Linfoma Associado a Imunodeficiencia

8/3/2019 Linfoma Associado a Imunodeficiencia

1/7

case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f m ed i c i n e

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Sally H. Ebeling,Assistant EditorJo-Anne O. Shepard, m.d.,Associate Editor Christine C. Peters, Assistant Editor

n engl j med 354;11 www.nejm.org march 16, 20061178

From the Gastrointestinal Unit (D.K.P.)and the Departments of Radiology (R.G.G.)and Pathology (R.P.H.), MassachusettsGeneral Hospital; and the Departmentsof Medicine (D.K.P.), Radiology (R.G.G.),and Pathology (R.P.H.), Harvard MedicalSchool.

N Engl J Med 2006;354:1178-84.Copyright 2006 Massachusetts Medical Society.

Presentation of Case

A 71-year-old woman was admitted to the hospital because of left-sided weaknessand a mass in the brain. She had had Crohns disease for many years but was in her

usual state of health until three months before admission, when she became fa-tigued and required daily naps. Two months before admission, episodes of blurring

of vision, occipital headaches, and an unsteady gait occurred. The patients husbanddescribed her as tilting to the left when she walked, and she appeared to be de-

pressed and angry.Two weeks before admission, the patient noted an enlarging, nontender mass

in her right inguinal area. A f ine-needle aspiration of the mass performed 10 days

before admission disclosed necrosis, heterogeneous lymphoid cells, and epithelioidhistiocytes suggestive of granulomatous inflammation. Several days later nausea

developed, the patients appetite decreased, and over the course of the next week,she lost weight (2 kg). She did not vomit; she had chronic diarrhea from her

Crohns disease, which did not change in frequency or character. Six days beforeadmission, she was too weak to get out of bed, and her husband took her to theemergency room of another hospital, where she was admitted. Her temperature was

38.8C; other vital signs were normal. The chest was clear, and the heart soundswere normal. The abdomen was mildly tender to palpation, without rebound or

guarding. There was no organomegaly. A firm, fixed, nontender mass, 3 cm by 3 cm,was present on the right side of the inguinal region. There was rectal tenderness on

digital examination. The patient was alert and oriented. The results of a neurologicexamination showed no abnormalities. Cultures of blood and stool were obtained,and broad-spectrum antibiotics were administered.

On the second hospital day, the temperature was 38.8C. That evening, the patienthad a sudden loss of coordination. A neurologic consultant noted a left-sided facial

droop; the motor strength on the right side was normal and 4/5 on the left side.There was left pronator drift, and f inger-to-nose and heel-to-shin movements were

poor on the left side. On stimulation of the plantar reflexes in both feet, the toesturned down. The neck was supple, but her headache was worse on neck flexion.A Romberg test was positive, and the patient leaned toward her left side when

walking.Magnetic resonance imaging (MRI) of the brain showed a mass, 3 cm in di-

Case 8-2006: A 71-Year-Old Woman withCrohns Disease and Altered Mental Status

Daniel K. Podolsky, M.D., R. Gilberto Gonzalez, M.D., Ph.D.,and Robert P. Hasserjian, M.D.

Copyright 2006 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by CARLOS S. LOPES MD on April 3, 2009 .


2/7

case records of the massachusetts general hospital

n engl j med 354;11 www.nejm.org march 16, 2006 1179

ameter, in the right thalamus adjacent to the

lateral ventricle. Computed tomography (CT) ofthe abdomen and pelvis revealed the right ingui-

nal mass; there were no other abnormalities. Treat-ment with dexamethasone was started. On the

third hospital day, the patient had less nausea

and headache, and the left-sided facial droopwas not seen. The temperature rose to 38.9C.

