Originally published as JCO Early Release 10.1200/JCO.2006.07.5671 on October 16 2006

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Clinicopathologic Characteristics and Outcome of Diffuse Large B-Cell Lymphomas Presenting With an Associated Low-Grade Component at Diagnosis

Hervé Ghesquières, Françoise Berger, Pascale Felman, Evelyne Callet-Bauchu, Paul-André Bryon, Alexandra Traverse-Glehen, Catherine Thieblemont, Lucile Baseggio, Anne-Sophie Michallet, Bertrand Coiffier, Gilles Salles

From the Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Service d'Hématologie, Service d'Anatomie Pathologique, and Laboratoire d'Hématologie; Equipe d'Accueil, Pathologie des Cellules Lymphoïdes, Université Claude Bernard, Pierre-Bénite; Laboratoire d'Hématologie, Hôpital E. Herriot, Lyon, France

Address reprint requests to Gilles Salles, MD, PhD, Service d'Hématologie, Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite, France; e-mail: gilles.salles{at}chu-lyon.fr

	ABSTRACT

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Purpose: Some diffuse large B-cell lymphomas (DLBCL) present at diagnosis with associated morphologic features of small B-cell non-Hodgkin's lymphoma (NHL) and may arise from the transformation of a previously unknown indolent low-grade lymphoma. The characteristics and prognosis of these particular DLBCL are not well known.

Patients and Methods: The strict morphologic review of consecutive DLBCL patients diagnosed over 12 years in our department (Hematology Department, Centre Hospitalier Lyon-Sud, Lyon, France) allowed to retrieve 60 DLBCL that could be have occurred from the transformation of marginal zone B-cell NHL (32 patients), follicular NHL (22 patients), and small lymphocytic NHL (6 patients). We compared them to 180 matched patients of de novo DLBCL.

Results: Patients median age was 55 years and presented the following clinical characteristics: poor performance status in 33%, disseminated disease in 97%, more than one extranodal site in 50%, and increased lactate dehydrogenase level in 55%. Complete remission with multidrug chemotherapy regimens was achieved in 60% of the patients, but 48% relapsed: 28% with aggressive and 20% with indolent histology, respectively. Overall survival (OS) and freedom-from-progression rates at 5 years were 57% and 33%, respectively. The matched-control analysis showed that patients with transformed NHL at diagnosis had lower complete response to chemotherapy (P = .004) and higher progression rate (P = .03), whereas no difference was observed in OS (P = .21).

Conclusion: Compared to de novo DLBCL, transformed NHL at diagnosis have similar overall survival but lower complete response to initial treatment and higher risk of indolent relapses.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Diffuse large B-cell lymphomas (DLBCL) represent a heterogeneous group of non-Hodgkin's lymphomas (NHL).¹ Approximately one half of DLBCL patients achieve long-term remission and it appears necessary to identify particular subgroups that would benefit from specific treatment.² Recent studies using gene expression analysis discriminated molecularly distinct forms of DLBCL with distinct prognoses, but this new tool is not yet applicable in routine practice.^3-6

At diagnosis, the morphologic characterization of DLBCL subentities can be complicated by the presence of a small B-cell component. In most cases, this presentation occurs in patients with a history of indolent lymphoma, thus leading to the diagnosis of histologic transformation. However, histologic transformation may be the first manifestation of lymphoma without a history of small B-cell NHL. The heterogeneity of DLBCL could be explained in part by the fact that a proportion of DLBCL were indolent lymphomas diagnosed only at the time of their transformation into DLBCL.

The aim of this study was to identify instances of transformed lymphoma using detailed morphologic, immunophenotypic, and genetic features. We identified a cohort of 60 patients with diffuse large B-cell lymphoma with concomitant small B-cell component at diagnosis. We examined their clinical characteristics and compared their outcome with that of patients diagnosed with de novo DLBCL in a case-matched analysis.

	PATIENTS AND METHODS

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Patient Selection
Patients included in this study were retrospectively selected among 782 patients with DLBCL treated in our department between July 1988 and December 2000. An item in this database prospectively identified patients with DLBCL at diagnosis or at relapse with morphologic features defined by the presence of small B-cell proliferation. Patients with a previously known history of indolent lymphoma and secondary histologic transformation were excluded based on clinical history. With this criteria, 128 patients were initially identified. After histologic review, some patients were classified as small B-cell NHL without strict morphologic criteria for DLBCL diagnosis (41 patients). In 21 DLBCL patients, the formal characterization of indolent lymphoma at diagnosis or at relapse could not be confirmed. Two blastoid variant of mantle cell lymphomas and four unclassifiable lymphomas were further excluded. After this extensive patient review, 60 patients (8% of the DLBCL database) with strict criteria of DLBCL and features of transformed low grade lymphoma at diagnosis were included in this study.

