ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 25, No. 3 Copyright © 1995, Institute for Clinical Science, Inc.

Low Grade in the Elderly*

SERHAN ALKAN, M.D. and DONALD S. KARCHER, M.D.

Department of Pathology, H. Lee Moffitt Center, University of South Florida, Tampa, FL 33612 and Department of Pathology, George Washington University Medical Center, Washington, DC 20037

ABSTRACT Aging is considered to play an important role in the pathogenesis of non-Hodgkin’s (NHL). Recent epidemiological studies, both in the United States and worldwide, show an increasing incidence of NHL, with the increase also marked in the elderly population. Two hundred thirty-two patients with NHL, aged 60 years and older (44 percent female and 56 percent male), have been analyzed retrospectively. These patients represented 39 percent of all NHL cases seen over a seven-year period at a single institution. Among the elderly cases, 81 (35 percent) were classi­ fied as low-grade NHL, with 44 (19 percent) small lymphocytic lymphoma/ chronic lymphocytic , 2 ( 1 percent) small lymphocytic lympho- plasmacytoid, 13 ( 6 percent) diffuse small cleaved including mantle cell, and 22 (9 percent) follicular small cleaved and mixed cell types. Although the indolent lymphomas are currently treated similarly, recent studies indi­ cate differences in pathogenesis and survival among the classic subtypes. Also, several new low-grade clinicopathologic entities have been described. The clinical, morphologic, immunophenotypic, and genetic fea­ tures of the classic and newer low-grade lymphomas are discussed.

Introduction been shown to be higher than in younger age groups.2 The reason for the increased The overall incidence of non-Hodg­ incidence of NHLs in the elderly popu­ kin’s lymphoma (NHL) in the elderly has lation is not well understood. Aging is increased during the last few decades. 1,2 probably by itself one of the most impor­ The average age-adjusted incidence of tant factors in the development of lym­ NHL in patients older than 65 years has phom as.3,4 ,5 The immunologic deficits.6 T-cell proliferation abnormalities , 5 changes in immunoglobulin gene selec­ tion , 7 and decrease in 4 are * Send reprint requests to: Serhan Alkan, M.D., some of the factors considered to play an Department of Pathology, George Washington Uni­ versity, 23rd Eye Street, NW, Washington, DC important role. Long term exposure to 20037. environmental factors, including chemi­ 218 0091-7370/95/0500-0218 $01.50 © Institute for Clinical Science, Inc. LOW GRADE LYMPHOMAS IN THE ELDERLY 219 cals used in farming, forestry, building Thus, the clinical, morphologic, immu- and painting, are also shown to be risk fac­ nophenotypic, and genetic features of tors in the development of NHL .8,9,10,11,12 both the classic and newer low-grade Although the low-grade NHLs are con­ NHLs are reviewed. sidered to be indolent, they are often fatal diseases. The response to conven­ tional in patients 60 years Patients and Methods of age and older is worse than in the younger population . 13 Although the vari­ Clinical and pathologic data from 232 ous subtypes of low-grade NHLs are cur­ NHL patients 60 years of age and over rently treated similarly, they represent were analyzed. These cases were lymphoid neoplasms with heterogeneous extracted from a total of593 cases of NHL cellular origin, pathogenesis, morpho­ registered at the H. Lee Moffitt Cancer logic features, and clinical behavior. Center (LMCC), Tampa, Florida, from Most of the indolent lymphomas seen January 1987 through May 1994. The in the US and Europe are tumors of cases were classified according to the B-cell origin. of NHL for clinical The low-grade lymphomas in the usage. 14 Survival data were calculated by Working Formulation (WF) classification the Kaplan-Meier method. All patients system include small lymphocytic lym­ underwent physical examination, routine phoma/chronic lymphocytic leukemia laboratory testing, and staging according (SSL/CLL), small lymphocytic lym­ to the Ann Arbor criteria. 15 Eighty-one phoma with plasmacytoid features cases in patients 60 years of age and older (SLL,P1), and , small were classified as indolent NHL, includ­ cleaved cell and mixed cell types (FSC/ ing SLL/CLL, SLL,P1, FSC/M, and dif­ M). In recent years, new low-grade B-cell fuse small cleaved (DSC) cell types. lymphoma entities have been described. Examples of these disorders are man­ tle cell lymphoma, monocytoid B-cell Results and Discussion lymphoma and lymphomas of mucosa associated lymphoid tissues (MALT), and splenic lymphoma with vil­ In figure 1 is shown the distribution of lous . the NHLs in patients 60 years of age and To illustrate the importance of low- older according to the grades of the WF. grade NHLs in elderly patients, the Thirty-five percent were classified as low results are briefly summarized of a retro­ grade, 44 percent intermediate grade, spective analysis of 232 NHL patients and 1 1 percent were representative of aged 60 years and older, concentrating on /Sezary syndrome. the 81 patients (35 percent) diagnosed Male patients were more common than with indolent NHL. These lymphomas female patients (M:F = 1.6:1). In figure 2 were classified according to the WF. is shown the distribution of the indolent Because of lack of adequate immunophe- NHLs according to the WF. Most of the notypic and genotypic data in these patients with indolent lymphomas pre­ cases, re-classification was not possible. sented with stage III or IV. The SLL/CLL Because of the common occurrence of was the most common low-grade lym­ low grade NHLs in elderly patients, it is phoma, followed by FSC/M. The survival particularly important for those who care of the older patients with indolent lym­ for these patients to be familiar with phomas was worse than in the younger major characteristics of these disorders. NHL patient population (figure 3). 220 ALKAN AND KARCHER

