Posttransplant primary CNS lymphoma

The records and neuro-imaging studies of 8 cases of post-transplant primary CNS lymphoma (PT-PCNSL) diag-nosed at Mayo Clinic Rochester between 1970 and 1998were reviewed retrospectively All patients received organtransplantation Patients who had hematologic transplan-tation were not included in the analysis The median andmean age of the 4 men and 4 women was 45 years (range34 to 50 years) The median duration of symptoms beforediagnosis was 36 days (range 5 to 98 days) At diagnosisthe neurologic examination was focally abnormal in 6 of 8patients Compared with the initial computed tomo-graphic study MRI showed 25 additional brain lesionsOnly 437 of lesions enhanced with contrast agent ofthose that did all but one were heterogeneous Ependymalcontact occurred in 5 patients MRI lesion burdenincreased proportionally to the interval between scansDiagnostic tissue was obtained by stereotactic biopsy from6 patients and by open biopsy from 2 Hemorrhageoccurred in the biopsy area in 4 patients who had stereo-tactic biopsy and 2 died (all had normal coagulation stud-ies) Slides available for review (7 patients) showed that thetumors were of CD20-positive lineage and were positivefor Epstein-Barr virus using in situ hybridization Sixpatients died Median survival for the cohort was 13weeks PT-PCNSL has clinical and imaging features dis-tinct from typical PCNSL In our series (1) PT-PCNSLpresented nonspecically and progressed rapidly (2)stereotactic brain biopsy had signicant morbidity and (3)despite multimodal therapy survival was poor Neuro-Oncology 2 229ndash238 2000 (Posted to Neuro-Oncology

[serial online] Doc 00-034 September 13 2000 URLltneuro-oncologymcdukeedugt)

PT-PCNSL3 is an uncommon and potentially fatalside effect of immunosuppression for organ trans-plantation The pathogenesis is thought to be

related to impairment in the cellular arm (T cell) of theimmune response leading to proliferation of B cellsimmortalized by EBV (Hanto et al 1985) ConsequentlyEBV has been documented by in situ hybridization inalmost all patients with PT-PCNSL (Morrison et al1994) Before transplantation the presence of EBVseronegativity and cytomegalovirus sero-mismatchincreases the risk of any posttransplant PTLD (Aris et al1996 Walker et al 1995) However the use of antiviralagents has not been shown to decrease the incidence ofPTLD in an EBV-negative person (Aris et al 1996) Theuse of immunosuppressive agents such as cyclosporineand rescue drugs in instances of rejection such asmuromonab-CD3 (OKT3) also increases the risk ofPTLD (Walker et al 1995) Deletions of the interferon- agene have been found in patients with PTLD and treat-ment with interferon- a has led to clinical improvementthrough an effect on type 2 helper T cells (Faro et al1996 Wood et al 1997)

The clinical course and neuro-imaging features inPCNSL have been well characterized (Johnson et al1997 OrsquoNeill and Illig 1989 Roman-Goldstein et al1992 Schwaighofer et al 1989 Tomlinson et al1995) The typical patient is male in his seventh decadeand presents with the syndrome of a subacute masslesion In rare instances PCNSL can be preceded by pro-dromal symptoms and even inammatory demyelinatinglesions (Alderson et al 1996 Bender and Schapiro1989 Brecher et al 1998 DeAngelis 1990) The typi-cal MRI features of PCNSL are isointense tohypointense and hyperintense parenchymal masses onT1-weighted proton density and T2-weighted scanshomogeneous and intense contrast enhancement con-tact with CSF either at the ependymal or the pial sur-face and decreased contrast enhancement in patientsgiven corticosteroids (Jack et al 1986) Important dis-tinctions have been described between the contrast

Neuro-Oncology

Posttransplant primary CNS lymphoma

Thanh G Phan Brian P OrsquoNeill and Paul J KurtinDepartment of Neurology (TGP BPO) and the Division of Hematopathology (PJK) Mayo Clinic andMayo Foundation Rochester MN 55905

Received 5 June 2000 accepted 17 July 2000

1Supported in part by the Linse Bock Program in Neuro-OncologyMayo Clinic Cancer Center and the National Cancer Institute CancerCenters Support Grant (P30CA15083) Mayo Clinic Cancer CenterRochester MN 55905

2Address correspondence and reprint requests to Brian P OrsquoNeillDepartment of Neurology Mayo Clinic 200 First St SW RochesterMN 55905

3Abbreviations used are as follows EBV Epstein-Barr virus PTLD post-transplant lymphoproliferative disorder PCNSL primary CNSlymphoma PT-PCNSL posttransplant primary CNS lymphoma

Neuro-Oncology n OCTOBER 2000 229

by guest on July 11 2016httpneuro-oncologyoxfordjournalsorg

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enhancement pattern seen on MRI in PCNSL inimmunocompetent patients and in PCNSL associatedwith acquired immunodeciency syndrome In the latterPCNSL lesions are often multiple and may appear cyst-like or necrotic (Johnson et al 1997)