Morphologic Features of the 60 Selected Patients
All available pathologic and cytologic specimens obtained at diagnosis and at relapse were reviewed by three hematopathologists (F.B., P.F., P.A.B.). For each specimen, the morphologic aspects of large B-cell and small B-cell components were described in accordance to the WHO classification.⁷ The presence of small cell proliferation was proven in 56 patients by histologic and cytologic analysis. In four patients, small cell proliferation was only identified by cytologic methods. We analyzed the localization of small B-cell and large B-cell proliferations for each patient and distinguished two situations. In 51 patients, small and large B-cell proliferations coexisted in the same tissue sample. In the follicular lymphoma (FL) group, histologic transformation was revealed by the presence of a diffuse pattern of large B-cell proliferation with remaining features of FL. In marginal zone B-cell lymphoma (MZL) and small lymphocytic lymphoma (SLL) groups, small B-cell and large B-cell populations were generally mixed. In accordance with previous studies, the diagnosis of transformation was established when large B-cell population represented more than 20% of the cell population with a high mitotic count or when well defined sheets of cohesive large cells were observed.^8,9 In the second situation, the diagnosis of small B-cell proliferation was made in a distinct localization from that of the aggressive component (nine patients). For some patients, these two situations were observed simultaneously (29 patients) with, for instance, small and large B-cell populations in the lymph nodes and only small-cell proliferation in the bone marrow.

Immunophenotype and Cytogenetic Analyses
Immunohistochemistry was performed in 52% of cases on formalin or Bouin's fixed paraffin-embedded tissue sections. An antigen retrieval method was used before the avidin-biotin complex immunoperoxidase technique on an automated immunostainer (NEXES Ventana Medical System, Illkirch, France), according to manufacturer's instructions. A panel of monoclonal antibodies including anti-CD20 (Dako, Carpinteria, CA), CD5, CD10, CD23, and CD43 (Novocastra, Newcastle, United Kingdom), Bcl-2, Bcl-6, and Ki-67 (Dako) was used. All the other cases were immunophenotyped on cell suspensions using flow cytometry.

Cytogenetic studies were performed on lymph nodes (22 patients), peripheral blood (four patients), spleen tissue (two patients), and bone marrow (one patient) using RHG-banded metaphases.¹⁰

Clinical Data
Initial staging procedures included complete physical examination, thorax, abdomen, and pelvic computed tomography scans, lumbar puncture, as well as determination of lactate dehydrogenase (LDH), ß 2-microglobuline, and serum albumin levels, blood counts, and protein electrophoresis. Ann Arbor stage and Eastern Cooperative Oncology Group performance status were collected at diagnosis and International Prognostic Index (IPI) and age-adjusted IPI score were further determined.¹¹

Treatment
For induction therapy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) regimens were administrated in 16 patients (27%) and 44 patients (73%), respectively. Twenty-three patients (38%) underwent high-dose therapy (HDT) with stem cell or bone marrow transplantation as part of their initial treatment. None of these patients received monoclonal antibodies as part of their primary treatment.

Statistical Analysis
Overall survival (OS) was defined as the time interval between diagnosis and death or last follow-up. Freedom-from-progression (FFP) was defined as the duration from the onset of therapy to the date of first relapse or disease progression or last follow-up. Complete responses (CR) were defined as the disappearance of all clinical or radiologic lymphoma lesions. Partial responses (PR) were defined as the regression of all measurable lesions by more than 50%. Responses with less than 50% decrease and progressive disease were considered as treatment failures. Survival was analyzed according to the Kaplan-Meier method.¹² Differences between survival curves were evaluated with the log-rank test.¹³ A P value less than .05 was considered significant.

Case-matched analysis was performed by matching one patient with transformed lymphoma at diagnosis with three patients with de novo DLBCL diagnosed during the same period, according to the age-adjusted IPI score, which was only available for 56 patients, so the four remaining patients were matched with an additional group of 12 patients based on age and available characteristics.