50 -

45 -

40 -

35 -

3 0 -

2 5 -

20 - is ­ le­ s' 0- Low Inter High NHL.nos MF/SS

FIGURE 1. Percent of distribution of non- FIGURE 3. Overall survival of patients with low Hodgkin’s lymphoma in patients 60 years of age and grade non-Hodgkin’s lymphoma treated at H. Lee older seen at H. Lee Moffitt Cancer Center, 1987- Moffitt Cancer Center and showing survival for two 1994, classified according to the Working Formula­ age groups (p < 0.01). tion: low, intermediate, and high grades; not other­ wise specified (NOS); and mycosis fungoides/ Sezary syndrome (MF/SS). apparent increased incidence is the development of improved diagnostic cri­ teria. There is a male predominance. The S m a l l L y m p h o c y t i c patients with nodal disease also gener­ L y m p h o m a /C h r o n i c ally show involvement. L y m p h o c y t i c L e u k e m i a The histologic features of involvement in SLL and CLL are identi­ This is the most common indolent lym­ cal. 17 In general, the lymph node archi­ phoma. There has been a recent overall tecture is effaced by diffuse infiltration of increase in the incidence rate of SLL/ small, round lymphocytes with clumped CLL . 16 One possible explanation for this and scanty cytoplasm (figure 4). Nodular growth is uncommon and should raise a suspicion of other diag­ noses, Pseudoproliferation centers and paraimmunoblasts are good morphologic clues in support of SLL/CLL. The pres­ ence of an increased number of paraim­ munoblasts indicates more aggressive clinical behavior. 18 The most common chromosomal abnormalities are 1 2 and struc­ tural abnormalities of the long arms of chromosomes 13 and 14.19,20 Although trisomy 12 is a common finding in CLL/ FIGURE 2. Percent of distribution of subtypes of SLL (up to 54 percent by fluorescent in indolent non-Hodgkin’s lymphoma diagnosed at situ hybridization [FISH] studies), it also the H. Lee Moffitt Cancer Center, 1987—1994, occurs in other lymphomas.21 The small according to the Working Formulation: small lym­ phocytic lymphoma/chronic lymphocytic leukemia lymphocytic lymphomas express CD19, (SLL/CLL); small lymphocytic lymphoma with CD20, CD22, CD23, and surface immu­ plasmacytoid features (SLL,PI); diffuse small noglobulin, most commonly IgM and cleaved/ (DSC/MCL); and follicular lymphoma, small cleaved cell and mixed IgD types.22 These neoplasms are char­ cell types (FSC/M). acterized by expression of CD5 anti- LOW GRADE LYMPHOMAS IN THE ELDERLY 221