Although posttransplant systemic non-Hodgkinrsquos lym-phoma has been amply described PT-PCNSL has beendescribed in isolated case reports or as part of cohorts ofposttransplant non-Hodgkinrsquos lymphoma (Barnett andSchwartz 1974 Ciancio et al 1997 Donnelly et al1998 Hardwidge et al 1990 Krikorian et al 1978Kwan et al 1992 Matas et al 1976 Miller et al 1997Morrison et al 1994 Murray et al 1986 Penn andStarlz 1972a 1972b Penn et al 1969 Schneck andPenn 1970 1971 Schwechheimer et al 1994 Tubmanet al 1983 van Diemen-Steenvoorde et al 1986 Wein-traub and Warnke 1982) Only 39 such cases have beenpublished in the English language literature (Table 1)and most of these antedate modern neuro-imaging Fur-thermore no study has described serial neuro-imagingevaluations in these patients Although the method ofdiagnosis of PCNSL and PT-PCNSL is usually stereotac-tic brain biopsy (OrsquoNeill et al 1987) previous reportshave not commented on the potential complications ofthe procedure in this group of patients

Herein we report the rst single-institution series withclinical imaging pathologic and outcome data ofpatients with PT-PCNSL and summarize cases reportedin the literature

Methods

We identied patients with PT-PCNSL by reviewing thedata from the Mayo Clinic Tumor Registry the Lym-phoma Registry and the Mayo Surgical Index between1970 and 1998 For the purposes of this report we denedPT-PCNSL as lymphoma involving exclusively the CNSAlthough the extent and method of systemic staging variedduring the nearly 3-decade span of this review no patienthad evidence of systemic lymphoma All patients were neg-ative for antibodies to human immunodeciency virus andhad received organ transplantation Patients who hadhematologic transplantation including peripheral bloodand stem cell transplantation were not included in theanalysis The total number of organ transplants and thetotal number and types of systemic and CNS tumorsoccurring in those patients over the same period of studywere available for comparative calculations

The medical records of the patients were reviewed todene the clinical and neuro-imaging features Patients 6and 7 (Table 2) were previously reported as part of aninfectious disease study of immunosuppressed patients(Walker et al 1995) CT was performed on second- andthird-generation scanners CT imaging of Patient 1 wasnot available for review CT was the initial imagingmodality in 6 patients and only 2 of these studies wereperformed with contrast material All except one patientunderwent MRI with a 15-T scanner Contrast material(gadopentetate 01 mmolkg) was given by iv to all 7patients For each patient the neuro-imaging lms werereviewed by two of the authors (TGP BPO) and the

number size and locations of the lesions were deter-mined Conict resolution was not necessary because allreviews were congruent with the original reports

A retrospective review (PJK) of the brain biopsyspecimens was possible for 7 of the 8 patients The lym-phomas were classied according to the Revised Euro-pean-American Lymphoma Classication criteria (Harriset al 1994) PT-PCNSL was further characterized asmonomorphic or polymorphic type by the criteria ofNalesnik et al (1988) In all cases immunophenotypingstudies were performed on either frozen or paraffin-embedded tissue using the labeled streptavidin-biotin-immunoperoxidase technique as previously reported(Kurtin et al 1999) In addition in 6 cases the tumorswere assessed for the presence of EBV with in situhybridization with probes that recognize EBV-encodedRNA (EBER 1 and EBER 2) according to a previouslypublished method (Myers et al 1995) In 3 cases suf-cient tissue was available to perform Southern blot assaysfor EBV with a probe that recognizes the terminal repeatsequence of the virus (Raab-Traub and Flynn 1986Southern 1975) Next the membranes were subjected toautoradiography

Patients were not treated according to a standard pro-tocol However for all patients the initial treatment con-sisted of a reduction in immunosuppressive therapy andclose surveillance for response Treatment with cyclo-sporine (when used) was stopped and treatment withprednisone and azathioprine was reduced to the lowesttolerable dose in all patients Antiviral treatment withacyclovir or valacyclovir was at the discretion of thetreating physician This treatment was commenced in 5patients If there was no evidence of efcacy the patientswere offered whole-brain radiotherapy Outcome wasdetermined by the duration of survival and the clinical

TG Phan BP OrsquoNeill and PJ Kurtin Posttransplant primary CNS lymphoma

Neuro-Oncology n OCTOBER 2000230

Table 1 Characteristics of previously reported patients with post-transplant primary CNS lymphoma

Characteristic Value

Age

Mean (year) 28

Median (year) 23

Range (year) 8-52

No of patients reported 39

No of cardiac transplantations 439

No of renal transplantations 3539

No with solitary lesion on CT 915

No with EBV viremia 37

No with CMV viremia 311

No with rejection 1115

No of survivors at time of report 339

Abbreviations CMV cytomegalovirus EBV Epstein-Barr virus

These patientsrsquo characteristics were summarized from previous reports on posttransplant

primary CNS lymphoma (Barnett and Schwartz 1974 Ciancio et al 1997 Donnelly etal 1998 Hardwidge et al 1990 Krikorian et al 1978 Kwan et al 1992 Matas et al

1976 Miller 1997 Morrison et al 1994 Murray et al 1986 Penn and Starlz 1972a1972b Penn et al 1969 Schneck and Penn 1970 Schwechheimer et al 1994 Tubman

et al 1983 van Diemen-Steenvoorde et al 1986 Weintraub and Warnke 1982)


