Primary Brain Lymphoma: A Report of Eight Cases from A Medical Center in Southern Taiwan

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1 Chi nese Med i cal Jour nal (Taipei) 2002;65: Orig i nal Primary Brain Lymphoma: A Report of Eight Cases from A Medical Center in Southern Taiwan Shih-Sung Chuang 1 Po-Shing Lee 1 Ching-Nan Lin 1 Tsung-Chia Tsai 2 Chung-Ching Chio 3 Jenny Que 4 Chien-Tai Huang 5 1 De part ment of Pa thol ogy; 2 De part ment of Ra di ol ogy; 3 De part ment of Neu ro sur gery; 4 De part ment of Ra di a tion On col ogy; 5 Di vi sion of He ma tol ogy/on col ogy; De part ment of In ter nal Med i cine, Chi-Mei Med i cal Cen ter, Tainan, Tai wan, R.O.C. Key Words anaplastic large cell lym phoma; brain; lym phoma Background. Pri mary brain lym phoma (PBL) in Tai wan has been re - ported only in three se ries with very lim ited immunophenotypic char - acterization. Methods. We retrospectively studied PBL cases with his tory re view, immunohistochemistry, and in situ hybridization (ISH) for Epstein- Barr vi rus-encoded mrna (EBER) from a sin gle in sti tu tion in south - ern Tai wan dur ing Results. We found eight cases of PBL in clud ing four males and four fe - males with mean age of 64.1 years and me dian of The ma jor pre - senting symp toms were head ache, poor mem ory, slurred speech, and hemiplegia in three pa tients each. All pa tients had stage I sol i tary tu - mor. Half of the patients received tumor excision, the other half, stereotactic biopsy. Seven cases were of diffuse large B-cell type (DLBL), with ex pres sion of bcl-2 in six cases. They were all neg a tive for CD5, CD10, bcl-6, and EBER. The eighth patient had anaplastic large cell lym phoma (ALCL) of T-cell phe no type with ex pres sion of cytotoxic mark ers and was pos i tive for EBER. Two were lost to fol low up. The me dian fol low-up time for the re main ing six was 11.2 months (range, ). They all re ceived ra dio ther apy with ini tial com plete re mis sion. Two died of the dis ease, an other of cardiopul monary fail - ure, and the other of stroke or re cur rence. The re main ing two were free of dis ease for 9.6 and 25.0 months af ter ra dio ther apy alone. The 1-year sur vival rate was 60%. Conclusions. We have fully char ac ter ized eight cases of PBL, in clud - ing seven DLBLs and one ALCL, in south ern Tai wan that oc curred in an older age group. Old age, immunophenotype (bcl-2-positivity and bcl-6-negativity), and lack of systemic chemotherapy were probably re spon si ble for the shorter sur vival as com pared to other stud ies. Ra - dio ther apy seems to be ef fec tive for in duc ing com plete re mis sion and even long-term sur vival in some pa tients, how ever, sys temic che mo - ther apy should be ad min is tered to pre vent re cur rence and to achieve long-term sur vival. [Chin Med J (Taipei) 2002;65: ] Pri mary brain lym phoma (PBL) is very rare. It ac - counted for 2.5% of all non-hodgkin s lym - phoma (NHL) in south ern Tai wan ac cord ing to our pre vi ous study. 1 There have been only three larger se - ries on PBL from Tai wan. Huang et al re ported seven cases in 1987, with em pha ses on the pro tean clin i cal and ra dio log i cal man i fes ta tions. 2 There were five dif - fuse histiocytic lym pho mas and one case each of dif - Re ceived: April 30, Ac cepted: November 15, Cor re spon dence to: Ching-Nan Lin, MD, De part ment of Pa thol ogy, Chi-Mei Med i cal Cen ter, 901, Chung Hwa Road, Yung Kang City, Tainan 710, Tai wan. Fax: ; cnlinhhc@ms5.hinet.net

