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972 Am J Clin Pathol 2010;134:972-981972 DOI: 10.1309/AJCPWY1SGJ9IEAOR

© American Society for Clinical Pathology

Hematopathology / Transformation of Follicular to Plasmablastic Lymphoma

Transformation of Follicular Lymphoma to Plasmablastic Lymphoma With c-myc Gene Rearrangement

Ihsane Ouansafi, MD,1 Bing He, PhD,2 Cory Fraser, MD,1 Kui Nie, MD,1 Susan Mathew, PhD,3 Rumina Bhanji, MD,1 Rana Hoda, MD,4 Melissa Arabadjief, MD,1 Daniel Knowles, MD,1 Andrea Cerutti, MD,2 Attilio Orazi, MD,1 and Wayne Tam, MD, PhD1

Key Words: Follicular lymphoma; Plasmablastic lymphoma; Transformation; c-myc

DOI: 10.1309/AJCPWY1SGJ9IEAOR

A b s t r a c t

Follicular lymphoma (FL) is an indolent lymphoma that transforms to high-grade lymphoma, mostly diffuse large B-cell lymphoma, in about a third of patients. We present the first report of a case of FL that transformed to plasmablastic lymphoma (PBL). Clonal transformation of the FL to PBL was evidenced by identical IGH/BCL2 gene rearrangements and VDJ gene usage in rearranged IGH genes. IGH/BCL2 translocation was retained in the PBL, which also acquired c-myc gene rearrangement. Genealogic analysis based on somatic hypermutation of the rearranged IGH genes of both FL and PBL suggests that transformation of the FL to PBL occurred most likely by divergent evolution from a common progenitor cell rather than direct evolution from the FL clone. Our study of this unusual case expands the histologic spectrum of FL transformation and increases our understanding of the pathogenetic mechanisms of transformation of indolent lymphomas to aggressive lymphomas.

Follicular lymphoma (FL) is a neoplasm of centrocytes and centroblasts with a follicle center B-cell immunophe-notype, characterized in most cases by the presence of the reciprocal chromosomal translocation t(14;18)(q32;q21) that results in juxtaposition of the BCL2 gene to the immuno-globulin heavy chain (IGH) gene. Although FL is often clinically indolent with a median survival of more than 7 or 8 years, it is an incurable malignancy. The natural history of FL has been well documented, with 25% to 35% of cases progressing to a high-grade lymphoma,1 usually diffuse large B-cell lymphoma (DLBCL). In these cases, the most common morphologic pattern is one of sheets of large transformed cells with centroblastic morphologic features and a germinal center immunophenotype.2,3 However, cases of transformation to other lymphoma subtypes have been documented, including B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma (BL),4-7 CD30+ large cell lymphoma with anaplastic cytologic features,8 prolymphocytoid transfor-mation,9 and blastic/blastoid transformation.10

Transformation of FL to B-lymphoblastic lympho-ma/leukemia has been documented11; some of the older B-lymphoblastic lymphoma/leukemia reported cases show an additional c-myc translocation12,13 and are now better classi-fied as B-cell lymphoma with features intermediate between DLBCL and BL.6 Morphologic transformation is usually characterized by an aggressive course, poor response to che-motherapy, and short survival. Because of the clinical impli-cations, it is important for pathologists to recognize the variety of histologic features of transformed FL to avoid misinterpret-ing the noncentroblastic forms of transformation as de novo lymphomas. The clonal relationship between the original low-grade FL and the transformed higher grade lymphoma

Am J Clin Pathol 2010;134:972-981 973973 DOI: 10.1309/AJCPWY1SGJ9IEAOR 973


Hematopathology / Case Report

can usually be proven by molecular studies demonstrating similar immunoglobulin gene rearrangement. In light of this, we describe a case of FL with an unusual transformation to plasmablastic lymphoma (PBL). An extensive literature search revealed that no such transformation has been reported thus far in the English literature.

Case Report

A 69-year-old man with a recent history of prostate adenocarcinoma treated with radiation therapy seeds sought care because of newly developed inguinal lymphadenopathy. A right inguinal lymph node excisional biopsy resulted in a diagnosis of FL, grade 1 of 3. A staging bone marrow biopsy was negative for lymphoma. The patient was not treated but was closely followed up.