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and imaging response to therapy Before any patient datawere reviewed the study was approved by the MayoFoundation Institutional Review Board

Results

Clinical Features

The cohort consisted of 8 patients with PT-PCNSL (Table2) Over the same period (1970-1998) there were 65cases of posttransplant non-Hodgkinrsquos lymphoma among2745 organ transplantations (1645 renal transplanta-tions 73 renal-pancreas transplantations 860 liver trans-plantations 33 lung transplantations and 134 cardiactransplantations) None of the 134 patients who had aheart transplant developed PT-PCNSL At Mayo ClinicRochester PT-PCNSL occurred in 03 of organ trans-plantations and 124 of all posttransplant non-Hodg-kinrsquos lymphoma cases during the study period

Seven of the patients received cyclosporine and 4received muromonab-CD3 Two patients received cyclo-sporine muromonab-CD3 and antilymphocyte globulin(Patients 2 and 6 Table 2) The median time to onset ofPT-PCNSL was 19 months (range 3 to 61 months) Most

of the patients still maintained a functioning graftalthough 5 of the 8 patients experienced graft rejectionphenomena The mean duration of symptoms beforediagnosis was 36 days (range 5 to 98 days) The com-monest presenting symptom was lethargy (6 patients)followed by headache (5 patients) fever (4 patients) andconfusion (4 patients) Six patients (75) had focal nd-ings on neurologic examination at diagnosis One patient(Patient 8) became stuporous because of obstructivehydrocephalus and required emergency placement of aventricular shunt and a suboccipital craniotomy

Six patients had opportunistic infections presumablyreflecting the severity of immunosuppression and ofthese 5 had documented cytomegalovirus viremia and 1had cryptococcal meningitis within 3 months after thediagnosis of PT-PCNSL All 6 patients who had in situEBV hybridization studies on brain tissue were positivefor the virus Clonality of EBV was documented in the 2patients in whom the test was done

Outcome

Median survival after the diagnosis of PT-PCNSL was 13weeks with the longest survivor alive after 93 months(Table 3) Five patients had intracranial hemorrhages



Table 2 Characteristics of 8 patients with posttransplant primary CNS lymphoma

CMV EBV status CMV EBV Time toAge Type Immuno- Functioning sero- before viremia viremia development

Patient (yearsex) transplant suppression Rejection graft mismatch transplant within 3 mo within 3 mo PT-PCNSL (mo)

1 50M Kidney Prednisone Yes Yes Not known Not known NA NA 53azathioprine

2 58F Kidney Prednisone No Yes No Positive No NA 61azathioprine cyclosporine

ALG

3 43F Kidney Prednisone No No No Negative Yes Yes 11azathioprine cyclosporine

mycophenolate

4 50Ma Kidney Prednisone Yes No No Not known Yes NA 7azathioprine cyclosporine

muromonoab-CD3

5 46M Kidney- Prednisone Yes No Yes Positive Yes No 4pancreas azathioprine

cyclosporine muromonoab-CD3

6 43F Kidney- Prednisone Yes Yes No Positive No No 12pancreas azathioprine

ALG cyclosporine

muromonab-CD3

7 36F Liver Prednisone Yes Yes Yes Negative Yes No 3azathioprine cyclosporine

muromonoab-CD3

8 34M Lung Prednisone No Yes Yes Negative Yes No 4azathioprine cyclosporine

Abbreviations CMV cytomegalovirus EBV Epstein-Barr virus NA not available ALG antilymphoblast globulin PT-PCNSL posttransplant CNS lymphoma muromonoab-CD3 OKT-3

aPatient 4 had 2 kidney transplants Immunosuppression was stopped 4 weeks before diagnosis of PT-PCNSL


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Hemorrhage occurred at the biopsy site in 4 patients(Patients 4-7) who had stereotactic biopsies and along thecourse of a ventricular catheter in the patient (Patient 8)who required an emergency shunt Two patients died ofparenchymal hemorrhage Antiviral therapy had noeffect on the progression of lymphoma in our patientsThis step-up regimen from reduction of immunosuppres-sion to radiotherapy was possible in only 4 patients

CSF Analysis

The CSF was analyzed in all 8 patients and in 6 of them(Patients 1-3 5 7 and 8) while they were still receivingtheir usual dose of immunosuppressive drugs (Table 4)In Patient 4 treatment with all immunosuppressive

agents ceased 4 weeks before CSF analysis because of anonfunctioning graft and in Patient 6 cyclosporinetreatment had stopped 9 months before CSF analysisbecause of a presumed drug-related leukoencephalopa-thy CSF ndings were normal in 2 patients and non-specically abnormal in the other 6 The most commonnding was an increased protein concentration (median72 mgdl)

Results of CSF ow cytometry were abnormal in 1(Patient 5) of the 2 patients in whom it was performedFive CSF analyses were performed over 8 weeks inPatient 2 to monitor treatment of cryptococcal meningi-tis Despite serial CSF examinations the development ofPT-PCNSL in this patient was not heralded by abnormalcytologic ndings or by an increase in the CSF cell countor protein concentration but by the development of new



Table 3 Tumor type treatment and outcome of 8 patients with posttransplant primary CNS lymphoma