2 April 2002 Pri mary Brain Lym phoma in South ern Tai wan 173 fuse poorly-differentiated lymphocytic lym phoma and T-cell lymphoblastic lym phoma. Limited immu - nophenotyping was de scribed in only two cases. A re - cent re port by Cheng et al stressed the ef fi cacy of sys - temic che mo ther apy with the BOMES pro to col in treat ing 14 PBL. 3 One was of T-cell lin eage, the oth - ers, B-cell. The other re cent re port by Chen et al de - scribed 10 ce re bral and three spi nal NHL from south - ern Tai wan with fo cus on the ef fi cacy of ra dio ther - apy. 4 They found that the ini tial re sponse to ra di a tion ther apy was sat is fac tory but lo cal re lapse fre quently oc curred. Dif fuse large cell lym phoma was the most com mon his tol ogy type and ac counted for 11 of 14 cases. How ever, immunophenotyping was not de - scribed in any of these cases. In a re port of PBL in 18 Hong Kong Chi nese pa tients, one case had post-trans - plant lymphoproliferative dis or der, the re main ing 17 immunocompotent pa tients had dif fuse large B-cell lym phoma (DLBL) ex cept one case of Bur kitt s lym - phoma. 5 For a better un der stand ing of the clini - copathologic char ac ter iza tion of PBL in south ern Tai - wan, we ret ro spec tively stud ied eight cases of PBL in our hos pi tal with re view of history and hemat - oxylin-eosin sec tions, immunohistochemical study, and in situ hy brid iza tion (ISH) for Ep stein-barr vi - rus-encoded mrna (EBER). Methods A to tal of eight cases of PBL dur ing were re trieved from the Pa thol ogy files of Chi-Mei Med i cal Cen ter, lo cated in Tainan, a city in south ern Tai wan. The first five cases had been in cluded in our pre vi ous study of the clas si fi ca tion of ma lig nant lym - phoma in south ern Tai wan. 1 The eighth case was the sub ject of a case re port. 6 His tory of all pa tients was re viewed. The Ann Ar - bor stag ing sys tem for extranodal lym phoma was used for stag ing. 7 The over all sur vival time was cal cu lated from the date of di ag no sis to the date of last fol low-up or death. The spec i mens from all the cases were fixed ei ther in 10% unbuffered for ma lin or B-5 so lu tion, pro - cessed by rou tine meth ods, and em bed ded in par af fin. All the orig i nal hematoxylin and eosin-stained sec - tions were re viewed. Immunohistochemical stains were per formed for each case based on the light mi - cro scopic and clin i cal find ings. Sec tions of 4-µm thick ness were used for hematoxylin-eosin, immuno - histochemical stain, and in situ hy brid iza tion. Immunohistochemical study was per formed in the OptiMax Plus au to matic cell stainer (BioGenex, San Ramon, CA, USA) using the la beled streptavidinbiotin peroxidase method (Horse rad ish peroxidase kit, BioGenex) with Super Sen si tive Immunode - tection Sys tem (BioGenex). An an ti gen re trieval tech - nique was ap plied when needed for each in di vid ual an ti body. The ini tial panel of an ti bod ies for immuno - phenotyping in cluded CD3, CD20, CD79a (DAKO, Carpinteria, CA, USA) and CD43 (BioGenex). Tu - mors were as signed to be B-cell lin eage when the neo - plas tic cells were re ac tive for CD20 and/or CD79a but not CD3 and/or CD43. T-cell lin eage was con sid ered when the neo plas tic cells ex pressed CD3 and/or CD43 but not CD20 and/or CD79a. The B-cell neoplasms were fur ther stained us ing an ti bod ies against bcl-2, CD5, CD30 (DAKO), bcl-6, CD10, and cyclin D1 (Novocastra, New cas tle upon Tyne, UK). Ad di tional an ti bod ies were used for the case of T-cell lym phoma in clud ing