	RESULTS

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Morphologic and Immunologic Features
Three groups were determined according to the morphologic features of small B cells: DLBCL arising from transformation of FL (22 patients), MZL (32 patients), and SLL (six patients).

In the FL group, the morphologic aspect of the large B-cell proliferation was centroblastic in 19 patients, while two patients showed features of Burkitt-like lymphoma and one of anaplastic large B-cell lymphoma. Seventeen patients had simultaneous FL and aggressive large B-cell NHL in the same sample (14 lymph nodes and three bone marrow); nine of these patients also had another localization involved only by the low-grade component (four bone marrow, two lymph nodes, one blood, one pleura, and one muscle). In contrast, five patients presented morphologic characteristics of de novo DLBCL, and signs of follicular proliferation were only present in a distinct localization (four bone marrow and one lymph node).

These patients were characterized by the expression of CD10 (22 of 22 tested), Bcl-2 (12 of 12 tested), and Bcl-6 (six of eight tested), a rare expression of CD23 (two of eight tested), and CD5 negativity (nine of nine tested). A BCL2-J_H rearrangement was detected in 10 of 16 patients examined. Cytogenetic analyses demonstrated a t(14;18) translocation in all eight patients examined. One patient with Burkitt-like lymphoma had an associated t(8;22) translocation. In addition, one 6q deletion, one patient with trisomy 7, two patients with trisomy 5, three patients with trisomy 12, and six patients with abnormalities of 17p arm were also observed.

In the MZL group, three clinical subtypes were identified: 24 patients (75%) had features reminiscent of nodal MZL, five of splenic MZL and three of mucosa-associated lymphoid tissue lymphoma. In 29 patients, tissue sample analysis showed morphologic features of transformed MZL with either more than 20% of large B-cells and mitoses or with sheets of large B-cells; 16 of those also presented low-grade MZL features in a distinct biopsy site (13 bone marrow, one lymph node, one blood, one liver). The remaining three patients presented with morphologic features of DLBCL with presence of low-grade MZL in a distinct localization (two bone marrow and one spleen).

The expression of CD5, CD10, and CD23 were analyzed in 20 patients and CD43 was analyzed in five patients. All were negative for CD5 and CD10, three patients expressed atypically CD23 and one patient was positive for CD43. Of the 16 patients with cytogenetic analyses, four exhibited a normal caryotype, whereas trisomy 3 and others structural rearrangements of chromosome 3 were observed in six patients. Four patients presented trisomy 18 and four patients exhibited a 7q deletion. One t(11;14) translocation was observed in this group but the morphology was not that of blastoid mantle-cell lymphoma. Two patients presented respectively a t(3;14) and a t(3;22) translocation. Two patients presented abnormalities of the long arm of chromosome 17.

In the SLL group of six patients, five patients were diagnosed with large and small B-cell proliferations in the same localization and four of them also had an isolated low-grade component in the bone marrow. The last patient of this group was considered to have Burkitt-like lymphoma with a small lymphocytic proliferation in the bone marrow.

All six patients were CD5+, CD23+ and CD10–, and CD43 was positive in the five tested cases. One patient presented both 11q and 13q deletions and another one trisomy 12 together with 14q deletion. A third patient exhibited both 17p and 6q deletions. The Burkitt-like lymphoma patient had a t(8;22) with 6q deletion, trisomy 3, and deletions of 7q and 17p. One patient had a normal karyotype and cytogenetic analysis was not performed for one patient.

Clinical Presentation
Differences observed in the clinical presentation within the three morphologic groups are listed in Table 1. The sex ratio was 1.8:1 and the median age was 55 years (range, 34 to 78). Approximately one third of the patients had a poor performance status (33%) or presented with B symptoms (32%). Most patients (89%) had advanced Ann Arbor stage at diagnosis and more than one extranodal site was involved in 50% of patients. Of note, CNS involvement was present in 12% of the patients. Bone marrow involvement was present in 72% of patients consisting in most instances (48% of patients) as small B-cells. High LDH level and ß 2-microglobulin level above 3 mg/L were observed in 55% and 56% of the patients, respectively, anemia in 48% and low serum albumin level in 29%. Nineteen patients (32%) had an M component, predominantly in the MZL group. For this last group, characteristics of each clinical subtypes, nodal MZL, splenic MZL, and mucosa-associated lymphoid tissue lymphoma (Table 2) reflect the predominance of transformed nodal marginal zone lymphoma cases (24 of 32 patients) presenting as a widely disseminated disease (multiple site of involvement including various nodal areas and bone marrow).