A computed tomography scan performed about 6 months after the lymphoma diagnosis showed abdominal lymphade-nopathy. The patient subsequently received 4 cycles of ritux-imab and showed a good response.

A few months later, he had hematuria. A bladder biopsy was diagnosed as involved by PBL. Chest and abdominal com-puted tomography did not show osseous lesions. Creatinine and blood urea nitrogen levels were both unremarkable. Serum and urine protein electrophoresis were not performed. The patient began chemotherapy with rituximab, cyclophosphamide, doxo-rubicin, vincristine, and prednisone and received a total of 6 cycles. During the course of treatment, the patient had a 1.2-cm right cystic neck mass. A fine-needle aspiration of the mass was positive for malignant cells, consistent with a poorly dif-ferentiated malignant neoplasm. The neck mass was resected, and a diagnosis of PBL was made.

The patient sought care 1 month later because of an extratesticular scrotal mass. Core biopsies again showed PBL. The patient received 2 cycles of dexamethasone, ifosfamide, cisplatin, and etoposide infusional chemotherapy and was being evaluated for stem cell transplantation. The patient died of disease less than 6 months after the diagnosis of PBL.

Materials and Methods

Morphologic and Immunophenotypic StudiesCase material was retrieved from Weill Cornell Medical

Center, New York, NY. The FL and PBL were diagnosed according to the current diagnostic criteria published by the World Health Organization (WHO) in 2008. The inguinal lymph node, the bladder biopsy specimen, and the cystic neck mass specimen were fixed in 10% neutral buffered formalin, and the bone marrow biopsy specimen was fixed in Bouin. All

samples were embedded in paraffin, and 4-μm sections were cut and stained with H&E for histologic evaluation.

For immunohistochemical studies, paraffin-embedded tissue sections were stained using a Leica autostainer (Leica Microsystems, Bannockburn, IL) following the standard immunoperoxidase staining protocol for each antibody. An external positive control was run against each antibody and a negative control run with each case. The antibodies used to immunophenotype the PBL are listed in ❚Table 1❚. Four-color flow cytometry of the lymph node showing FL was performed using a Becton Dickinson FACSCalibur (BD Biosciences, San Jose, CA) for acquisition and analysis. Becton Dickinson monoclonal antibodies (BD Biosciences) were used and con-jugated to the fluorochromes peridinin chlorophyll protein, fluorescein isothiocyanate, phycoerythrin, and allophyco-cyanin. Direct smears of the fine-needle aspirate of the neck mass were stained with rapid Romanowsky (air-dried) and Papanicolaou (alcohol-fixed) stains.

Immunoglobulin Heavy Chain and BCL2 Gene Rearrangement Analysis by Polymerase Chain Reaction and Sequencing

Molecular studies were performed on DNA extracted from formalin-fixed, paraffin-embedded tissues from the inguinal lymph node involved with FL and the cystic neck mass involved with PBL. Polymerase chain reaction (PCR) to assess the presence of IGH gene rearrangements was performed using the IGH Somatic Hypermutation Assay kit (InVivoScribe Technologies, San Diego, CA) with primers that target the framework 1 (FR1) and joining regions of the IGH gene. The amplified products were visualized in 10% polyacrylamide gel. PCR using primers corresponding to the leader sequence, which is capable of analyzing the entire VH region in conjunction with the JH primers, were also attempt-ed. However, an amplicon of this size could not be obtained from the DNA material extracted from formalin-fixed tissues. A multiplex PCR for the presence of BCL2 gene rearrange-ments was performed to detect the common breakpoints in the major breakpoint region and the minor cluster region of the BCL2 gene.14 PCR products were analyzed by agarose gel electrophoresis, extracted, and cloned for sequencing.

FISH AnalysisFluorescence in situ hybridization (FISH) was performed

on paraffin section slides of the PBL and FL according to the manufacturer’s instructions (Vysis/Abbott Molecular, Des Plaines, IL) with minor modifications. Commercially avail-able LSI IGH/BCL2 dual-color dual fusion probes and the LSI Myc dual-color break-apart probe (Abbott Molecular, Abbott Park, IL) were used to look for t(14;18)(q32;q21) (IGH/BCL2) and c-myc gene rearrangements, respectively. About 200 interphase nuclei were screened for each probe.