ALK-1, CD30 and p80 (DAKO), CD45RO (UCHL-1), ep i the lial mem brane an ti gen (EMA) (BioGenex), CD56, granzyme B (Monosan, Mono - san/caltag, San Fran cisco, CA), βf1 (Endogen, Woburn, MA), and T-cell intracellular an ti gen-1 (TIA-1) (Immunotech, Coul ter/immunotech, West - brook, ME). The immunostainings for p80 and ALK-1 were done at Mayo Clinic, Roch es ter, MN us - ing the Techmate De tec tion Sys tem (Ventana Corp., Tuc son, AZ) with steam EDTA for an ti gen re trieval. The ISH study for EBER was per formed in the case of anaplastic large cell lym phoma. Poly mer ase chain re ac tion-derived, digoxigenin-labeled DNA probes spe cific for EBER were used, as pre vi ously de - scribed. 8 Patho logic find ings and clin i cal data were cor re - lated and all cases were clas si fied ac cord ing to the Re - vised Eu ro pean-american Clas si fi ca tion of Lym - phoid Neo plasms (REAL) scheme. 9 The DLBL sub - type in the REAL clas si fi ca tion was fur ther clas si fied

3 174 Shih-Sung Chuang, et al. Chi nese Med i cal Jour nal (Tai pei) Vol. 65 No. 4 us ing the Kiel scheme into centroblastic lym phoma with four morphologic vari ants (monomorphic, poly - mor phic, multilobated, and centrocytoid) and immu - noblastic lym phoma. 10 Du ra tion of fol low-up was cal cu lated from the time of di ag no sis to ei ther death or un til March, The causes of death were re corded as ei ther due to dis - ease pro gres sion or other spec i fied un re lated dis eases. One-year sur vival rate was cal cu lated by the num ber of pa tients sur viv ing lon ger than one year di vided by the num ber of deaths within this pe riod plus the num - ber of those sur viv ing lon ger than one year. Re sults The clin i cal find ings are sum ma rized in Ta ble 1. There were equal num bers of male and fe male pa - tients. They were all immunocompetent with out any sign of immunosuppression. The mean age was 64.1 with a me dian of All pa tients had mul ti ple neu - ro logic symp toms. The most com mon symp toms were head ache, poor mem ory, slurred speech, and hemip - legia in three pa tients each. All pa tients had a sin gle tu mor and stage I dis ease at di ag no sis by CT and/or MRI study. Se ro logic tests for HIV and HTLV-1 in - fection were neg a tive in Case 8. The other seven pa - tients were not tested for both vi ruses. Five re ceived tu mor ex ci sion as the pri mary ther apy; three, stereo - tactic bi opsy. Cases 1 and 2 re ceived sec ond ex ci sion for re cur rent tu mors. In this co hort of eight pa tients, two (Cases 2 and 3) were lost to fol low-up. Case 2 had lo cal re cur rence three weeks af ter tu mor ex ci sion. She was then lost to fol low-up af ter the first frac tion of ra dio ther apy. The me dian fol low-up time for the re main ing six pa tients was 11.2 months (range, ). They all re ceived ra dio ther apy with ini tial com plete re mis sion and sub - se quent re cur rence in two pa tients. Two (Cases 1 and 4) died of the dis ease. Case 4 ex pe ri enced com plete re mis sion af ter ra dio ther apy for at least 9 months judged by CT scan. She de vel oped re cur rence with Table 1. Clinical features of eight primary brain lymphomas Case/sex/ age(y) CC Location Size (cm) Op C/T R/T Outcome Survival (mo.) 1/M/76 Poor memory, slurred speech, R t hemiplagia L t temporal 5 Ex twice 2/F/53 Headache, vomiting R t temporal 4 Ex twice 3/M/72 R t paralysis, stool and urine incontinence, aphasia 4/F/60 5/F/66 6/M/80 Conscious disturbance, urinary incontinence Poor memory, speech disturbance, general weakness Conscious