Tumor Southern Survival afterPatient type Necrosis CD20 CD3 EBV-ISH blot for EBV Radiology Treatment diagnosis of PT-PCNSL

1 Diffuse NA NA NA NA NA R parietal Reduction of 32 moB-cell (contrast immunosuppression (died of

lymphoma enhancement) local brain pulmonary embolism)(not reviewed) radiotherapy 4600 cGy No recurrence of PT-PCNSL

2 Mono-morphic Yes + ndash NA Single Ependymal contact Ceased 2 wkB-cell EBV-specic caudate (homogeneous immunosuppression (died no autopsy)

lymphoma band enhancement) enlarged onlyventricles

3 Mono-morphic No + ndash + NA Cerebellar peduncle Cyclosporine ceased 6 mo (alive)B-cell (ring enhancement) acyclovir whole-brain

lymphoma new white matter lesions radiotherapy 5000 cGy16 days later amp meningeal followed by rejection

enhancement requiring higher dose of prednisone

4 Mono-morphic No + ndash + NA Ependymal contact Off immunosuppression 1 dayB-cell periventricular (ring 4 weeks before (died of ICH

lymphoma enhancement) amp thalamus diagnosis of PTLD after brain biopsy)cerebral peduncle pons cerebellum white matter

lesions meningeal enhancement

5 Mono-morphic Yes + ndash + Single Ependymal contact caudate Cyclosporine ceased 1 wkB-cell EBV-specic white matter lesions acyclovir (died of ICH

lymphoma band (misdiagnosed as infarcts) palliative whole- after brain biopsy)subtle contrast enhancement brain radiotherapy

intracerebral hemorrhage 1080 cGyafter biopsy

6 Mono-morphic Yes + ndash + NA L frontal glioblastoma Azathioprine ceased 86 moB-cell multiforme-like lesion acyclovir (died no autopsy)

lymphoma heterogeneous contrast whole-brain radiotherapyenhancement edema 5040 cGy CHOP (1 cycle)

7 Mono-morphic Yes + ndash + NA Ependymal contacts Reduction of 93 mo (alive)B-cell caudate putamen centrum immunosuppression

lymphoma semiovale (hemorrhage) whole-brainfrontal temporal white radiotherapy 4980 cGy

matter lesions

8 Mono-morphic Yes + ndash + NA Ependymal contact Debulking valacyclovir 2 wk (died no autopsy)B-cell cerebellar (heterogeneous ceased azathioprine Hemorrhage after shunt

lymphoma enhancement amp edema) frontal caudate white matter

lesions obstructive hydrocephalus meningeal

enhancement

Abbreviations EBV Epstein-Barr virus ISH in situ hybridization PT-PCNSL posttransplant CNS lymphoma NA not available R right PTLD posttransplant lym-phoproliferative disorder ICH intracerebral hemorrhage L left CHOP cyclophosphamide hydroxydaunomycin (doxorubicin) vincristine (Oncovin) prednisone


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neurologic symptoms In the one patient (Patient 3) whohad polymerase chain reaction performed the resultswere negative for both EBV and cytomegalovirus Noneof the patients had any complication from lumbar punc-ture In one patient (Patient 7) CSF was obtained at thetime of ventricular shunting

Neuro-imaging

The initial CT findings were abnormal in 4 of the 6patients in whom the study was performed and thePT-PCNSL lesions varied in appearance from hypo-dense to moderately hyperdense In one patient thehypodense area was initially interpreted as subcorticalinfarction Contrast enhancement occurred in one-thirdof these CT-visible lesions Heterogeneous enhancementwas the predominant pattern (as it was with enhance-ment on MRI) Two symptomatic patients had normalCT ndings (Fig 1)

Overall 25 more lesions were seen on the initial MRIperformed 1 to 15 days after the initial CT examina-tion A second MRI study was performed in 5 patientsand showed 9 additional lesions Lesion size rangedfrom 5 to 40 mm Of the 32 lesions seen on the initialMRI studies in 7 patients 13 (406) were located inthe basal ganglia 8 (25) in the frontal lobe 3 (9)were in the temporal lobe 3 (9) in the brain stem and3 (9) in the cerebellum There was ependymal contactin 5 patients 4 of whom died The lesions were welldened and appeared hypointense on T1-weighted and

T2-weighted sequences or as a high signal T2 rim with ahypointense center on T1-weighted and T2-weightedsequences Uncommonly a lesion appeared as heteroge-neously hyperintense on T2- and isointense on T1-weighted sequences (Patients 4 and 7)



Fig 1 CT study in Patient 5 (A-D) Alternating noncontrast CT and T2-weighted MRI scans of delayed evolution to abnormal imaging resultsdespite onset of dysphasia and left hemiparesis 3 days previously T2-weighted sequence on 81992 showed evidence of minimal hemosiderindeposition that suggested an old hemorrhage in the lesion (E) CT showing hemorrhage after biopsy

Fig 2 T1-weighted MRI with gadolinium showing lesion resemblinghigh-grade glioma (Patient 6)