Ouansafi et al / Transformation of Follicular to Plasmablastic Lymphoma

Somatic Hypermutation Analysis

A DNA fragment obtained from IGH gene rearrange-ment analysis with the FR1 and JH primers was extracted from the gel and cloned for sequencing. About 30 clones were analyzed. The sequences were compared with the IGH-VDJ germline sequence using IMGT/V-QUEST (http://imgt.cines.fr/IMGT_vquest/share/textes/15) and were aligned by ClustalW2 (http://www.ebi.ac.uk/Tools/clustalw2/index.html). Genealogic trees were constructed based on analysis of these aligned sequences.

Results

Histologic and Immunophenotypic Studies

Histologic examination of the inguinal lymph node revealed complete architectural effacement by an abnormal lymphoid proliferation displaying a nodular growth pattern, composed mainly of small atypical lymphoid cells with cleaved nuclei (centrocytes), consistent with FL, grade 1 of 3. The atypical lymphoid cells were positive for CD20, PAX5, BCL6, and BCL2 by immunohistochemical analysis ❚Image 1❚. Flow cytometry demonstrated a monoclonal κ-restricted B-cell population that was positive for CD10 and negative for CD5. There was no morphologic evidence of metastatic carci-noma. A staging bone marrow biopsy showed no morphologic evidence of involvement by lymphoma or myeloma.

Fine-needle aspirates of the neck mass were hypercel-lular with many singly dispersed, highly atypical, large to intermediate tumor cells. Nuclei were round and eccentrical-ly located with 1 or 2 prominent nucleoli. Some cells were binucleated or multinucleated. The cytoplasm was densely basophilic with occasional fine vacuoles and varied from scant to moderate. The background showed mitoses and few lymphoglandular bodies. Histologic examination of the neck mass showed diffuse, cohesive sheets of large abnor-mal tumor cells with round nuclei, prominent eosinophilic nucleoli, and abundant amphophilic cytoplasm. Numerous mitoses were noted. The cytomorphologic features of these tumor cells were consistent with immunoblasts and plas-mablasts. Results of the immunohistochemical stains are summarized in Table 1. The tumor cells lacked CD45 and did not exhibit a B-cell phenotype, being negative for CD20, PAX5, CD79a, and BCL6. They were, however, immuno-reactive for plasma cell markers such as CD138, MUM1, and PRDM1/Blimp-1 but were negative for cytoplasmic immunoglobulins. Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization and human herpesvirus 8 (HHV-8)–associated latent protein LANA immunostain were both negative. The Ki-67 proliferation index was 90%. These findings are diagnostic of PBL ❚Image 2❚.

Histologic examination of the bladder biopsy and scrotal mass specimens showed similar histologic and immunophe-notypic findings (data not shown).

❚Table 1❚Antibodies Used to Immunophenotype Plasmablastic Lymphoma and the Immunohistochemical Results

Antibody Company Clone Number Results

CD138 AbD Serotec, Raleigh, NC B-A38 PositiveMUM1 DAKO, Carpinteria, CA MUM1p PositiveKi-67 DAKO MIB-1 Positive (90%)PRDM1/BLIMP-1 Santa Cruz Biotechnology, Santa Cruz, CA 3H2E8 PositiveEMA DAKO E29 PositiveCD20 DAKO L26 NegativePAX5 BD Biosciences, San Jose, CA 24/Pax-5 NegativeCD79a DAKO JCB117 NegativeCD3 NeoMarkers, Fremont, CA SP7 NegativeCD5 Vector, Burlingame, CA 4C7 NegativeCD10 Novocastra, Newcastle upon Tyne, England 56C6 NegativeCD45 DAKO 2B11+PD7/26 Negativep53 BioGenex, San Ramon, CA 180-1 NegativeCD22 Novocastra FPC1 NegativecIg-κ DAKO — NegativecIg-λ DAKO — NegativeBCL6 DAKO PG-B6p NegativeALK-1 DAKO ALK-1 NegativeCKAE1/3 Millipore, Temecula, CA AE1/AE3 NegativeCK7 DAKO OV-TL 12/30 NegativeCK20 DAKO Ks20.8 NegativeHMB-45 Enzo, Farmingdale, NY HMB45 NegativeAntihuman Melan-A DAKO A103 NegativeS-100 DAKO — NegativeSynaptophysin Thermo Scientific, Pittsburgh, PA SP11 NegativeChromogranin BioGenex LK2H10 Negative

ALK, anaplastic lymphoma kinase; cIg, cytoplasmic immunoglobulin; CK, cytokeratin; EMA, epithelial membrane antigen.