An incisional biopsy of the right-sided inguinalmass was performed. She was transferred to this

hospital on the sixth hospital day.Crohns disease had been diagnosed when the

patient was 22 years of age, by Dr. Burrill B. Crohn,the physician for whom the disease is named. Anileal resection was performed when she was 22

years of age, and a hemicolectomy at 59 years ofage. Beginning when she was 52 years of age, she

had been receiving treatment with prednisone, 40to 50 mg per day; this drug had been discontin-

ued 10 years before admission. Six years beforeadmission, treatment with mercaptopurine wasbegun; infliximab infusions every eight weeks

were added to her treatment regimen three yearsbefore admission. The patient continued to have

intermittent diarrhea and hematochezia. The lastinfusion of infliximab she received was four weeks

before admission.The patient had diabetes mellitus, hypertension,

and anemia, which was treated with monthly in-

jections of vitamin B12. She lived with her hus-band. She had smoked cigarettes for 16 years but

quit 30 years before admission. She drank alco-

hol infrequently. A daughter had Crohns disease.The patients medications included mesalamine,pantoprazole, losartan, hydrochlorothiazide, loper-amide, zolpidem, insulin, cefoxitin, vancomycin,

dexamethasone, and ondansetron in additionto those already mentioned.

The temperature was 36.1C, the pulse 69 beatsper minute, the respiratory rate 18 breaths per

minute, and the blood pressure 128/56 mm Hg.On physical examination, the patient appearedchronically ill. There was a small, white lesion on

the inferior aspect of the tongue. There was nocervical or axillary lymphadenopathy. There were

inspiratory crackles at the left lung base, and theheart sounds were normal. The abdomen was

soft and nontender, and the bowel sounds werenormal. There was a right-sided inguinal mass,

3 cm by 1 cm, with a recent incision over it.The patient was awake and alert. There was a

left homonymous hemianopia. The pupils were

equal and minimally reactive to light. Extraocular

movements were normal, but there was decreased

eye closure and reduced sensation to touch on theleft side of her face. She could not raise her left

arm above her head. The strength in her left armmeasured 3/5 proximally and 1/5 distally, as com-

pared with 4/5 for the entire right arm. The

strength in her left leg measured 2/5 proximallyand 3/5 distally, as compared with 4/5 for the entire

right leg. Finger-to-nose touch and heel tappingwere intact on the right side and slow on the left

side. The patient was too weak to walk.The results of laboratory tests are shown in

Table 1. A lumbar puncture showed 94 white cells,with 32 percent lymphocytes, 8 percent neutro-phils, 40 percent monocytes, and 19 percent large

cells with nucleoli and basophilic cytoplasm; theresults of flow cytometry, cytologic examination,

and cultures were pending.Early in the morning of the second hospital

day, the patient had a generalized tonicclonicseizure and became unresponsive. The trachea wasintubated to maintain airway protection, and she

was transferred to the intensive care unit. CTscanning of the brain showed a heterogeneous

mass, 4.3 cm (from anterior to posterior) by 4.2 cm(from left to right) in greatest dimension, cen-

tered in the right side of the thalamus, with arelatively low attenuation center and a rim of highattenuation. There was an eccentric nodular com-

ponent anteriorly and medially. Local mass effectwas noted on the right lateral ventricle, but there

was no subfalcine or transtentorial herniation.

There was architectural distortion that resultedin crowding of the foramen of Monro and mildprominence of the right temporal horn, suggest-ing outflow obstruction.

A diagnostic procedure was performed.

Table 1. Laboratory-Test Results on Admission.

Variable Value Normal Range

Sodium (mmol/liter) 131 135145

Potassium (mmol/liter) 3.4 3.44.2

Alanine aminotransferase (U/liter) 45 730

Aspartate aminotransferase (U/liter) 36 932

Lactic dehydrogenase (U/liter) 290 110210

Alkaline phosphatase (U/liter) 41 30100

Amylase (U/liter) 53 3100

Hematocrit (%) 36.9 36.046.0

White cells (per mm3) 6,800 450011,000

Platelets (per mm3) 187,000 150,000350,000



3/7



Differential Diagnosis

Dr. Daniel K. Podolsky: May we review the radio-logic studies?