A B C

D E


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On MRI contrast enhancement occurred in only 44of the lesions (all the patients except Patient 4 were takingcorticosteroids at the time of the scan) Homogeneousenhancement occurred in only one patient (Patient 2) Therest had rim enhancement or heterogeneous enhancementIn one patient the MRI features resembled those of a high-grade glioma because of the vasogenic edema heteroge-neous T2 signal abnormality and heterogeneous contrastenhancement giving a ldquonecroticrdquo appearance (Fig 2) Eachof the progressively multiple lesions seen on serial MRIscans also had variable enhancement with contrast agent

A mass effect was seen in 3 patients (Patients 6 7 and8) and was associated with a poor outcome only in Patient8 who required emergency craniectomy and ventricularshunting because of a cerebellar vermal lesion that causeddisplacement of the fourth ventricle and partial obstructivehydrocephalus Meningeal enhancement was seen in 3patients (Patients 3 4 and 8) In Patient 3 the MRI fea-tures proceeded from normal to abnormal T2 signal togadolinium contrast enhancement of the parenchyma andeventually the meninges

Brain Biopsy and Hemorrhage

Stereotactic biopsy was performed in 6 patients and openbiopsy in the other 2 Hemorrhage occurred at the biopsysite in 4 patients (Patients 4-7) who had stereotacticbiopsy and one other patient had hemorrhage along thetrack of the external ventricular drain Two of thesepatients died of hemorrhage 1 died 1 day after biopsy ofa caudate lesion and the other died 1 week after biopsy ofa thalamic lesion Delayed hemorrhage occurred at thebiopsy site and other sites after radiotherapy in Patient 7No risk factors such as lesional hemorrhage on preopera-tive neuro-imaging or abnormal coagulation studies wereidentied Although no hemorrhage was apparent on thepreoperative CT study in Patient 5 MRI showed evidenceof minimal hemosiderin deposition that suggested an oldhemorrhage in the lesion (Fig 1)

Pathology

Similar histologic features were observed in all 7 tissuesamples and are illustrated in Fig 3 Five of the 7 tissuesamples had foci of necrosis In all 7 samples the neoplas-tic cells were CD20+ CD3ndash B cells and in all 6 samplesstudied with in situ hybridization the cells were stronglypositive for EBV Clonality was assessed with the EBV ter-minal repeat assay in 3 samples and a single dominantband was observed in all of them indicating the presenceof EBV and clonality of the lymphoma Using the RevisedEuropean-American Lymphoma classication the neo-plasms would be classied as diffuse large B-cell lym-phomas Using the criteria of Nalesnik et al (1988) forclassication of PTLD all would be included in themonomorphic category

Discussion

The present study has several limitations One it is a ret-rospective study from a single institution and thus has



Fig 3 Histologic features in tissue samples (A) Architectural features ofdiffuse large B-cell lymphoma Note prominent perivascular tumor cellinltrates (left) diffuse inltration of cerebral parenchyma (right) andcentral focus of necrosis (Hematoxylin and eosin original magnica-tion 3 200) (B) Immunoperoxidase stain for CD20 in posttransplantprimary CNS lymphoma The membrane staining of lymphoma cells isstrong for B-cell lineage antigen CD20 (Immunoperoxidase stainaminoethyl carbazole chromagen and hematoxylin counterstain origi-nal magnication 3 400) (C) In situ hybridization for Epstein-Barr virusin posttransplant primary CNS lymphoma Nearly all lymphoma cellsexhibit strong uniform nuclear staining for Epstein-Barr virus (In situhybridization for Epstein-Barr virus nitroblue tetrazolium chromagennuclear fast red counterstain original magnication 3 400)


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an inherent selection bias Two because of the smallnumber of patients studied generalizations cannot bemade about the clinical and neuro-imaging characteris-tics or treatment of PT-PCNSL Nevertheless there areseveral noteworthy differences between our cohort andthe 39 cases of PT-PCNSL reported in the English lan-guage literature Of the 39 reported patients only 4 hadcardiac transplantation and most had renal transplanta-tion (Barnett and Schwartz 1974 Ciancio et al 1997Donnelly et al 1998 Hardwidge et al 1990 Krikorianet al 1978 Kwan et al 1992 Matas et al 1976 Milleret al 1997 Morrison et al 1994 Murray et al 1986Penn et al 1969 Schneck and Penn 1970 1971 Pennand Starlz 1972a 1972b Schwechheimer et al 1994Tubman et al 1983 van Diemen-Steenvoorde et al1986 Weintraub and Warnke 1982) The patients in ourcohort were older and there was no sex bias in our seriesand no sex bias in the reported cases The median timefrom transplantation to onset of PT-PCNSL in the litera-ture (126 months range 2 to 50 months) was similar tothat in our series None of our patients were children oradolescents but 6 of the 39 reported patients wereyounger than 14 years (Penn et al 1969) Altogetheronly 5 of the 39 patients had onset of PT-PCNSL morethan 36 months after transplantation (Barnett andSchwartz 1974 Ciancio et al 1997 Donnelly et al1998 Hardwidge et al 1990 Kwan et al 1992 Kriko-rian et al 1978 Matas et al 1976 Miller et al 1997Morrison et al 1994 Murray et al 1986 Penn andStarlz 1972a 1972b Penn et al 1969 Schneck andPenn 1970 1971 Schwechheimer et al 1994 Tubmanet al 1983 van Diemen-Steenvoorde et al 1986 Wein-traub and Warnke 1982) The predominance of cases ofPT-PCNSL among patients with kidney or kidney andpancreas transplants in our cohort and in those reportedin the literature may represent a selection bias (thesetransplantations have been performed for a longer periodand more frequently than for other organs) Howeverthe low incidence of PT-PCNSL among heart lung andliver transplant recipients may indicate a biologic predis-position from disease or treatment Nevertheless therecurrently is no difference between the various transplanttypes in terms of selecting patients based on EBV statusbut individual variations may exist in matchingcytomegalovirus donorndashrecipient status (Arcasoy andKotloff 1999 McGiffin et al 1997 Walker et al