A B

C D

E F

❚Image 1❚ Histologic and immunophenotypic findings of follicular lymphoma. A, Sections of inguinal lymph node showing neoplastic follicles with attenuated mantle zones (H&E, ×40). B, The nodules are composed predominantly of atypical small cleaved lymphoid cells and a few (<15 per high-power field) atypical large noncleaved lymphoid cells (H&E, ×400). C-F, Immunohistochemical staining showed that the tumor cells express CD20 (C, ×40), PAX5 (D, ×40), BCL2 (E, ×40), and BCL6 (F, ×40).




A B

C D

E F G

❚Image 2❚ Cytologic, histologic, and immunophenotypic findings of plasmablastic lymphoma. A, Fine-needle aspiration of the cystic mass showing large atypical cells composed of abundant cytoplasm and eccentrically located round nuclei with prominent nucleoli (rapid Romanowsky, ×600). B, Sections of the neck mass showing diffuse proliferation of immunoblast-like cells with prominent nucleoli (H&E, ×400). C-G, Immunohistochemical staining showed that the tumor cells express CD138 (C, ×400) and MUM1 (D, ×400) and lack CD45 (E, ×400), CD 20 (F, ×400), and PAX5 (G, ×400).




Gene Rearrangement AnalysisPCR to assess the presence of IGH gene rearrangements

showed distinct monoclonal bands that were similar in the FL (lymph node) and the PBL (cystic neck mass), suggesting that these 2 neoplasms were clonally related. PCR analysis for t(14;18)(q32;q21) (IGH/BCL2) yielded clonal rearrangements at the major breakpoint region with identical migration patterns in the FL and PBL ❚Image 3A❚. Sequencing of the amplicons for IGH/BCL2 rearrangement from the FL and PBL showed an identical junction sequence consisting of BCL2 sequence from

the 3' untranslated region in exon 3 and JH6 sequence, confirm-ing that the 2 tumors are clonally related ❚Image 3B❚.

FISH AnalysisFISH analyses performed in the neck mass involved by

PBL identified the presence of a variant IGH/BCL2 transloca-tion in approximately 100% of the interphase nuclei evalu-ated. In addition, a c-myc gene rearrangement was identified in the PBL in almost all nuclei ❚Image 4❚. FISH did not detect a c-Myc gene rearrangement in the FL.

FLBCL2 exon3 nt 2341-2521

BCL2 exon3 nt 2341-2521

BCL2 exon3 nt 2341-2521

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❚Image 3❚ A, Polymerase chain reaction analysis for IGH and IGH/BCL2 gene rearrangements showed similar rearranged bands between the follicular lymphoma (FL) and the plasmablastic lymphoma (PBL). M, size markers; MBR, major breakpoint region. B, Sequencing of the BCL2/IGH rearrangement from the FL and the PBL demonstrated identical junction sequences, confirming that the 2 tumors are clonally related. T, de novo nucleotide additions; nt, nucleotide.

BA

❚Image 4❚ A, Fluorescence in situ hybridization using a c-myc break-apart rearrangement probe showed 1 normal (orange/green) fusion signal representing 1 nonrearranged myc allele and separate red and green signals (arrows) representing the rearranged myc allele. B, Fluorescence in situ hybridization using a SpectrumOrange-labeled BCL2 probe and a SpectrumGreen-labeled IGH probe (dual-color–dual-fusion translocation probes) showing a variant t(14;18) translocation; 1 yellow fusion signal (long arrow), 2 separate green and red signals (arrows), and normal 14 and normal 18 (arrowheads).