Figure 4. T h ere is diffuse effacement of lymph node architecture, with pale growth centers, a characteristic pattern of small lymphocytic lym­ phoma/chronic lympho­ cytic leukemia (SLL/ CLL). No residual germinal centers are present. At higher magni­ fication, uniform infiltra­ tion of small round lym­ phocytes with scant cytoplasm admixed with larger cells with promi­ nent nucleoli (paraimmu- noblasts) is demon­ strated. (H&E 40x, 400x).

gen .23,24 The majority of the previously is over 60 years.27,28 Response rates to classified SLLs in extranodal sites are treatment are worse in patients older now thought to represent low-grade than 60 years.27 Involved lymph nodes B-cell lymphomas of MALT. Although typically show diffuse or partial efface­ most SLLs show round to oval nuclei, ment by a proliferation of small round to occasional moderate nuclear irregularity ovoid lymphocytes, with admixed plas- can be seen and may raise a suspicion of macytoid lymphocytes and plasma cells mantle cell lymphoma. The CD23 is (figure 5). Some neoplastic cells may reported to be useful in distinguish­ show intranuclear inclusions (Dutcher ing SLL/CLL from mantle cell lym­ bodies), and mast cells may be present. phom a .2 5 The level of expression of Immunophenotypic features include CD20 and surface immunoglobulin tends expression of B-cell markers CD19, to be lower in SLL/CLL than mantle CD20, and CD22. These cases usually cell lymphoma.26 lack CD5 and CD10 expression . 2 9 ,3 0 There is no reported consistent specific chromosomal abnormality associated L ymphoplasmacytoid L y m p h o m a with this lymphoma. Only 2 of 82 patients in our study were M a r g in a l Z o n e B -C e l l L y m p h o m a classified in this category. Patients with (M o n o c y t o id B -C e l l L y m p h o m a ) this neoplasm usually present with clini­ cal features of hyperviscosity (related to Monocytoid B-cell lymphoma (MBCL) IgM hypergammaglobulinemia), orga­ is currently referred to as nomegaly and .27 The median age B-cell lymphoma in the newly proposed 222 ALKAN AND KARCHER

FIGURE 5. Small lym­ phocytic lymphoma with plasmacytoid features. Lymph node architecture is effaced by diffuse pro­ liferation of plasmacytoid lymphocytes with moder­ ately abundant cyto­ plasm. (H&E 400x).

European-American classification . 31 “inverted follicular appearance” owing Extranodal marginal zone lymphomas to the expansion of neoplastic monocy­ frequently occur in patients with autoim­ toid B cells; the lighter staining neoplas­ mune disease such as Sjogren’s syn­ tic monocytoid B cells surround the drome. The median age of patients with darker staining normal germinal centers monocytoid B-cell lymphomas is 65 (figure 6 ). This is the inverse appearance years. Some of these neoplasms were of a normal lymph node in which the probably previously classified as SLL/ lighter staining is sur­ CLL or SLL/P1. These lymphomas are rounded by the darker staining man­ characterized by the proliferation of tle zone. monocytoid B-cells. The monocytoid Abnormalities of chromosome 3 and B-cells consist of lymphocytes with abun­ the t( 1 1 ; 18) translocation have been dant cytoplasm and irregular nuclei. Plas­ reported in MALT lymphomas; however, macytoid differentiation is commonly no specific abnormality has been present. Most low-grade lymphomas aris­ reported for the nodal MBCLs. These ing from mucosa-associated lymphoid tis­ tumors show absence of the bcl - 1 sue share many histologic, immunophe- [t(l 1; 14)] and bcl-2 [t(14;18)] gene trans­ notypic, and clinical features with locations.34,35,36 The MBCLs are positive MBCL, and may represent an extra- for B-cell markers CD19, CD20 and nodal counterpart.32,33 CD22. They are CD5, CD 10, and CD23 One of the characteristic findings in negative, which help to differentiate involved lymph nodes is so called them from other low-grade lymphomas. LOW GRADE LYMPHOMAS IN THE ELDERLY 223