1995) The 3 standard immunosuppressive agents fororgan transplantation are prednisone azathioprine andcyclosporine Newer agents such as tacrolimus andmycophenolate mofetil are beginning to be used clini-cally however this would not have been soon enough tohave affected the higher incidence of PT-PCNSL amongrenal transplant recipients and these drugs are used moreoften in lung and liver than in renal transplantation(Arcasoy and Kotloff 1999)

PT-PCNSL has clinical and imaging features distinctlydifferent from those of typical PCNSL In our seriesPT-PCNSL presented nonspecically and generally pro-gressed rapidly clinically and on serial imaging studies Intypical PCNSL the median duration of symptoms is 8weeks compared with 5 weeks in our patients (Tomlisonet al 1995) Admittedly transplant recipients may betested more frequently than other patients leading to ear-lier detection However in some patients the disease hada protracted course Patients 2 and 6 had symptoms for along period and lumbar puncture and serial neuro-imag-ing studies did not disclose the diagnosis These patientsalso recently had had an opportunistic infection whichmay have masked the development or presentation ofPT-PCNSL

MRI was the preferred imaging technique in ourcohort for several reasons The number of lesions identi-ed on MRI was greater than that on CT with contrastagent and response to therapy can be monitored Thebetter resolution of tissue characteristics on MRI is valu-able in immunosuppressed patients because the differen-tial diagnosis is broader and the imaging appearancemore varied The characteristic feature of PT-PCNSL inthis cohort is the variable T2-signal characteristic and theheterogeneous enhancement or rim enhancement withcontrast This may be related to necrosis seen on histo-logic examination (Johnson et al 1997) The pattern ofprogressive heterogeneous contrast enhancement multi-plicity of the lesions and the predisposition to ependymallocation is similar to that seen in PCNSL in acquiredimmunodeficiency syndrome patients (Johnson et al1997) In contrast PCNSL in immunocompetent patientshas homogeneous enhancement with contrast agent(Johnson et al 1997 Roman-Goldstein et al 1992)The neuro-imaging data from the cases of PT-PCNSLreported in the literature are limited and are not sufcientto make comparisons (Barnett and Schwartz 1974



Table 4 CSF prole of 8 patients with posttransplant primary CNS lymphoma

Patient Glucose Protein (normal Number of Flow EBV PCR CMV PCR Meningeal(mgdl) 14-45 mgdl) nucleated cells Cytology cytometry from CSF from CSF involvement

1 48 173 0 Normal NA NA NA No


3 72 97 34 Normal No monoclonal B cells Negative Negative Yes

4 32 55 3 Normal NA NA NA Yes

5 29 89 13 Abnormal B lymphoid cells NA NA No




Abbreviations EBV Epstein-Barr virus PCR polymerase chain reaction CMV cytomegalovirus NA not available


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Alderson L Fetell MR Sisti M Hochberg F Cohen M and Louis DN

(1996) Sentinel lesions of primary CNS lymphoma J Neurol Neurosurg

Psychiatry 60 102-105

Arcasoy SM and Kotloff RM (1999) Lung transplantation N Engl J Med

340 1081-1091

Aris RM Maia DM Neuringer IP Gott K Kiley S Gertis K and

Handy J (1996) Post-transplantation lymphoproliferative disorder in the

Epstein-Barr virus-naive lung transplant recipient Am J Respir Crit Care

Med 154 1712-1717

Balmaceda C Gaynor JJ Sun M Gluck JT and DeAngelis LM (1995)

Leptomeningeal tumor in primary central nervous system lymphoma

Recognition signicance and implications Ann Neurol 38 202-209

Barnett LB and Schwartz E (1974) Cerebral reticulum cell sarcoma after

multiple renal transplants J Neurol Neurosurg Psychiatry 37 966-970

Ciancio et al 1997 Donnelly et al 1998 Hardwidge etal 1990 Krikorian et al 1978 Kwan et al 1992Matas et al 1976 Miller et al 1997 Morrison et al1994 Murray et al 1986 Penn and Starlz 1972a1972b Penn et al 1969 Schneck and Penn 1970 1971Schwechheimer et al 1994 Tubman et al 1983 vanDiemen-Steenvoorde et al 1986 Weintraub andWarnke 1982)

