ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 25, No. 3 Copyright © 1995, Institute for Clinical Science, Inc. Low Grade Lymphomas in the Elderly* SERHAN ALKAN, M.D. and DONALD S. KARCHER, M.D. Department of Pathology, H. Lee Moffitt Cancer 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 lymphoma (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 leukemia, 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 cytokines 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 chemotherapy 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. Working Formulation 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 follicular lymphoma, 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 lymphocytes. 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 mycosis fungoides/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 bone marrow involvement. L y m p h o c y t i c L e u k e m i a The histologic features of lymph node 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 chromatin 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 trisomy 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/mantle cell lymphoma (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.