disturbance, poor memory, slurred speech None MTX for Recur Yes, unknown dose 1 st Recur 1 mo. after R/T, 2 nd Recur 3 mo. after re-ex. DOD Unknown Recur in left cerebellum in 0.7 mo.; LTF in 1 mo. after C/T L t caudate 4 Ex Unknown Unknown LTF - L t frontal 5 Ex MTX for Recur L t frontal 4 Stereo bx Bil basal ganglia 5 Stereo bx 7/M/60 Dizziness, headache R t occipital 3 Stereo bx 8/F/46 Headache, blurred vision, R t hemiplagia L t occipitoparietal WB: 46; TBB: 8; WB: 18 for Recur CR; Recur with ventricular seeding in 11 mo.; DOD None WB: 40; TBB: 20 CR DOUD (cardiopulmonary failure) none WB: 45; TBB: 14 CR for 5 mo. then conscious change till death. DOD or DOUD (recurrence or stroke?) None WB: 50.4; TBB: 14.4 CR NED 5 Ex None WB: 40; TBB: 20 CR NED CC = chief complaint; Op = operative method; C/T = chemotherapy; R/T = radiotherapy; Ex = excision; DOD = died of disease; MTX = intrathecal methotrexate; LTF = loss to follow up; WB = whole brain; TBB = tumor bed boost; CR = complete remission; Stereo bx = stereotactic biopsy; DOUD = died of unrelated disease; Bil = bilateral; NED = no evidence of disease

4 April 2002 Pri mary Brain Lym phoma in South ern Tai wan 175 Table2. Immunohistochemical results of the seven primary brain diffuse large B-cell cell lymphomas Case No CD Bcl-2 Bcl a Cyc D 1 P N N N N P P* N P N 2 P N N N N P N N P N 3 P N N N N P N N P N 4 P N N N N P N N P N 5 P N N N N P N N P N 6 N N N N N P N N P N 7 P N N N N P N N P N CD = cluster designation; Cyc D = cyclin D1; P = positive; N = negative; P* = weak cytoplasmic positivity. A B MRI show ing ven tric u lar ce re bral spi nal fluid (CSF) seed ing with subependymal in va sion at the trigone of the right fron tal and oc cip i tal horns 11 months af ter op er a tion. Nu mer ous large lym phoma cells were iden ti fied in the CSF. Her dis ease pro gressed de spite sec ond course of ra dio ther apy to the whole brain and intrathecal methotrexate in fu sion. She died of lym - phoma 13.7 months af ter di ag no sis. Case 5 died of cardiopulmonary fail ure with com plete re mis sion of her lym phoma. Case 6 was 80 years-old and re ceived ra dio ther apy for a to tal of 59 Gy. A CT scan taken 5 months later dur ing his ad mis sion for transurethral re - sec tion of pros tate re vealed com plete re mis sion of the brain tu mor. One month later, his con scious ness de te - ri o rated pro gres sively and he be came bed-ridden with fo cal signs sug ges tive of stroke or tu mor re cur rence. He passed away 6.7 months af ter di ag no sis with out au topsy. The re main ing 2 pa tients (Case 7 and 8) were free of dis ease for 9.6 and 25.0 months af ter ra dio ther - apy. The 1-year sur vival rate was 60%. The neo plas tic cells in Cases 1-7 were in a dif fuse growth pat tern and were com posed mainly of large non-cleaved centroblasts with two to three dis tinct nu - clei. Many neo plas tic gi ant cells, with or with out nu - clear lobulation, were ad mixed with the centroblasts in Case 1 that was di ag nosed ac cord ingly as poly mor - phic vari ant of centroblastic lym phoma us ing the Kiel scheme (Fig. 1A). Cases 2-7 were clas si fied as mono - morphic vari ant of centroblastic lym phoma. The im - munohistochemical find ings of these cases are listed C Fig. 1. Case 1. Dif fuse large B-cell lym phoma of the poly - mor phic vari ant. (A) Multinucleated gi ant cells and large non-cleaved cells (Hematoxylin & Eosin stain, x132). (B) and (C) Pos i tive immunoreactivity for CD79a, and bcl-2, re spec tively (Immunoperoxidase stain, x132).