pathways. Typically, the presence of serum paraprotein and/or lytic bone lesions in older patients favors MM. However, widely disseminated bone disease and monoclonal serum immunoglobulin have been described in PBL and could lead to major confusion with MM.22,23 Although PBL and MM have nearly identical immunophenotypic profiles,24 CD56 positivity, occasionally cyclin D1 positivity, and a relatively lower Ki-67 can help identify secondary extramedullary plas-mablastic MM.17 Extranodal localization, a history of immune deficiency, the occasional absence of cytoplasmic immuno-globulins, and the presence of EBV by in situ hybridization are also useful for the diagnosis of PBL.21

Immunoblastic variants of DLBCL and BL with plasma-cytoid differentiation are also part of the differential diagnosis and can be distinguished immunophenotypically from PBL by their strong positivity for B-cell markers, even though CD138 can be occasionally positive. Anaplastic lymphoma kinase–positive DLBCL can show plasmablastic differentiation and is differentiated from PBL by anaplastic lymphoma kinase expression.

Large B-cell lymphoma arising in HHV-8–associated multicentric Castleman disease, also called HHV-8+ PBL, also needs to be distinguished from PBL. The former entity originates from a CD20+ naive B cell that expresses IgM without IGH gene somatic hypermutation and consistently shows stippled nuclear staining for HHV-8–associated latent protein LANA-1, while PBL is not related to HHV-8 infec-tion and arises from a B cell that has switched its phenotype to the plasma cell gene expression program with class-switch and hypermutated immunoglobulin genes. Primary effusion lymphomas and their recently described solid counterparts are also composed of a proliferation of large immunoblastic or plasmablastic cells and are associated with HHV-8 with EBV coinfection. The diagnosis of PBL can be challenging, and it is important for surgical pathologists and hematopathologists to recognize this entity and differentiate it from its numerous mimickers and also be aware that PBL can represent a form of high-grade transformation of a lower grade B-cell lymphoma because of the clinical and therapeutic implications.

It may be argued that rituximab therapy may have accounted for the absence of CD20 in the aggressive lym-phoma. Several studies have shown that B-cell non-Hodgkin lymphomas show CD20– relapse after rituximab therapy. Maeshima et al25 studied 59 B-cell non-Hodgkin lymphomas, including 34 FLs, treated with chemotherapeutic regimens including rituximab and observed postrituximab CD20 loss in relapsed lymphomas in 27% of the cases. However, CD20– DLBCL after rituximab treatment in FL remains positive for CD79a.26 The absence of all pan–B-cell markers together with the uniform strong expression of plasma cell–associated markers in this case cannot be accounted for by rituximab treatment and supports the diagnosis of PBL.

Somatic Hypermutation Analysis

We tried to determine whether the PBL in this case was transformed from the FL through direct evolution from an FL clone or by divergent evolution from a common progenitor cell (CPC) by analysis of the somatic hypermutation (SHM) pattern of the rearranged IGH genes in these 2 tumors. Sequence analysis demonstrated V3-23/D1-26/J4 usage in both tumors, further confirming that they were clonally related. The FL showed a high SHM rate, with homology to the germline sequence ranging from 77.3% to 79.2% and high intraclonal diversity. The PBL demonstrated a similar mutation rate, with 78.6% to 79.8% homology. However, it exhibited a much lower intraclonal diversity compared with the FL. Genealogic trees generated from analysis of multiple sequence clones in both tumors revealed a pattern compatible with divergent evolution from a CPC ❚Figure 1A❚. A hypo-thetical model of transformation of FL to PBL for this case is presented ❚Figure 1B❚.

Discussion

The clinical course of FL has been well described, includ-ing transformation to DLBCL, most commonly with centro-blastic morphologic features and germinal center immunophe-notype.2,3 Maeshima et al,3 in a retrospective study of patients with DLBCL with preexisting or coexisting FL, showed that 95% (41/43) of DLBCLs were of the centroblastic type with only 5% (2/43) showing anaplastic morphologic features. It is important to note that all DLBCLs were CD20+ and CD138–. Rare cases with an immunoblastic appearance have been described,16,17 but a detailed immunophenotype was not included. Changes in terminology and definitions make inter-pretation of these previous reports difficult.

