We have continued our work on lymphomas in the pediatric age group, and their often distinctive features. Follicular lymphoma (FL), a common lymphoma in adults, occurs rarely in pediatric and young adult patients. The criteria to distinguish the pediatric variant of FL from usual FL seen in adults are not well defined. We undertook a study of FL in patients under the age of 30. We identified 63 cases, which were analyzed by morphology, immunohistochemistry, and polymerase chain reaction analysis of IGH@ and IGK@ clonality. These data were correlated with clinical findings including stage, treatment, and outcome. Among the 63 cases, 34 cases were classified as the pediatric variant of FL, 22 presenting in lymph nodes, 8 in the Waldeyer ring, and 4 in the testis. Clonal immunoglobulin gene rearrangement was detected in 97% of PFL cases, but fluorescence in situ hybridization analysis showed an absence of the BCL2/IGH@ translocation in all cases tested. Twenty-nine cases were classified as usual FL, 28 of which presented in lymph nodes. The nodal pediatric tumors were observed exclusively in male patients in both children and young adults with a median age of 15 years. They showed marked head/neck predilection, blastoid cytologic features with a high proliferation rate, lack of BCL2 protein and t(14;18), low clinical stage at presentation, and good prognosis. Pediatric FLs involving the Waldeyer ring were distinguished by MUM1 expression, 50% (3/6) of which carried IRF4 breaks. BCL2 expression was common (63%) in the absence of BCL2/IGH@ translocation. Usual FLs were more common in female patients, exclusively in young adults (median age, 24 y), with no cases reported in patients under the age of 18. Twenty-five of 29 cases were of grade 1-2, and 4 cases were classified as grade 3A. They exhibited a higher clinical stage at presentation. Eighty-three percent expressed BCL2. Our results showed that histologic and immunophenotypic criteria can reliably separate the pediatric variant of FL the usual adult form, and that usual FL is exceptionally rare in the pediatric age group. Additionally, there are biological correlates with the site of presentation, and nodal tumors differ from those presenting in testis or Waldeyer's ring. Our studies also showed that many of these patients can be managed conservatively, and may not require chemotherapy.(1, 2) In an separate study published in 2013, we provided new insight into an ongoing debate as to whether there is a T-cell form of classical Hodgkin lymphoma (CHL). Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens, but the clinical significance of this finding is uncertain, and has not been clear whether these tumors positive for T-cell antigens were truly of T-cell derivation. Fifty cHLs expressing any T-cell associated antigen on the HRS cells were identified in two cohorts (National Cancer Institute, n = 38;Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor gamma rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for T-cell associated antigens (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the T-cell antigen positive group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the antigens expressed, CD4 and CD2 were most commonly, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. Nearly all cases expressed the B-cell associated transcription factor PAX5. Thus, the T-cell antigen expression seen is an aberrancy in a neoplasm of B-cell origin. During a median follow up of 113 months, T-cell antigen expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84];P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49];P = .001). Cases of CHL with T-cell antigens often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with cases of Hodgkin lymphoma lacking T-cell antigens.(3) We also provided new insights into peripheral T-cell lymphomas of T-follicular helper cell (TFH) origin. Peripheral T-cell lymphomas (PTCLs) are functionally and morphologically complex. Epstein-Barr virus (EBV)-positive B cells have been reported in angioimmunoblastic T-cell lymphoma (AITL) and other PTCLs and may mimic Hodgkin/Reed-Sternberg (HRS) cells, but EBV-negative HRS-like B cells have not been described. We wished to assess the nature of the PTCL associated with HRS-like cells and to determine whether EBV-negative HRS-like cells may be seen. We identified 57 PTCL cases reported as containing HRS-like cells. These included 32 AITL, 19 PTCL, not otherwise specified (NOS), 3 PTCL-NOS, follicular variant, 1 PTCL-NOS, T-zone variant, and 2 adult T-cell leukemia/lymphoma cases. All patients were adults with a median age of 63 and presented with lymphadenopathy. The male:female ratio was 31:26 (1.2:1). Clonal TRG rearrangement was detected in 46/53 cases. Six of 38 cases had a concomitant clonal immunoglobulin gene rearrangement. In 52/57 cases the HRS cells were positive for EBV. Five cases, 3 classified as AITL and 2 as PTCL-NOS, follicular variant, contained HRS-like cells negative for EBV. All PTCLs with EBV-negative HRS cells had a T follicular helper cell immunophenotype. The neoplastic T cells expressed CD3, CD4, and PD-1 and formed rosettes around the HRS-like cells. The HRS-like cells were positive for CD20 (variable intensity), PAX5, CD30, and CD15 (4/5). We conclude that both EBV-positive and EBV-negative HRS-like B cells may occur in the background of PTCL;caution is needed to avoid misdiagnosis as classical Hodgkin lymphoma. The close interaction between the HRS-like cells and the rosetting PD-1-positive T cells suggests a possible pathogenetic role in this phenomenon and provides new insights into the abnormal B-cell proliferations that occur in the context of TFH malignancies.(4, 5) Key references: 1. 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. The American journal of surgical pathology. 2013;37:333-343. 2. Jaffe ES. Follicular lymphomas: a tapestry of common and contrasting threads. Haematologica. 2013;98:1163-1165. 3. Venkataraman G, Song JY, Tzankov A, et al. Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival. Blood. 2013;121:1795-1804. 4. Nicolae A, Pittaluga S, Venkataraman G, et al. Peripheral T-cell Lymphomas of Follicular T-Helper Cell Derivation With Hodgkin/Reed-Sternberg Cells of B-cell Lineage: Both EBV-positive and EBV-negative Variants Exist. The American journal of surgical pathology. 2013;37:816-826. 5. Huppmann AR, Roullet MR, Raffeld M, et al. Angioimmunoblastic T-cell lymphoma partially obscured by an Epstein-Barr virus-negative clonal plasma cell proliferation. J Clin Oncol. 2013;31:e28-30.

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Price, Susan; Shaw, Pamela A; Seitz, Amy et al. (2014) Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 123:1989-99
Parrilla Castellar, Edgardo R; Jaffe, Elaine S; Said, Jonathan W et al. (2014) ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood 124:1473-80
Bouska, Alyssa; McKeithan, Timothy W; Deffenbacher, Karen E et al. (2014) Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma. Blood 123:1681-90
Huppmann, Alison R; Nicolae, Alina; Slack, Graham W et al. (2014) EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38:316-24
Mamessier, Emilie; Song, Joo Y; Eberle, Franziska C et al. (2014) Early lesions of follicular lymphoma: a genetic perspective. Haematologica 99:481-8
Aung, Phyu Phyu; Climent, Fina; Muzzafar, Tariq et al. (2014) Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T-cell lymphomas: a clinicopathologic study of three cases. J Cutan Pathol 41:51-7
Salaverria, Itziar; Martin-Guerrero, Idoia; Wagener, Rabea et al. (2014) A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 123:1187-98
Attygalle, Ayoma D; Cabecadas, Jose; Gaulard, Philippe et al. (2014) Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology 64:171-99
Mamessier, Emilie; Broussais-Guillaumot, Florence; Chetaille, Bruno et al. (2014) Nature and importance of follicular lymphoma precursors. Haematologica 99:802-10
Iqbal, Javeed; Wright, George; Wang, Chao et al. (2014) Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 123:2915-23

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