with available solid tumor material (n = 42/56) the preliminary diagnosis was confirmed by histopathology. Burkitt lymphoma, lymphoblastic lymphoma, and, in a few cases, some large cell lymphomas could be classified reliably by cytomorphology and immunophenotyping of freshly obtained tumor cell material, enabling an early start of specific lymphoma treatment.     

State of the Art and Future Needs in Cytogenetic/Molecular Genetics/Arrays in childhood lymphoma: summary report of workshop at the First International Symposium on childhood and adolescent non-Hodgkin lymphoma, April 9, 2003, New York City, NY

BACKGROUND: A significant number of studies describe the cytogenetics and molecular genetics of adult non-Hodgkin lymphoma (NHL); however, similar knowledge is lacking regarding pediatric NHL. METHODS: A workshop to discuss the "State of the Art and Future Needs in Cytogenetic/Molecular Genetics/Arrays" in pediatric NHL was held in conjunction with the First International Symposium on Childhood and Adolescent Non-Hodgkin Lymphoma on April 9, 2003 in New York City. RESULTS: Cytogenetic characteristics of pediatric NHL include 14q11.2 rearrangements in T-cell lymphoblastic leukemia/lymphomas (LBL), ALK rearrangements in anaplastic large cell lymphomas (ALCL), and CMYC translocations in both Burkitt and Burkitt-like lymphomas (BL/BLL). Pediatric diffuse large B-cell lymphoma (DLBCL) is cytogenetically different from DLBCL in adults, suggesting a different disease in children. Microarray studies demonstrate three types of T-cell leukemia, the leukemic counterpart of LBL, that block T-cell differentiation at different stages of T-cell development, corresponding to LYL, TAL1, and HOX-expressing leukemias. ALCL cell lines have a unique expression profile compared to normal T-cells. Germinal centers of BL have CMYC expression signatures, indicating that CMYC expression is ectopic and does not reflect the physiology of the normal cell counterpart. CONCLUSIONS: Additional cytogenetic, molecular and microarray investigations of NHL in children are vital to better understand these diseases, their etiology, and differences from adult NHL. A greater understanding of pediatric NHL will lead to disease-specific and patient-individualized therapies of these diseases.     

De Novo MYC and BCL2 Double-hit B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) in Pediatric and Young Adult Patients Associated With Poor Prognosis

MYC and BCL2 translocations in B-cell lymphomas are defined as “double-hit” associated with poor prognosis in adult patients. Such double-hit events are extremely rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), especially in pediatric patients or young adults. This study is to investigate the clinical manifestation of de novo MYCyBCL2 double-hit BCP-ALL in young patients. Two pediatric and one young adult patients were identified after a retrospective data review and all without previous history of lymphoma. There were two females and one male aged 15, 18, and 24, respectively. All patients had an unremarkable medical history before presenting with extensive bone marrow and central nervous system involvement at diagnosis. Flow cytometry immunophenotypic analysis showed an immature B-cell immunophenotype (CD10+, CD19+, TdT+, surface Ig-) and immunohistochemistry showed high expression of MYC and BCL2 in all cases. All patients showed complex karyotypes associated with 8q24 abnormalities in the form of t(8;9)(q24;p13) or t(8;14)(q24;q32) and t(14;18)(q32;q21) and fluorescence in situ hybridization confirmed MYC and BCL2 rearrangements. Two patients died of refractory disease or disease progression 7 and 13 months after initial diagnosis, respectively, and the third patient was treated with protocol AALL0232 under the Children's Oncology Group study, achieved complete remission and remained in remission for 53 months at last follow-up. Our study showed that De novo MYCyBCL2 double-hit BCP-ALL is a rare disease that also occurs in pediatric and young adult patients and associated with complex karyotypes and poor prognosis. Younger patients may benefit from intensified chemotherapy.     

The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence

PURPOSE OF REVIEW: This review evaluates whether rituximab has efficacy in high-grade pediatric B-cell lymphoma/leukemia. Current pediatric protocols for CD20+ B-cell lymphoma/leukemia significantly improve survival, but with major morbidity. To assess whether rituximab has efficacy in very high-grade pediatric disease, all published data on rituximab therapy for Burkitt's lymphoma/B acute lymphoblastic leukaemia (B-ALL) and pediatric patients with relapsed/refractory large B-cell lymphoma were reviewed. RECENT FINDINGS: Three trials in adult Burkitt's/B-ALL showed a significant survival advantage when rituximab was added to standard chemotherapy. Minimal pediatric data have been published, but 19 children with mature B-cell lymphoma/B-ALL received rituximab, alone or in combination with chemotherapy, as salvage therapy, after failure of intensive chemotherapy. Fifteen of 19 (79%) responded, 12 (63%) remained alive in continuous complete remission at 5+ to 48+ months of follow-up. Two patients were alive in partial remission. Five patients died, four of progressive disease. Only one patient had no response to rituximab. SUMMARY: Rituximab has demonstrated efficacy in Burkitt's disease in adults. Although positive reporting bias is suspected, it appears that rituximab, even as monotherapy, has efficacy in heavily pretreated pediatric patients with high-grade B-lymphoma/B-ALL. Rituximab use can be justified in a prospective controlled chemotherapy dose-reduction study.     

Malignant B-cell lymphoma following and associated with infectious mononucleosis. A comparison of two cases

The present report describes two young males with clinically diagnosed infectious mononucleosis (IM) who subsequently were diagnosed as having malignant B-cell lymphoma (i.e., immunoblastic sarcoma of B-cells). Despite these apparent similarities, there were fundamental differences between the two cases. The first patient, who lymphoma was diagnosed 9 months after IM, was one of a well-described kindred with the X-linked lymphoproliferative syndrome (XLP) in which affected young males lack the ability to mount an effective immune response to primary infection with the Epstein-Barr virus (EBV) (i.e., infectious mononucleosis), and subsequently develop fatal lymphoproliferative disorders of the B-cell type. This was in contrast to a second patient, also a young male, who did not have the X-linked lymphoproliferative syndrome, who did develop specific antibodies to the Epstein-Barr virus and whose malignant lymphoma was closely associated in time (i.e., 5 weeks) with the clinical diagnosis of infectious mononucleosis. The comparative immunologic and virologic features are discussed as well as the importance of careful clinicopathologic correlation in young adults and children developing malignant lymphoma both following and in association with infectious mononucleosis.