Transformation of FL to PBL is highly unusual and has not been previously reported. PBL represents a group of neoplasms that have immunoblastic or plasmablastic morpho-logic features and an immunophenotype of terminally differ-entiated B cells, ie, absence of CD20 and PAX5 with positive CD38 and CD138.18 PBL was first described in 199719 and was initially classified in the WHO 200120 as a rare variant of DLBCL that manifests in the oral cavity in the setting of HIV infection. In the more recent WHO 2008, PBL is recognized as a separate entity that can arise outside the oral cavity and can occasionally be seen in non-HIV patients, mostly iatro-genic immunosuppressed patients (eg, in posttransplantation settings) or immunocompetent elderly patients.21

The differential diagnoses of PBL include several other neoplasms characterized by a proliferation of atypical cells with plasmablastic/immunoblastic morphologic features. Plasmablastic multiple myeloma (MM) must be distinguished from PBL because of the different clinical management




samples of DLBCL transformed from FL indicates that the DLCBL may arise from a CPC by divergent evolution or may derive from direct evolution from the FL subclone.27 To investigate these 2 possibilities, we analyzed the SHM patterns of the IGH-VDJ regions of the FL and PBL and

We definitively demonstrated that this PBL represented a transformed FL by identifying a clonal relationship between these 2 neoplasms using PCR analysis of IGH and BCL2 gene rearrangements and IGH/BCL2 FISH studies. A recent study based on analysis of the IGH-VH regions of FL and paired

IgVH3-23*01/D1-26/J4

77.29%-79.18%homology

80.13%homology

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?? ** 78.55%-79.81%

homology

Bonemarrow

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t(14;18)

Pre–B cell Naïve B cell

Lymph node Neck mass

GCFL

PBL

c-mycrearrangement

Periphery

A

B

❚Figure 1❚ A, Genealogic trees constructed from analysis of IgVH sequences obtained from follicular lymphoma (FL) and plasmablastic lymphoma (PBL) cloned polymerase chain reaction products. The germline sequence is depicted as a black filled circle, the FL clones as gray filled circles, and the PBL clones as unfilled circles. The putative common progenitor cell (CPC) is not identified experimentally, but its presence is inferred from the common pattern of somatic hypermutations (SHMs) observed in the clones from the FL and PBL samples. The asterisks indicate that these clones from FL and PBL share identical sequence. The numbers inside the circles indicate the number of clones with the same sequence, and the numbers beside the arrows indicate additional mutations in the subsequent clone. The percentage indicates the degree of homology to the germline sequence. The origin of the PBL clone that shares identical sequence with the FL clone is uncertain. It may be derived from evolution from the CPC or from the FL clone. B, Hypothetical model of transformation of FL to PBL in this case. A pre–B-cell acquired chromosomal translocation t(14;18) in the bone marrow and migrated to the periphery. In the lymph node, this cell entered the germinal center (GC), acquired further genetic alterations, and became the CPC, which also spread to other sites. The CPC in the inguinal lymph node gave rise to FL, while the CPC survived the initial line of therapy and gave rise to the dominant clone in the PBL. A minor clone in the PBL (half-filled circles) may be derived from a subclone in the FL that disseminates from the initial lymph node or possibly evolved from the CPC.




rearranged c-myc may be important in the pathogenesis of aggressive lymphomas with plasmablastic features, as a de novo lymphoma or a lymphoma transformed from low-grade B-cell lymphoma. It is conceivable that for c-myc expression to be deregulated in this type of lymphomas, translocation of c-myc may be necessary for it to escape from the normal con-trol of its transcription repressor PRDM1/Blimp-1,33 which is present at high levels in lymphomas showing plasma cell differentiation and in plasma cell myelomas.

We presented the first case of FL transforming to PBL containing t(14;18)(q32;q21) (IGH/BCL2) and c-myc rear-rangements. This study widens the histologic spectrum of FL transformation and also highlights the need for pathologists to be mindful that FL can transform to other subtypes of aggressive lymphomas besides the “garden-variety” DLBCL. Additional molecular study on this unusual case of FL trans-formation may provide further insights on the intriguing pathologic process underlying transformation of indolent lymphomas.

From the 1Division of Hematopathology, 3Laboratory of Cytogenetics, and 4Division of Cytology, Weill Cornell Medical Center-New York Presbyterian Hospital, New York, NY; 2Division of Clinical Immunology, Mount Sinai School of Medicine, New York.