ft i t

A * t A F i g u r e 6 . Lymph node is infiltrated by monocytoid B cells sur­ rounding germinal cen­ ters. This pattern is also referred to as “inverted follicular pattern.” The monocytoid B cells have abundant; lightly staining cytoplasm and irregular nuclei. (H&E 40x, 400 x).

S p l e n i c M a r g i n a l Z o n e M a n t l e C e l l L y m p h o m a L y m p h o m a , W i t h o r This tumor represents most of the lym­ W i t h o u t V i l l o u s L y m p h o c y t e s phomas classified as diffuse small This is a proposed provisional entity in cleaved (DSC) cell type in the WF .36 the new European-American classifica­ Although rare cases of tumors originating tion of lymphoid neoplasms.31 Most of from follicular center cells may be the clinical and pathologic features were included, most DSC cell lymphomas take described in the past as splenic lym­ origin from cells normally found in the phoma with villous lymphocytes . 3 7 ,3 8 surrounding germinal cen­ The mean age is over 60 years in most ters in lymph nodes.31 ,3 6 The median age patients. Patients usually present with a at presentation is in the late 50s to mid markedly enlarged and a low 60s. The survival of patients with mantle level of paraproteinemia. Most patients cell lymphoma is much shorter than the have circulating lymphocytes with vil­ patients with other low-grade lympho­ lous cytoplasmic projections (figure 7). mas.39 Involved lymph nodes show dif­ The diagnosis can be made by noting fuse to vaguely nodular infiltration by characteristic involvement of splenic small to medium sized lymphoid cells, white pulp. There is usually bone mar­ frequently with scattered uninvolved row and peripheral blood involvement germinal centers (figure 8 ). Although without lymph node involvement. The most cases show irregular nuclei, there clinical course is usually indolent, and are some with rounder nuclei which splenectomy without chemotherapy may could be difficult to differentiate from be curative in some patients.38 SLL/CLL. A diffuse small lymphoid infil­ 224 ALKAN AND KARCHER

Figure 7. Spleen sec­ tion shows marked white pulp infiltration by small lymphocytes, particularly with marginal zone expansion. The periph­ eral blood smear shows a circulating with villous projections. Unlike hairy cell leuke­ mia the villous projec­ tions show polar distribu­ tion. (H&E 40x , WG 1000 x).

trate without pseudoproliferation centers ing of small cleaved and/or large non­ and paraimmunoblasts should raise a sus­ cleaved cells. The relative number of picion of mantle cell lymphoma. large cells determines the grade.31 The The t(ll;14)(ql3;q32) translocation is tumor cells are usually CD5 negative. characteristic of mantle cell lym­ The presence of CD10 expression is use­ phoma.35,36 This translocation causes a ful in confirming the follicular center cell protein, cyclin Dl, to be over­ origin of this lymphoma; however, expressed in low-grade lymphomas.40 it is not present in all cases of follicu­ The tumor cells are positive for B-cell lar lymphomas. markers CD 19, CD20, and surface immu­ The t(14;18)(q32;q21) chromosome noglobulin, IgM and/or IgD types, and translocation is reported to be present in express CD5, but usually lack the CD23 60 to 85 percent of cases.42 This translo­ antigen.25 The intensity of CD20 and cation causes overexpression of bcl-2 pro­ immunoglobulin chain expression tein which prevents programmed cell is usually higher than that of SLL/CLL.26 death known as .43 Immu- nophenotypic demonstration of bcl-1 pro­ F o l l i c u l a r C e n t e r C e l l L y m p h o m a tein expression within follicles is helpful in differentiating follicular lymphoma The prognosis of follicular lymphomas from .44 However, is worse in the elderly than in younger this protein is also expressed in other patients.41 The neoplastic cells originate low-grade lymphomas, and its expression from the germinal centers of lymph cannot be used for differentiating from nodes. Involved lymph nodes character­ other types of lymphomas. The detection istically show a follicular pattern consist­ of bcl-2 translocation by polymerase LOW GRADE LYMPHOMAS IN THE ELDERLY 225