Dr. R. Gilberto Gonzalez: The CT scanning of thehead performed without the administration of

contrast material on the second hospital day(Fig. 1A) revealed a large mass centered withinthe right side of the thalamus. The mass was

predominantly hyperdense, although regions oflow density were observed; it exerted mass effect

on adjacent structures and appeared to extend intothe ventricular system. The mass extended infe-

riorly to involve the temporal lobe and superiorlyto the centrum semiovale.

Dr. Podolsky: This 71-year-old woman with an

almost 50-year history of Crohns disease requir-ing long-term immunosuppressive therapy was

found to have a mass involving the central ner-

vous system after the onset of symptoms of weak-ness and various neurologic findings. The imag-ing characteristics of the central nervous system

abnormality are unlikely findings for a vascularprocess such as stroke or hemorrhage, and thedifferential diagnosis is narrowed to infection

and cancer.

Infection

Infectious processes, including abscess, tubercu-

losis, and opportunistic infections, are importantconsiderations. Although Crohns disease wouldnot predispose this patient to either an abscess

or an opportunistic infection, immunosuppressivetreatment could. In particular, reactivation of la-

tent tuberculosis after the administration of in-fliximab has been well recognized1; the majority

of patients in whom this reactivation has occurredhave had extrapulmonary or disseminated disease,including central nervous system infection. In

this regard, it is noteworthy that fine-needle as-piration of the inguinal mass yielded granuloma-

tous tissue. Were it not for the brain lesion, thefinding from the mass might also raise concern

about the possibility of Crohns disease involvinga lymph node. However, the characteristics of thebrain images are not suggestive of an infectious

process, and although the patient had fever, thereare few other specific signs to suggest an infec-

tious process.

Cancer

The appearance of the brain mass is highly sug-gestive of a neoplasm. Considered in isolation, the

A

B

Figure 1. CT and MRI Scans of the Head.

A CT scan (Panel A), obtained without the adminis-

tration of contrast material, shows a large mass,centered in the right side of the thalamus (arrows).

The mass is heterogeneous, is predominantly hyper-

dense, and extends into the right lateral ventricle.

An MRI (Panel B), obtained six days after the CTscan, shows that the mass had increased in size. It

has heterogeneous signal characteristics, includingareas of relatively low T2-weighted signal correspond-ing to the regions of hyperdensity seen on the CT

scan. The mass prevents the egress of cerebrospinal

fluid, resulting in hydrocephalus.



4/7



imaging studies would raise concern for a primary

cancer of the brain. However, given the knowndiagnosis of Crohns disease and the presence of

a mass in the groin, there are two more likelydiagnoses: metastatic carcinoma and lymphoma.

Patients with Crohns disease are at increased

risk for adenocarcinoma, particularly of the smallintestine, but also in the colon. These cancers are

most likely to develop in areas affected by Crohnsdisease; the risk of cancer in the small intestine

in patients with Crohns disease has been esti-mated to be 5 to 25 times higher than that of un-

affected persons,2,3 and the risk of colorectal ad-enocarcinoma 2 to 5 times higher than that ofunaffected persons.4-6 The risk correlates with

extent of disease, duration, and independently, theage at onset. This patients surgical history sug-

gests that she has had Crohns disease affectingboth the small intestine and the colon, and she

appears to have had active disease for almost 50years. However, the lesion observed on brain im-aging is unlikely to represent metastatic adeno-

carcinoma in the absence of evidence of othermetastatic disease nor would this diagnosis

account for the type of atypical cells that wereseen in the cerebrospinal fluid.