5 176 Shih-Sung Chuang, et al. Chi nese Med i cal Jour nal (Tai pei) Vol. 65 No. 4 A B C in Ta ble 2. All seven cases were re ac tive for the B-cell mark ers CD20 and CD79a (Fig. 1B), con firm ing their B-cell phe no type and they were clas si fied as DLBL ac cord ing to the REAL scheme. All seven cases were re ac tive for bcl-2 (Fig. 1C) ex cept Case 6. The im - munostainings for bcl-6, CD3, CD5, CD10, CD30, CD43, and cyclin D1 were all neg a tive ex cept weak cy to plas mic positivity for CD30 in Case 1. All seven cases were neg a tive for EBER by ISH. In Case 8, the neo plas tic cells were large, some with reniform or em bryo-like nu clei, the so-called hall mark cells oc cur ring in all morphologic vari ants of anaplastic large cell lym phoma (ALCL) as re ferred to by Benharroch et al. (Fig. 2A). Multinucleation of the neo plas tic cells was fo cally noted. The immuno - histochemical find ings and T-cell re cep tor (TCR) gene re ar range ment study are de tailed else where. 5 In brief, the neo plas tic cells ex pressed CD30, CD43, gra - nzyme B, and T-cell intracellular an ti gen-1 (TIA-1). The immunostaining pat tern for CD30 was mem bra - nous with ac cen tu a tion in the Golgi area (Fig. 2B), while that for both TIA-1 and granzyme B was gran u - lar and cy to plas mic (Fig. 2C). The neo plas tic cells were neg a tive for CD3, CD15, CD20, CD45, CD45RO, CD79a, cytokeratin, and EMA. They were dif fusely pos i tive for EBER by ISH. Poly mer ase chain re ac tion study of for ma lin-fixed tis sue showed clonal gene re - ar range ment of the TCR-γ chain (data not shown). The di ag no sis was ALCL of T-cell lin eage with cytotoxic phe no type. Discussion Fig. 2. Case 8. Anaplastic large cell lym phoma. (A) A ren - iform or em bryo-like hall mark cells in the lower field (Hematoxylin & Eosin strain, x 330). (B) and (C) Pos i tive immunoreactivity of mem bra nous pat - tern with ac cen tu a tion in the Golgi area for CD30 and gran u lar pat tern for granzyme B, re spec tively (Immunoperoxidase stain, x132). We have fully char ac ter ized the patho logic find - ings in eight cases of pri mary brain lym phoma in South ern Tai wan. Seven were DLBL. The ma jor dif - fer en tials for these B-cell lym pho mas were follicular lym phoma (FL), man tle cell lym phoma (MCL) and plasmacytoma. FL was ex cluded by the dif fuse growth pat tern and neg a tive immunostaining for CD10 in all cases. The pos si bil ity of MCL was ex cluded by mor - phol ogy (large centroblasts) and neg a tive immuno - staining with cyclin D1. Plasmacytoma or mul ti ple myeloma may in volve the brain, es pe cially in the set -

6 April 2002 Pri mary Brain Lym phoma in South ern Tai wan 177 ting of im mu no de fi ciency state. Myeloma cells usu - ally have abun dant amphophilic cy to plasm and are non-reactive to CD20 and bcl-2. The anaplastic and poly mor phic mor phol ogy and weak cy to plas mic ex pres sion of CD30 of the neo plas - tic cells in Case 1 raised the pos si ble dif fer en tial di ag - no sis of ALCL. This tu mor was of B-cell lin eage with expression of CD20 and CD79a. Based on extensive bi o logic and clin i cal stud ies, B-cell lym phoma ex - press ing the CD30 an ti gen was not felt re lated to ALCL of T-cell or null cell phe no type as de fined by the In ter na tional Lym phoma Group in the REAL clas - si fi ca tion. 8 Those B-cell lym pho mas like our Case 1 with anaplastic cy tol ogy and CD30 ex pres sion are con sid ered a morphologic vari ant of large B-cell lym - phoma rather than ALCL. 11 Bcl-2 pro tein is the gene prod uct of bcl-2 gene on chro mo some 18q21, with the ma jor func tion of in hib - it ing apoptosis by sup press ing cell death. 