F i g u r e 8. Mantle cell lymphoma. The lymph node shows a diffuse lym­ phocytic infiltrate, with occasional residual ger­ minal centers. The lym­ IS ^ $ ¿ • 3 ' -7-'' " - wt&Z -*C- r ‘ phocytic infiltrate is com­ wm^ÊÊmm posed of small cells with |S8Qj scant cytoplasm and slightly irregular, cleaved nuclei. (H&E 40x, 400 x). :pf -v-«

ïÿ s c Ô À i'® I s V V chain amplification allows extremely References high sensitivity in detecting the presence 1. Devesa SS, Fears T. Non-Hodgkin’s lymphoma of tumor cells.45 time trends: United States and International Data. Cancer Res 1992;52:5432s—544s. Conclusion 2. Baranovsky A, Myers MH. Cancer incidence and survival in patients 65 years of age and The low-grade lymphomas are in gen­ older. CA-A Cancer Journal for Clinicians 1986;36:26-41. eral diseases of the elderly, and outcome 3. Potter M. Pathogenetic mechanisms in B-cell of therapy with current treatment modali­ non-Hodgkin’s lymphomas in humans. Cancer ties is frequently disappointing. The Res 1992;52:5522s-5528s. diagnosis of low-grade lymphomas usu­ 4. Russo C, Schwab R, Weksler ME. Immune dys- regulation associated with aging. Aging: Immu­ ally requires a comprehensive analysis of nol Infec Dis 1990;2:211-6. the clinical, histologic, immunopheno- 5. Beckman I, Dimopoulos K, Xaioning X, Bradley typic, and genetic findings. The precise J, Henschke P, Ahern M. activation in the elderly: evidence for specific deficiencies in T classification of these neoplasms is prob­ cell/accessory cell interactions. Mech Aging ably the first step in understanding their Dev 1990;51:265-76. basic pathogenic mechanisms and 6. Whisler RL, Williams JW Jr, Newhouse YG. Human proliferative responses during designing a rational approach toward aging. Reduced RNA synthesis and DNA rep­ effective therapy. lication after signal transduction by surface immunoglobulins compared to B cell antigenic Acknowledgment determinants CD20 and CD40. Mech Aging Dev 1991;61:209-22. Thanks are extended to Susan K. Smith for her 7. Klinman NR. Discussion: aging and the expres­ help in obtaining the clinical data for statisti­ sion of the B cell repertoire. Aging Immunol cal analysis. Infect Dis 1990;2:139-42. 226 ALKAN AND KARCHER