Response to Treatment and Relapse
Patients achieved CR or PR after induction therapy in 47% and 40% of the cases, respectively (Table 3). Among the 28 patients in CR after induction treatment, 12 underwent HDT and 16 underwent conventional chemotherapy. The remaining 24 PR patients received consolidation with HDT (n = 11) or conventional chemotherapy (n = 13). At the end of first line therapy, 36 patients (60%) were then in CR, 16 in PR (27%), and eight in primary refractory (13%).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Overall survival and (B) freedom-from-progression survival of patients with diffuse large B-cell lymphomas (DLBCL) and patients with transformed lymphomas at diagnosis; the dotted line denotes patients with transformed DLBCL and the complete line denotes the control matched group with de novo DLBCL.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival of patients with transformed lymphomas at diagnosis according to the type of initial consolidation treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
We report here 60 patients with DLBCL with the presence of morphologic features of indolent lymphoma at time of initial diagnosis. According to the small B-cell component morphology and the immunophenotype, patients could be discriminated into three groups originating from follicular, marginal zone B-cell, and SLLs, respectively. Chromosomal aberrations usually found in the related indolent lymphomas were also present, such as a t(14;18) in each case of the FL group analyzed, recurrent aberrations of chromosomes 3, 18, and 7 usually described in MZL in the corresponding group and common deletions (6q, 11q, 13q, 14q) or trisomy (3 and 12) of chronic lymphocytic leukemia in the SLL group.^14-17 A majority of these patients also exhibited additional genetic alterations with abnormalities of chromosomes 5, 6, 7, 12, and 17 associated with histologic transformation of FL into aggressive lymphoma—for instance in the FL group.^18-21 Although all these cytogenetic abnormalities were already observed in large series of DLBCL,^22,23 they were not associated with specific clinicopathologic context. In this series, these cytogenetic aberrations represent the hallmark of the low grade component at the origin of lymphoma.

In our study, three patterns of morphologic transformation could be observed: DLBCL with presence of low-grade lymphoma in a distinct area; colocalization, in the same biopsy specimen, of DLBCL and a lesion of low-grade lymphoma; and aspect of low-grade lymphoma with an increased number of large cells and mitoses or increased proliferation index, or with sheets of large B cells. While there is actually no consensus on the definition of transformation, the proportion of more than 20% of large cells with mitoses or increased proliferation index was already proposed by other authors.^8,15,24-26

Although we definitely established the morphologic association of high- and low-grade lymphomas, we could not prove the clonal relationship between the two lymphoma components.²⁷ The retrospective nature of our study and the strict selection criteria may also have underestimated the real numbers of those cases. Of note, these transformed DLBCL are distinct from composite lymphomas, which frequently include markedly distinct histologic entities.²⁸

Clinical characteristics of aggressiveness described in large DLBCL series^11,29 were apparently more frequent in these transformed lymphomas; for instance, elevated LDH and poor performance status in one half and one quarter of patients, respectively. The majority of the patients also presented a disseminated disease partly due to bone marrow involvement by small B-cells, but only six patients were categorized as stage IV based on the sole bone marrow involvement as an extranodal disease site.

Previous clinical reports of DLBCL with divergent histology at initial staging are rare and generally limited to aggressive lymphomas with presence of small cells in the bone marrow.^30-33 In these reports, DLBCL with discordant bone marrow involvement had a similar prognosis to DLBCL without bone marrow infiltration. To evaluate more accurately the prognosis of transformed lymphomas at diagnosis, patients were compared with a control group of de novo DLBCL matched according to the age-adjusted IPI. Patients received similar first-line treatment and CR rate in the transformed lymphoma group was lower than in de novo DLBCL (60% v 79%). Half of the patients with transformed lymphomas presented a relapse, which was indolent lymphoma in 41% of patients. Cabanillas et al³⁴ reported 43% of relapse rate for DLBCL with initial discordant histology compared with only 3% for pure DLBCL and Robertson et al³² observed that DLBCL with discordant bone marrow involvement at diagnosis presented a continuous risk of indolent relapse. However, two other studies did not confirm this increased risk of relapse in DLBCL with small B-cell bone marrow involvement.^30,33 These indolent relapses could explain, in our series, the shorter FFP of transformed lymphomas compared with de novo DLBCL. At time of indolent relapse, salvage treatment elicits new objective response in about half of the cases eventually accounting for the similar OS of transformed lymphomas and DLBCL.