To our knowledge the relationship between brainbiopsy and hemorrhage in PT-PCNSL has not beenreported previously even in immunocompetent patientswith PCNSL (Johnson et al 1997 Roman-Goldstein etal 1992 Schwaighofer et al 1989 Sherman et al1991 Tomlinson et al 1995) Delayed hemorrhage atthe biopsy site and hemorrhage at other sites as in one ofour patients suggest that it may be a characteristic of PT-PCNSL rather than a fault of the biopsy technique Thereare reports of hemorrhage before treatment in PCNSLassociated with acquired immunodeficiency syndromeand rare reports of hemorrhage in PCNSL in immuno-competent patients and as a late complication after treat-ment of childhood CNS lymphoma (Claviez et al 1998Fukui et al 1998 Kothbauer et al 1979 Poussaint etal 1995 Zimmerman and Bilaniuk 1980) However nopredictive characteristics either of the patient or of theneuro-imaging features were identied to guide biopsyAlthough acute hemorrhage was associated with death in2 patients the patient who had delayed hemorrhage hadthe best long-term outcome

The pattern of spread of PT-PCNSL in Patient 3 wasfrom a parenchymal lesion to involvement of themeninges This suggests that PCNSL or at least PT-PCNSL may be an ldquoinside-outrdquo rather than an ldquooutside-inrdquo process (DeAngelis 1999) Furthermore our groupof patients demonstrated that contrast enhancementmdashoften thought pathognomonic for PCNSLmdashmay be a latephenomenon and may depend on many factors includ-ing cytokine release perivascular ldquocufngrdquo and endothe-lial cell disruption (Molnar et al 1999) Patient 3demonstrates the pitfalls of MRI studies in early stages ofthe disease Conversely the absence of this pattern in theother patients may indicate only that MRI was per-formed at a well-advanced stage of disease

In our series CSF examination was helpful only inshowing inammation in the CNS indicating a need tofocus investigation in this area Although an increase inCSF protein concentration correlates with involvement ofthe meninges this was not necessarily the case in ourcohort (Balmaceda et al 1995) Only one of our patients

had positive cytologic ndings The nonspecic clinicalfeatures and CSF ndings in our series could have beenthe result of masking by continuation of corticosteroidand other immunosuppressive therapy Unlike PCNSL inacquired immunodeciency syndrome patients we can-not recommend complete cessation of immunosuppres-sive therapy for this evaluation because of the risk ofrejection in transplant recipients Brink et al (1998) sug-gested that the presence of EBV in CSF of patients withhuman immunodeciency virus infection is strongly sug-gestive of PCNSL Our experience is limited with thistechnique in the diagnosis of PCNSL but reports in theliterature suggest this technique has promise in the earlydiagnosis of PCNSL in immunocompromised patients(Brink et al 1998)

The poor outcome in monomorphic PT-PCNSL inour cohort despite multimodal therapy was disap-pointing This was similar to the experience reported inthe literature in which only 3 of the 39 patients werealive at the time of the reports comparisons (Barnettand Schwartz 1974 Ciancio et al 1997 Donnelly etal 1998 Hardwidge et al 1990 Krikorian et al1978 Kwan et al 1992 Matas et al 1976 Miller etal 1997 Morrison et al 1994 Murray et al 1986Schneck and Penn 1970 1971 Penn and Starlz 1972a1972b Penn et al 1969 Schwechheimer et al 1994Tubman et al 1983 van Diemen-Steenvoorde et al1986 Weintraub and Warnke 1982) Sequential step-up therapy may not be the approach to take for patientswith PT-PCNSL Because all patients who survived hadreceived the combination of antiviral therapy reducedimmunosuppressive therapy and radiotherapy perhapsall modalities should be combined at the outset oftreatment

Whether even more modalities should be used is opento debate and likely awaits future discoveries in thepathogenesis of PT-PCNSL and indeed PCNSL BecausePT-PCNSL is morphologically and immunologically sim-ilar to its systemic counterparts adapting the treatmentregimens of those diseases to the special needs of the CNSmay be worthwhile

Acknowledgments

We thank Leslie B Ottjes for secretarial assistance andKay M Ristow for maintaining the Mayo LymphomaProject database



References


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nloaded from



Bender GP and Schapiro RT (1989) Primary CNS lymphoma presenting as

multiple sclerosis A case study Minn Med 72 157-160

Brecher K Hochberg FH Louis DN de la Monte S and Riskind P (1998)

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enhancement pattern seen on MRI in PCNSL inimmunocompetent patients and in PCNSL associatedwith acquired immunodeciency syndrome In the latterPCNSL lesions are often multiple and may appear cyst-like or necrotic (Johnson et al 1997)

Although posttransplant systemic non-Hodgkinrsquos lym-phoma has been amply described PT-PCNSL has beendescribed in isolated case reports or as part of cohorts ofposttransplant non-Hodgkinrsquos lymphoma (Barnett andSchwartz 1974 Ciancio et al 1997 Donnelly et al1998 Hardwidge et al 1990 Krikorian et al 1978Kwan et al 1992 Matas et al 1976 Miller et al 1997Morrison et al 1994 Murray et al 1986 Penn andStarlz 1972a 1972b Penn et al 1969 Schneck andPenn 1970 1971 Schwechheimer et al 1994 Tubmanet al 1983 van Diemen-Steenvoorde et al 1986 Wein-traub and Warnke 1982) Only 39 such cases have beenpublished in the English language literature (Table 1)and most of these antedate modern neuro-imaging Fur-thermore no study has described serial neuro-imagingevaluations in these patients Although the method ofdiagnosis of PCNSL and PT-PCNSL is usually stereotac-tic brain biopsy (OrsquoNeill et al 1987) previous reportshave not commented on the potential complications ofthe procedure in this group of patients