Lymphoma in Crohns disease

It has long been suspected that there is an in-

creased frequency of lymphoma in the setting ofCrohns disease, although this premise remains

controversial. Several studies1,3,7,8 have found a

risk of lymphoma among patients with Crohnsdisease that is two to four times the risk amongthose without the disease, although others havenot found any significant increase.5,9 In the ag-

gregate, these studies support the impression ofan increased risk of lymphoma in patients with

Crohns disease, but it is unlikely that the magni-tude of this increase is more than twice that in

patients without Crohns disease.The risk of lymphoma may be increased by im-

munosuppressive agents used in the treatment of

these patients.10,11 The results of studies attempt-ing to define the risks of lymphoma conferred

by immunosuppressive therapy with azathioprineor mercaptopurine have been equivocal,10,12,13 with

relative risk ranging from less than or slightlygreater than 19,14 to almost 60.15,16

Infliximab and Lymphoma

Understanding how to assess the risk of lympho-

ma in patients with Crohns disease has taken on

new urgency with the increasing use of inflix-

imab, a chimeric antitumor necrosis factor (TNF)monoclonal antibody. This antibody was initially

presumed to act through neutralization of the solu-ble form of the proinflammatory cytokine TNF,

but recent studies suggest that apoptosis of cells

expressing the transmembrane precursor afterbinding by infliximab may be necessary for ther-

apeutic benefit. In the several years since its ini-tial approval, infliximab has been found to have

diverse adverse effects17; some of these effectsmay be due to the development of antiinf liximab

antibodies, whereas others may reflect the bio-logic effects of infliximab, such as abscess for-mation and opportunistic infections, including

reactivation of latent tuberculosis.Several reports have suggested that infliximab

may increase the risk of lymphoma.17,18 The in-cidence of non-Hodgkins lymphoma in patients

with Crohns disease treated with infliximab inseveral large studies ranged from 0.2 percent17 to1.4 percent.19 A summary of all the lymphomas

reported in patients receiving infliximab (includ-ing patients with rheumatoid arthritis and those

with Crohns disease) yielded an overall incidenceof 0.6 percent.18 As in the setting of other types of

immunosuppressive therapy, large-B-cell lympho-mas that are positive for EpsteinBarr virus (EBV)appear to predominate. Dr. Siegel and my other

colleagues at Massachusetts General Hospitalhave recently completed a survey to assess the

risk of lymphoma in patients with Crohns dis-

ease treated with infliximab.Dr. Corey A. Siegel (Gastroenterology): We per-

formed a systematic literature search to identifyall of the studies with a minimum follow-up pe-

riod of 48 weeks that specifically reported adverseeffects of inf liximab in the treatment of Crohns

disease. There were 5 patients with lymphoma re-ported among approximately 1700 patients (0.3

percent). As compared with a healthy age-matchedpopulation from the Surveillance, Epidemiologyand End Results database, this percentage repre-

sents an increase in the incidence of lymphomain patients receiving infliximab that is approxi-

mately 20 times higher.Dr. Podolsky: In summary, this patient possess-

es at least three possible risk factors for non-Hodgkins lymphoma Crohns disease, im-

munosuppressive therapy with mercaptopurine,and infliximab therapy. Although the impact ofeach risk factor alone may be small, the overall

effects may be additive, if not synergistic. Ac-



5/7



cordingly, I believe that lymphoma may have devel-oped in this patient, probably large-B-cell lym-phoma that is positive for EBV. The diagnosis was

probably made by appropriate staining of the tissueobtained from the incisional biopsy of the inguinal

lymph node, flow cytometry analysis of the abnor-mal cells seen in the cerebrospinal fluid, or both.

Clinical Diagnosis

Probable non-Hodgkins lymphoma.

DR. DANIEL K. PODOLSKYS

DIAGNOSIS

B-cell lymphoma, probably large-B-cell lymphomathat is EBV-positive, associated with immunosup-

pression.

Pathological Discussion

Dr. Robert P. Hasserjian: The diagnostic procedures

were a review of the slides of the specimen obtainedfrom the inguinal lymph-node biopsy from theother hospital and an analysis of the cerebrospi-

nal fluid by cytology and flow cytometry. Thelymph-node architecture was effaced by sheets of

large lymphoid cells, with large areas of geograph-ic necrosis (Fig. 2A). The lymphoid cells had prom-

inent nucleoli, expressed the B-cell marker CD20,and contained encoded RNA for EBV (Fig. 2B, 2C,and 2D).