Altogether, our observations suggest that transformed lymphomas should be managed as aggressive lymphomas and, with an equivalent OS, there is presently no argument to distinguish them from de novo DLBCL. However, transformed lymphomas may benefit from specific treatments increasing the CR rate and reducing the risk of indolent relapse. In our study, FFP and OS seemed to be improved by HDT compared with sequential chemotherapy. For patients with indolent lymphoma relapse, new therapeutic approaches could be proposed, such as rituximab, that target effectively low-grade or residual disease. Monoclonal antibodies, now widely used in first-line treatment, may also increase the CR rate and influence the outcome of those transformed lymphomas.

In conclusion, our data indicate that a small proportion of DLBCL are indolent lymphomas diagnosed at the time of transformation. These lymphomas have an aggressive clinical presentation and a survival similar to de novo DLBCL when treated as aggressive lymphomas. Future therapeutic approaches have to consider the lower CR rate and frequent low-grade relapses of those patients. The identification of these lymphoma subtypes and their biologic characterization should be proposed in prospective studies for a better understanding of DLBCL heterogeneity.

	Appendix

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View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Overall survival of patients with transformed lymphomas at diagnosis according to the age-adjusted International Prognostic Index score.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Overall survival of patients with transformed lymphomas at diagnosis with or without complete response to initial treatment.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Hervé Ghesquières, Françoise Berger, Gilles Salles Administrative support: Bertrand Coiffier, Gilles Salles Provision of study materials or patients: Pascale Felman, Evelyne Callet-Bauchu, Paul-André Bryon, Alexandra Traverse-Glehen, Catherine Thieblemont, Lucile Baseggio, Anne-Sophie Michallet, Bertrand Coiffier, Gilles Salles Collection and assembly of data: Hervé Ghesquières, Françoise Berger, Pascale Felman, Evelyne Callet-Bauchu, Paul-André Bryon, Alexandra Traverse-Glehen, Catherine Thieblemont, Lucile Baseggio, Bertrand Coiffier, Gilles Salles Data analysis and interpretation: Hervé Ghesquières, Françoise Berger, Pascale Felman, Evelyne Callet-Bauchu, Paul-André Bryon, Alexandra Traverse-Glehen, Lucile Baseggio, Bertrand Coiffier, Gilles Salles Manuscript writing: Hervé Ghesquières, Françoise Berger, Bertrand Coiffier, Gilles Salles Final approval of manuscript: Hervé Ghesquières, Françoise Berger, Pascale Felman, Evelyne Callet-Bauchu, Bertrand Coiffier, Gilles Salles

 

	NOTES

 
published online ahead of print at www.jco.org on October 16, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Pileri SA, Dirnhofer S, Went P, et al: Diffuse large B-cell lymphoma: One or more entities? Present controversies and possible tools for its subclassification. Histopathology 41 : 482 -509, 2002[CrossRef][Medline]

2. Coiffier B: Diffuse large cell lymphoma. Curr Opin Oncol 13 : 325 -334, 2001[CrossRef][Medline]

3. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403 : 503 -511, 2000[CrossRef][Medline]

4. Shipp MA, Ross KN, Tamayo P, et al: Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8 : 68 -74, 2002[CrossRef][Medline]

5. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 : 1937 -1947, 2002[Abstract/Free Full Text]

6. Lossos IS, Czerwinski DK, Alizadeh AA, et al: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350 : 1828 -1837, 2004[Abstract/Free Full Text]

7. Harris NL, Jaffe ES, Stein H, et al: The World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues. Lyon, France, IARC press, 2001

8. Nathwani BN, Anderson JR, Armitage JO, et al: Marginal zone B-cell lymphoma: A clinical comparison of nodal and mucosa-associated lymphoid tissue types. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 17 : 2486 -2492, 1999[Abstract/Free Full Text]

9. Nathwani BN, Drachenberg MR, Hernandez AM, et al: Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Semin Hematol 36 : 128 -138, 1999[Medline]

10. Shaffer LG, Tommerup N (eds): ISCN: An International System for Human Cytogenetic Nomenclature (ed 2005). Basel, Switzerland, S. Karger Publishers, 2005