Herein we report the rst single-institution series withclinical imaging pathologic and outcome data ofpatients with PT-PCNSL and summarize cases reportedin the literature

Methods

We identied patients with PT-PCNSL by reviewing thedata from the Mayo Clinic Tumor Registry the Lym-phoma Registry and the Mayo Surgical Index between1970 and 1998 For the purposes of this report we denedPT-PCNSL as lymphoma involving exclusively the CNSAlthough the extent and method of systemic staging variedduring the nearly 3-decade span of this review no patienthad evidence of systemic lymphoma All patients were neg-ative for antibodies to human immunodeciency virus andhad received organ transplantation Patients who hadhematologic transplantation including peripheral bloodand stem cell transplantation were not included in theanalysis The total number of organ transplants and thetotal number and types of systemic and CNS tumorsoccurring in those patients over the same period of studywere available for comparative calculations

The medical records of the patients were reviewed todene the clinical and neuro-imaging features Patients 6and 7 (Table 2) were previously reported as part of aninfectious disease study of immunosuppressed patients(Walker et al 1995) CT was performed on second- andthird-generation scanners CT imaging of Patient 1 wasnot available for review CT was the initial imagingmodality in 6 patients and only 2 of these studies wereperformed with contrast material All except one patientunderwent MRI with a 15-T scanner Contrast material(gadopentetate 01 mmolkg) was given by iv to all 7patients For each patient the neuro-imaging lms werereviewed by two of the authors (TGP BPO) and the

number size and locations of the lesions were deter-mined Conict resolution was not necessary because allreviews were congruent with the original reports

A retrospective review (PJK) of the brain biopsyspecimens was possible for 7 of the 8 patients The lym-phomas were classied according to the Revised Euro-pean-American Lymphoma Classication criteria (Harriset al 1994) PT-PCNSL was further characterized asmonomorphic or polymorphic type by the criteria ofNalesnik et al (1988) In all cases immunophenotypingstudies were performed on either frozen or paraffin-embedded tissue using the labeled streptavidin-biotin-immunoperoxidase technique as previously reported(Kurtin et al 1999) In addition in 6 cases the tumorswere assessed for the presence of EBV with in situhybridization with probes that recognize EBV-encodedRNA (EBER 1 and EBER 2) according to a previouslypublished method (Myers et al 1995) In 3 cases suf-cient tissue was available to perform Southern blot assaysfor EBV with a probe that recognizes the terminal repeatsequence of the virus (Raab-Traub and Flynn 1986Southern 1975) Next the membranes were subjected toautoradiography

Patients were not treated according to a standard pro-tocol However for all patients the initial treatment con-sisted of a reduction in immunosuppressive therapy andclose surveillance for response Treatment with cyclo-sporine (when used) was stopped and treatment withprednisone and azathioprine was reduced to the lowesttolerable dose in all patients Antiviral treatment withacyclovir or valacyclovir was at the discretion of thetreating physician This treatment was commenced in 5patients If there was no evidence of efcacy the patientswere offered whole-brain radiotherapy Outcome wasdetermined by the duration of survival and the clinical



Table 1 Characteristics of previously reported patients with post-transplant primary CNS lymphoma

Characteristic Value

Age

Mean (year) 28

Median (year) 23

Range (year) 8-52

No of patients reported 39

No of cardiac transplantations 439

No of renal transplantations 3539

No with solitary lesion on CT 915

No with EBV viremia 37

No with CMV viremia 311

No with rejection 1115

No of survivors at time of report 339

Abbreviations CMV cytomegalovirus EBV Epstein-Barr virus

These patientsrsquo characteristics were summarized from previous reports on posttransplant

primary CNS lymphoma (Barnett and Schwartz 1974 Ciancio et al 1997 Donnelly etal 1998 Hardwidge et al 1990 Krikorian et al 1978 Kwan et al 1992 Matas et al

1976 Miller 1997 Morrison et al 1994 Murray et al 1986 Penn and Starlz 1972a1972b Penn et al 1969 Schneck and Penn 1970 Schwechheimer et al 1994 Tubman

et al 1983 van Diemen-Steenvoorde et al 1986 Weintraub and Warnke 1982)


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Results

Clinical Features





Outcome









ALG


mycophenolate


muromonoab-CD3




ALG cyclosporine

muromonab-CD3


muromonoab-CD3





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CSF Analysis

























matter lesions




enhancement



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Neuro-imaging








A B C

D E


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Pathology


Discussion






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340 1081-1091




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Acknowledgments




References


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217-223












563-572



(Wein) 49 35-45



639-643






































































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surgery 82 558-566











1346-1353











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Results

Clinical Features





Outcome









ALG


mycophenolate


muromonoab-CD3




ALG cyclosporine

muromonab-CD3


muromonoab-CD3





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CSF Analysis

























matter lesions




enhancement



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Neuro-imaging








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Posttransplant primary CNS lymphoma

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