8. Greenberg MR. Urbanization and cancer mor- 24. Sundeen JT, Longo DL, Jaffee ES. CD5 expres­ tality-The United States experience, 1950— sion in B-cell small lymphocytic malignancies: 1975. New York: Oxford University Press, 1983. Correlations with clinical presentation and 9. Boring CC, Squires TS, Tong T. Cancer statis­ sites of disease. Am J Surg Pathol 1992; 16: tics, 1991. Ca-Cancer J Clin 1991;41:19-36. 130-7. 10. Cantor KP. Farm ing and mortality from non- 25. Dorfman DM, Pinkus GS. Distinction between Hodgkin’s lymphoma: a case-control study. Int small lymphocytic and mantle cell lymphoma J Cancer 1982;29:239-47. by immunoreactivity for CD23. Mod Pathol 11. Scherr PA, Hutchison GB, Neiman RS. Non- 1994;7:326-31. Hodgkin’s lymphoma and occupational expo­ 26. Almasri NM, Duque RE, Iturraspe J, Everett sure. Cancer Res 1992;52:5503c-5509. ET, Braylan RC. Reduced expression of CD20 12. Pearce N, Bethwaite P. Increasing incidence of antigen as a characteristic marker for chronic non-Hodgkin’s lymphoma: Occupational and lymphocytic leukemia. Am J Hematol 1992;40: environmental factors. Cancer Res 1992;52: 259-63. 5496s. 27. Dimopoulos MA, Alexanian R. Waldenstrom’s 13. Weisdorf DJ, Anderson JW, Glick JH, Oken macroglobulinemia. Blood 1994;83:1452-9. MM. Survival after relapse of low-grade non- Hodgkin’s lymphoma: Implications for marrow 28. Facon T, Brouillard M, Duhamel A, Morel P, transplantation. J Clin Oncol 1992;10:942-7. Simon M, Jouet JP, Bauters F, Fenaux P. Prog­ 14. Rosenberg SA, Berard CW, Brown BW Jr, et al. nostic factors in Waldenstrom’s macroglobulin­ National Cancer Institute sponsored study of emia: A report of 167 cases. J Clin Oncol 1993; 11:1553-8. classification of non-Hodgkin’s lymphomas: Summary and description of a working formu­ 29. Harris N, Bhan A. B-cell neoplasms of the lym­ lation for clinical usage. Cancer 1982;49:2112- phocytic, lymphoplasmacytoid, and 35. types: Immunohistologic analysis and clinical 15. Carbone PP, Kaplan HS, M usshoff K, Smithers correlation. Hum Pathol 1985;16:829-37. DW, Tubiana M. Report of the committee on 30. Hall PA, D’Ardenne AJ, Richards MA, Stans- Hodgkin’s disease staging. Cancer Res 1971; feld AG. Lymphoplasmacytoid lymphoma: An 31:1860-1. immunohistological study. J Pathol 1987;153: 16. Call TG, Phyliky RL, Noel P, Habermann TM, 213-23. Beard CM, O’Fallon WM, Kurland LT. Inci­ 31. Harris NL, Jaffe ES, Stein H, Banks PM, et al. A dence of chronic lymphocytic leukemia in Olm­ revised European-American classification of sted County, Minnesota, 1935 through 1989, lymphoid neoplasms: A proposal form from the with emphasis on changes in initial stage at International Lymphoma Study Group. Blood diagnosis. Mayo Clin Proc 1994;69:323-8. 1994;84:1361-92. 17. Pangalis GA, Nathwani BN, Rappaport H. 32. Ngan B-Y, W arnke R, Wilson M, Takagi K, et al. Malignant lymphoma, well differentiated lym­ Monocytoid B-cell lymphoma: A study of 36 phocytic: Its relationship with chronic lympho­ cases. Hum Pathol 1991;22:409-21. cytic leukemia and macroglobulinemia of Wal­ 33. Nizze H, Cogliatti S, von Schilling C, Feller A, denstrom. Cancer 1977;39:999-1010. et al. Monocytoid B-cell lymphoma: Morpho­ 18. Pugh WC, Manning JT, Butler JJ. Paraimmuno- logical variants and relationship to low-grade blastic variant of small lymphocytic lymphoma/ B-cell lymphoma of the mucosa-associated lym­ leukemia. Am J Surg Pathol 1988;12:907-17. phoid tissue. 1991;18:403-14. 19. Juliusson G, Oscier DG, Fitchett M, et al. Prog­ 34. Pan L, Diss T, Cunningham D, Isaacson PG. nostic subgroups in B-cell chronic lymphocytic The bcl-2 gene in primary B-cell lymphomas of leukemia defined by specific chromosomal mucosa associated lymphoid tissue (MALT). abnormalities. N Engl J Med 1990;323:720-4. Am J Pathol 1989;135:7-11. 20. Faguet GB. Chronic lymphocytic leukemia: An updated review. J Clin Oncol 1994;12:1974-90. 35. Athan E, Foid D, Knowles D. Bcl-1 rearrange­ ment: Frequency and clinical significance 21. Younes A, Pugh WC, Goodacre A, Katz R, et al. among B cell chronic lymphocytic of chromosome 12 in 60 patients with and non-Hodgkin’s lymphomas. Am J Pathol non-Hodgkin’s lymphoma assessed by fluores­ 1991;138:591-9. cence in situ hybridization: differences between follicular and diffuse large cell lym­ 36. Medeiros L, van Krieken J, Jaffe E, Raffeld M. phoma. Genes, Chromosomes Cancer 1994; Association of bcl-1 rearrangements with lym­ 9(3):161-7. phocytic lymphoma of intermediate differentia­ 22. Medeiros LJ, Strickler JG, Picker LJ, et al. tion. Blood 1990;76:2086-90. “Well-differentiated” lymphocytic neoplasms: 37. Melo JV, Hedge U, Parreira A, et al. Splenic Immunologic findings correlated with clinical lymphoma with circulating villous lympho­ presentation and morphological features. Am J cytes: Differential diagnosis of B cell leu­ Pathol 1987;129:523-35. kaemias with large . J Clin Pathol 1987; 23. Burns BF, Warnke RA, Doggett RS, et al. 40:642-51. Expression of a T-cell antigen (Leu-1) by B-cell 38. Mulligan SP, Matutes E, Dearden C, Catovsky lymphomas. Am J Pathol 1983;113:165-71. D. Splenic lymphoma with villous lympho­ LOW GRADE LYMPHOMAS IN THE ELDERLY 227