12 The bcl-6 gene is lo cated on chro mo some 3q27. Both bcl-2 and bcl-6 ex pres sion are highly reg u lated dur ing B-cell dif fer en ti a tion in the ger mi nal cen ter (GC). The GC B-cells have a char ac ter is tic phe no type of bcl-2-/bcl-6+. Bcl-2 and bcl-6 pro tein ex pres sion are fre quent in FL It has been shown that the neo plas tic cells in 30% of extranodal DLBLs ex pressed bcl-2 pro tein and 71% of DLBLs ex pressed bcl-6 pro tein. 16 Low bcl-6 ex pres sion has been re ported to be as so ci ated with a shorter dis ease-free sur vival time in DLBL, while high bcl-2 ex pres sion tended to be as so ci ated with worse sur vival, al though the as so ci a tion was not sta tis ti cally sig nif i cant. 17 Six of seven DLBLs in our study ex pressed bcl-2, but none of them ex pressed bcl-6. This bcl-2+/bcl-6- phe no type has been proved to be use ful for dif fer en ti at ing pro lif er a tion cen ters (bcl-2+/bcl-6-) in small lymphocytic lym pho ma/chron - ic lymphocytic leu ke mia from the trapped nor mal GC in MCL that is bcl-2-/bcl The sig nif i cance of bcl-2-/bcl-6+ phe no type in DLBL is cur rently un - known. Fur ther in ves ti ga tion based on large case num bers is needed to clar ify this is sue. DLBL rep re sents a het er o ge neous group of lym - pho mas on the ba sis of clin i cal, morphologic, immu - nophenotypic, and mo lec u lar ge netic fea tures. The fre quency of CD5 ex pres sion (de novo CD5 + DLBL) has been re ported to be be tween 5% and 10% among DLBL cases. 18,19 De novo CD5 + DLBL has been re - ported to oc cur more fre quently in el derly women and in pa tients in whom there is extranodal in volve ment with poor treat ment out come. 19 De novo CD5 + DLBL has been re ported to be a het er o ge neous group con - tain ing an un usual form of splenic lym phoma with a dis tinc tive cordal in fil trat ing pat tern in the red pulp. 20 In our study of 20 cases of sur gi cally resected pri mary in tes ti nal DLBL, the neo plas tic cells did not ex press CD5 (Chuang et al, manu script sub mit ted). Like wise, the neo plas tic cells of these seven cases of PBL in this se ries did not ex press CD5. It seems that the rel a tive fre quency of CD5 ex pres sion in cases of extranodal DLBL in Tai wan is very low. Cur rently, we are con - duct ing a large study to de ter mine the rel a tive fre - quency and pos si ble clin i cal sig nif i cance of CD5 ex - pres sion in cases of nodal and extranodal DLBL in Taiwan. The base for the clas si fy ing ma lig nant lym pho - mas has been evolv ing from mor phol ogy and im mu - nol ogy to the in cor po ra tion of clin i cal and ge netic data. The Working For mu la tion (WF) was pro posed in 1982, not as a new clas si fi ca tion but as a means of trans la tion among the 6 ma jor clas si fi ca tion sys tems and to fa cil i tate clin i cal com par i son of case re ports and ther a peu tic tri als. 21 Morphologic cri te ria alone were used to sep a rate the dis eases into 10 cat e go ries of three grades and a group of mis cel la neous en ti ties. How ever, there are some prob lems with WF, in par tic - ular, the immunophenotyping of neo plas tic cells was not in cor po rated, and dif fer ent dis ease en ti ties with sim i lar mor pho log i cal find ings were lumped to gether. Since the pro posal of WF, much more new in for ma - tion has be come avail able, es pe cially in the ad vance - ment of immunophenotyping, re sult ing in rec og ni tion of new en ti ties and re fine ment of the pre vi ously rec - og nized cat e go ries. The In ter na tional Lym phoma Study Group (ILSG) pro posed the REAL scheme in 1994 with the con cept that the most prac ti cal ap proach to lym phoma cat e go ri za tion was to de fine the dis eases with the cur rently avail able morphologic, im mu no - logic, and ge netic tech nique. 9 A large-series study us - ing the REAL pro posal for test ing its clin i cal sig nif i - cance and prac ti cal util ity was pub lished in