Address reprint requests to Dr Tam: Division of Hematopathology, Dept of Pathology and Laboratory Medicine, Weill Cornell Medical College, 525 E 68th St, ST715, New York, NY 10021.

References 1. Harris NL, Swerdlow SH, Jaffe ES, et al. Follicular

lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:220-226.

2. Davies AJ, Rosenwald A, Wright G, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms. Br J Haematol. 2007;136:286-293.

3. Maeshima AM, Omatsu M, Nomoto J, et al. Diffuse large B-cell lymphoma after transformation from low-grade follicular lymphoma: morphological, immunohistochemical, and FISH analyses. Cancer Sci. 2008;99:1760-1768.

4. Leoncini L, Raphael M, Stein H, et al. Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:262-264.

5. Sham RL, Phatak P, Carignan J, et al. Progression of follicular large cell lymphoma to Burkitt’s lymphoma. Cancer. 1989;63:700-702.

6. Kluin PM, Harris NL, Stein H, et al. 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. Lyon, France: IARC Press; 2008:265-266.

concluded that the transformation of FL to PBL in this case occurred most likely by a divergent evolution from a CPC rather than a direct evolution. Based on the number of SHMs, we postulate that this CPC is derived from a germinal center B cell. However, the exact identity and genetic constituents of this CPC are unknown.

Our findings pointing to the existence of a CPC that links the FL and transformed FL are in line with those previ-ously described by Carlotti et al.27 Its putative existence helps explain the clinical features of this case. The CPC may have survived the initial FL treatment and subsequently acquired new genomic lesions that promoted FL transformation. The existence of a CPC may also provide a mechanistic explana-tion to the scenarios in which FL is transformed to a high-grade lymphoma with discordant stage of differentiation, for example, a precursor B lymphoblastic lymphoma/leukemia or, as seen in the current case, a PBL. It is possible that the CPC, unlike the major tumor clone in FL, has a higher plas-ticity for major transitions along the B-cell differentiation pathway. The molecular events underlying differentiation transition in these unusual forms of FL transformation remain to be found.

FLs undergoing transformation typically retain the IGH/BCL2 translocation, and subsequent secondary genetic abnormalities are believed to be important for the evolu-tion of the disease. The most commonly identified genetic alterations associated with higher grade transformation of FL are TP53 gene mutations, inactivation of CDKN2A and CDKN2B genes, and deregulation of the c-myc gene.28 We identified in our case c-myc rearrangement in association with the IGH/BCL2 translocation. The acquisition of the c-myc gene rearrangement on transformation is consistent with the complementation between c-myc and BCL2 in transgenic systems in which BCL2 is thought to protect against the proapoptotic properties of c-myc, thus allowing for a more robust proliferation signal.28 c-myc gene rear-rangement was reported in 8% (3/38) of transformed FLs in 1 series.29 None of the available matched pretransformation FL biopsy specimens from the corresponding cases demon-strated a rearranged c-myc gene.

Only a few cases of PBL harboring a translocation between the c-myc gene and the IGH gene have been report-ed.22,30-32 Although the actual prevalence of c-myc rearrange-ment in PBL is unknown, activation of c-myc by gene rear-rangement may not be uncommon in PBL. Taddesse-Heath et al22 demonstrated the presence of c-myc rearrangement in 4 of 6 PBLs studied. Bogusz et al30 studied 9 PBLs and detected a c-myc translocation in a third of their cases. All reported PBL cases with a c-myc translocation were de novo lymphoma described in HIV+ patients, and most were positive for EBV. Our case is the only reported case of PBL with c-myc trans-location occurring in an HIV– patient with negative EBV. A




21. Stein H, Harris NL, Campo E. Plasmablastic lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:256-257.

22. Taddesse-Heath L, Meloni-Ehrig A, Scheerle J, et al. Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features [published online ahead of print March 26, 2010]. Mod Pathol. 2010;23:991-999.

23. Teruya-Feldstein J, Chiao E, Filippa DA, et al. CD20-negative large-cell lymphoma with plasmablastic features: a clinically heterogenous spectrum in both HIV-positive and -negative patients. Ann Oncol. 2004;15:1673-1679.