cytes: natural history and response to therapy 42, Tsujimoto T, Cossman J, Jaffe E, Croce C. in 50 cases. Br J Haematol 1991;78:206-9. Involvement of the bcl-2 gene in human fol­ 39. Lardelli P, Bookman M, Sundeen J, Longo D, licular lymphoma. Science 1985;288:1440-3. Jaffe E. Lymphocytic lymphoma of intermedi- 43. McDonnell T, Deane N, Platt F, Nunez G, Jae­ ate differentiation. Morphologic and immu- ger U, McKeam J, Korsmeyer S. Bcl-2 immuno­ nophenotypic spectrum and clinical correla­ globulin transgenic mice demonstrate tions. Am J Surg Pathol 1990; 14:752. extended B cell survival and follicular lym- 40. Rosenberg C, Wong E, Petty E, Bale A, Tsuji- phoproliferation. Cell 1989;57:79-88. moto Y, Harris N, Arnold A. Overexpression of 44. Limpens J, de Jong D, van Krieken J, Price C, PRAD1, a candidate BCL1 breakpoint region Young B, van Ommen G, Kluin P. Bcl-2 in , in centrocytic lymphomas. Proc Natl benign lymphoid tissue with follicular hyper­ Acad Sci USA 1991;88:9638-42. plasia. Oncogene 1991;6:2271-6. 41. Morel P, Dupriez B, Plantier-Colcher I, Gosse- 45. Gribben JG, Freedman AS, Neuberg D, et al. lin B, Declercq C, Pollet JP, Bauters F. Long­ Immunologic purging of marrow assessed by term outcome of follicular low-grade lym­ PCR before autologous bone marrow transplan­ phoma. A report of 91 patients. Ann Hematol tation for B-cell lymphoma. N Engl J Med 1991; 1993;66:303-8. 325:1525-33.