7 178 Shih-Sung Chuang, et al. Chi nese Med i cal Jour nal (Tai pei) Vol. 65 No. 4 This study re vealed high di ag nos tic ac cu racy and reproducibility of the REAL clas si fi ca tion. The REAL scheme is also ap pli ca ble to the com mu nity hos pi tal, with high di ag nos tic con cor dant rate be tween pa thol - o gists in com mu nity hos pi tals and those in med i cal centers. 23 It is now world-widely ac cepted and is the most com monly used clas si fi ca tion scheme in re cent research on ma lig nant lym pho mas. 1,22-24 The up com - ing WHO clas si fi ca tion for lym pho mas is sim i lar to the REAL scheme, with mi nor mod i fi ca tions. 25,26 Pri mary ce re bral ALCL is ex tremely rare and may pose a di ag nos tic chal lenge in brain tu mors. Case 8 is the sev enth case of pri mary ce re bral ALCL in the lit - er a ture. The large neo plas tic cells with reniform or em bryo-like nu clei were ad mixed with abun dant eosinophils and histiocytes and some small lym pho - cytes, sim i lar to the rare vari ant of ALCL with ex ten - sive eosiophilic or neutrophilic in fil tra tion de scribed by McCulggage et al 27 Of the eight pa tients re ported, four had a pe riph eral neutrophilia and one a pe riph eral eosinophil. Case 8 in our study did not have ei ther neutrophila or eosinophilia at di ag no sis and through - out the fol low-up pe riod. Her neo plas tic cells ex - pressed CD30 and cytotoxic mark ers, as do the tu mor cells in usual ALCL. They were pos i tive for EBER by ISH, which is a rare phe nom e non in ALCL. The T-cell lin eage was con firmed by poly mer ase chain re ac tion study of for ma lin-fixed tis sue show ing clonal gene re - ar range ment of the T-cell re cep tor-γ chain. The pa - tient re ceived cra nial ir ra di a tion and is alive with out dis ease at 25 months of fol low-up. The prog no sis of PBL is poor, with a mean sur - vival around months and 5-yr sur vival around 20% Cra nial ir ra di a tion is usu ally ef fec - tive in achiev ing ini tial com plete re mis sion but with a high re cur rence rate. 31 Che mo ther apy with cyclo - phosphamide, doxorubicin, vincristine, and pred - nisolone (CHOP) has been re ported to have no role in the postradiotherapy treatment of PBL. 32 Using univariate anal y sis based on 248 cases, Bataille et al iden ti fied age youn ger than 60 years, ra di a tion ther - apy, ra di a tion ther apy with che mo ther apy, and che mo - ther apy con sist ing of anthracycline as fa vor able prog - nos tic fac tors and par tial ex ci sion an un fa vor able prog nos tic fac tor. 33 They rec om mended the treat ment of PBL with the fol low ing se quence: stereotactic bi - opsy, che mo ther apy with a methotrexate-and-anthra - cyclin-based reg i men, fol lowed by cra nial ir ra di a tion. In our cur rent study, the me dian age (63.0 yeas) of the eight pa tients was old. All six pa tients with fol low-up in for ma tion re ceived ra dio ther apy with ini tial com - plete re mis sion and sub se quent re cur rence in two or three pa tients. Al though our case num ber is lim ited, it seems that ra dio ther apy is ef fec tive in achiev ing com - plete re mis sion. The rel a tively short sur vival time of our se ries is prob a bly be cause sys temic che mo ther apy was not ad min is tered. Whether the bcl-2-positive, bcl-6-negative immunophenotype played a role in sur vival needs to be eval u ated by a large-scale, prob a - bly na tion-wide study. Che mo ther apy with a meth - otrexate-and-antracyclin-based reg i men as sug gested by Bataille et al might be ad min is tered to pre vent re - cur rence and for long-term re mis sion. 33 Acknowledgements This work was sup ported in part by re search grants #CMFHR8804 and 8912 from Chi-Mei Med i - cal Cen ter. References 1. Chuang SS, Lin CN, Li CY. Ma lig nant lym phoma in South - ern Tai wan ac cord ing to the re vised Eu ro pean-american clas si fi ca tion of lym phoid neoplasms. Can cer 2000;89: Huang CC, Chen ST, Hsi MS, Shih LY. Pro tean clin i cal and ra dio log i cal man i fes ta tions in 7 cases of pri mary ma lig nant lym phoma of the brain. J Formos Med Assoc 1987;86: Cheng AL, Yeh KH, Uen WC, Hung RL, Liu MY, Wang CH. Sys temic che mo ther apy alone for pa tients with non-acquired im mu no de fi ciency syn drome-related cen tral sys tem lym - phoma. Cancer 1998;82: Chen HC, Leung SW, Wang CJ, et al. Ra di a tion ther apy in pri mary cen tral ner vous sys tem lym phoma. Chang Gung Med J 1999;22: Au WY, Chan AC, Srivastava G, Leung SY, Liang R. In ci - dence and pa thol ogy of pri mary brain lym phoma in Hong Kong Chi nese pa tients. Leu ke mia Lym phoma 2000;37:

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