24. Vega F, Chang CC, Medeiros LJ, et al. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Mod Pathol. 2005;18:806-815.

25. Maeshima AM, Taniguchi H, Nomoto J, et al. Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin’s lymphoma after rituximab therapy. Cancer Sci. 2009;100:54-61.

26. Alvaro-Naranjo T, Jaen-Martinez J, Guma-Padro J, et al. CD20-negative DLBCL transformation after rituximab treatment in follicular lymphoma: a new case report and review of the literature. Ann Hematol. 2003;82:585-588.

27. Carlotti E, Wrench D, Matthews J, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood. 2009;113:3553-3557.

28. Lossos IS, Levy R. Higher grade transformation of follicular lymphoma: phenotypic tumor progression associated with diverse genetic lesions. Semin Cancer Biol. 2003;13:191-202.

29. Yano T, Jaffe ES, Longo DL, et al. MYC rearrangements in histologically progressed follicular lymphomas. Blood. 1992;80:758-767.

30. Bogusz AM, Seegmiller AC, Garcia R, et al. Plasmablastic lymphomas with MYC/IgH rearrangement: report of three cases and review of the literature. Am J Clin Pathol. 2009;132:597-605.

31. Chuah KL, Ng SB, Poon L, et al. Plasmablastic lymphoma affecting the lung and bone marrow with CD10 expression and t(8;14)(q24;q32) translocation. Int J Surg Pathol. 2009;17:163-166.

32. Dawson MA, Schwarer AP, McLean C, et al. AIDS-related plasmablastic lymphoma of the oral cavity associated with an IGH/MYC translocation: treatment with autologous stem-cell transplantation in a patient with severe haemophilia-A. Haematologica. 2007;92:e11-e12. doi:10.3324/haematol.10933.

33. Lin Y, Wong K, Calame K. Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science. 1997;276:596-599.

7. Mukhopadhyay S, Readling J, Cotter PD, et al. Transformation of follicular lymphoma to Burkitt-like lymphoma within a single lymph node. Hum Pathol. 2005;36:571-575.

8. Alsabeh R, Medeiros LJ, Glackin C, et al. Transformation of follicular lymphoma into CD30-large cell lymphoma with anaplastic cytologic features. Am J Surg Pathol. 1997;21:528-536.

9. Lau SK, Weiss LM, Zhang Y, et al. Prolymphocytoid transformation of follicular lymphoma with coexpression of CD5 and CD10. Leuk Lymphoma. 2006;47:541-547.

10. Natkunam Y, Warnke RA, Zehnder JL, et al. Blastic/blastoid transformation of follicular lymphoma: immunohistologic and molecular analyses of five cases. Am J Surg Pathol. 2000;24:525-534.

11. Kroft SH, Domiati-Saad R, Finn W, et al. Precursor B-lymphoblastic transformation of grade 1 follicle center lymphoma. Am J Clin Pathol. 2000;113:411-418.

12. De Jong D, Voetdijk BM, Beverstock GC, et al. Activation of the c-myc oncogene in a precursor-B-cell blast crisis of follicular lymphoma, presenting as composite lymphoma. N Engl J Med. 1988;318:1373-1378.

13. Gauwerky CE, Haluska FG, Tsujimoto Y, et al. Evolution of B-cell malignancy: pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene. Proc Natl Acad Sci U S A. 1988;85:8548-8552.

14. Van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257-2317.

15. Brochet X, Lefranc MP, and Giudicelli V. IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucl Acids Res.2008;36:W503-W508.

16. Cullen MH, Lister TA, Brearley RI, et al. Histological transformation of non-Hodgkin’s lymphoma: a prospective study. Cancer. 1979;44:645-651.

17. Yuen AR, Kamel OW, Halpern J, et al. Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol. 1995;13:1726-1733.

18. Teruya-Feldstein J. Diffuse large B-cell lymphomas with plasmablastic differentiation. Curr Oncol Rep. 2005;7:357-363.

19. Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89:1413-1420.

20. Gatter KC, Warnke RA. Diffuse large B-cell lymphoma. In: Jaffe ES, Harris NL, Stein H, et al, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:171-174.

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