11. The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329 : 987 -994, 1993[Abstract/Free Full Text]

12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53 : 157 , 1958

13. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II: Analysis and examples. Br J Cancer 35 : 1 -39, 1977[Medline]

14. Dierlamm J, Pittaluga S, Wlodarska I, et al: Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features. Blood 87 : 299 -307, 1996[Abstract/Free Full Text]

15. Lloret E, Mollejo M, Mateo MS, et al: Splenic marginal zone lymphoma with increased number of blasts: An aggressive variant? Hum Pathol 30 : 1153 -1160, 1999[CrossRef][Medline]

16. Camacho FI, Mollejo M, Mateo MS, et al: Progression to large B-cell lymphoma in splenic marginal zone lymphoma: A description of a series of 12 cases. Am J Surg Pathol 25 : 1268 -1276, 2001[CrossRef][Medline]

17. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343 : 1910 -1916, 2000[Abstract/Free Full Text]

18. Richardson ME, Chen QG, Filippa DA, et al: Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes. Blood 70 : 444 -447, 1987[Abstract/Free Full Text]

19. Armitage JO, Sanger WG, Weisenburger DD, et al: Correlation of secondary cytogenetic abnormalities with histologic appearance in non-Hodgkin's lymphomas bearing t(14;18)(q32;q21). J Natl Cancer Inst 80 : 576 -580, 1988[Abstract/Free Full Text]

20. Tilly H, Rossi A, Stamatoullas A, et al: Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood 84 : 1043 -1109, 1994[Abstract/Free Full Text]

21. Hough RE, Goepel JR, Alcock HE, et al: Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma. Br J Cancer 84 : 499 -503, 2001[CrossRef][Medline]

22. Schlegelberger B, Zwingers T, Harder L, et al: Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group. Blood 94 : 3114 -3120, 1999[Abstract/Free Full Text]

23. Bea S, Colomo L, Lopez-Guillermo A, et al: Clinicopathologic significance and prognostic value of chromosomal imbalances in diffuse large B-cell lymphomas. J Clin Oncol 22 : 3498 -3506, 2004[Abstract/Free Full Text]

24. de Jong D, Boot H, van Heerde P, et al: Histological grading in gastric lymphoma: Pretreatment criteria and clinical relevance. Gastroenterology 112 : 1466 -1474, 1997[CrossRef][Medline]

25. Ferreri AJ, Freschi M, Dell'Oro S, et al: Prognostic significance of the histopathologic recognition of low- and high-grade components in stage I-II B-cell gastric lymphomas. Am J Surg Pathol 25 : 95 -102, 2001[Medline]

26. Hsi ED, Eisbruch A, Greenson JK, et al: Classification of primary gastric lymphomas according to histologic features. Am J Surg Pathol 22 : 17 -27, 1998[CrossRef][Medline]

27. Kroft SH: Lymphoma transformation: Genetic relatedness, stealth lymphomas, and the final frontier. Am J Clin Pathol 116 : 811 -814, 2001[CrossRef][Medline]

28. Kim H: Composite lymphoma and related disorders. Am J Clin Pathol 99 : 445 -451, 1993[Medline]

29. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 : 2780 -2795, 1998[Abstract]

30. Fisher DE, Jacobson JO, Ault KA, et al: Diffuse large cell lymphoma with discordant bone marrow histology: Clinical features and biological implications. Cancer 64 : 1879 -1887, 1989[CrossRef][Medline]

31. Conlan MG, Bast M, Armitage JO, et al: Bone marrow involvement by non-Hodgkin's lymphoma: The clinical significance of morphologic discordance between the lymph node and bone marrow: Nebraska Lymphoma Study Group. J Clin Oncol 8 : 1163 -1172, 1990[Abstract]

32. Robertson LE, Redman JR, Butler JJ, et al: Discordant bone marrow involvement in diffuse large-cell lymphoma: A distinct clinical-pathologic entity associated with a continuous risk of relapse. J Clin Oncol 9 : 236 -242, 1991[Abstract]

33. Hodges GF, Lenhardt TM, Cotelingam JD: Bone marrow involvement in large-cell lymphoma. Prognostic implications of discordant disease. Am J Clin Pathol 101 : 305 -311, 1994[Medline]

34. Cabanillas F, Velasquez WS, Hagemeister FB, et al: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 : 1024 -1108, 1992[Abstract/Free Full Text]

Submitted May 25, 2006; accepted September 6, 2006.

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