Cytologic examination of the cerebrospinalfluid disclosed large, atypical lymphocytes, mor-

phologically similar to the nodal lymphoma cells(Fig. 3). Flow cytometry revealed a predominant

population of CD19+ and CD20+ B cells aber-

A B

C D

Figure 2. Inguinal Lymph-Node Biopsy Specimen.

The inguinal lymph-node architecture (Panel A) is totally effaced by diffuse sheets of cells with areas of geographic

necrosis (lower right; hematoxylin and eosin). The cells are large with round-to-irregular, vesicular nuclei and promi-

nent nucleoli (Panel B; hematoxylin and eosin). The cell-surface membrane of the large cells is positive for the B-cellmarker CD20 (Panel C; immunohistochemical staining for CD20). Nearly all the large cells contain EpsteinBarr

virus-encoded RNA (Panel D; in situ hybridization).



6/7



rantly expressing CD43 and lacking detectable

surface or cytoplasmic immunoglobulin expres-sion. These findings confirm an EBV-positive, dif-

fuse large-B-cell lymphoma involving the ingui-nal lymph node and cerebrospinal fluid.

EBV is typically absent in cases of B-cell non-Hodgkins lymphoma that occur in immunocom-petent persons,20 but it is a hallmark of lympho-

mas occurring in the setting of immunodeficiency.Patients who are immunodeficient are at increased

risk for the development of a variety of lympho-

proliferative disorders, which share a number ofclinicopathological features (Table 2).21 Lowergrades or early forms of these lymphoprolifera-tive disorders resemble f lorid, uncontrolled EBV

infection and are often polyclonal.22 In contrast,frank lymphomas contain clonal sequences of

EBV and antigen-receptor gene rearrangements,indicating derivation from a single transformed

EBV-infected cell.23,24 Lymphomas arising in pa-tients who are immunodeficient are typically dif-fuse large-B-cell, Burkitts, or Hodgkins lympho-

mas. In addition to the strong association withEBV, these lymphomas differ from lymphomas

in patients who are immunocompetent in thatsuch cases show a more limited histologic spec-

trum and a predilection for extranodal site in-volvement.

Lymphomas that arise in patients with inflam-matory bowel disease who have been treated withthe immunosuppressive agents azathioprine and

mercaptopurine have features resembling immu-

nodeficiency-associated lymphomas.25 In contrastto lymphomas that develop in patients with in-

flammatory bowel disease who are not receivingsuch therapies, these lymphomas are typically

EBV-positive and are almost exclusively high-grade B-cell and Hodgkins lymphomas. At least

one of the reported cases exhibited a viral anti-

gen expression pattern (latency pattern, type 3)that is characteristic of immunodeficiency-asso-

ciated lymphomas.26 Other recent studies havedocumented an increased incidence of lympho-

ma after relatively short periods of infliximabtherapy, although many of these patients had

also received immunosuppressants18,19,27; at leastone of the cases in these studies was EBV-posi-tive. The EBV-positive status and extranodal in-

volvement in the current patient, in the contextof mercaptopurine and infliximab therapy, sug-

gest that this case should be categorized as animmunodeficiency-associated lymphoma.

Dr. Nancy Lee Harris (Pathology): The intervalbetween starting infliximab therapy and develop-

ment of lymphoma was fairly long in this patient.Dr. Podolsky: Reports suggest that lymphoma

may occur within a very short time after inflix-

imab is first started, and an average of just threeinfusions before diagnosis of the cancer has been

described. However, the prolonged period that isdescribed for this patient is within the range re-

ported.Dr. Harris: Dr. Hochberg, can you discuss the

further care of this patient?

Dr. Ephraim P. Hochberg (HematologyOncology):The chemotherapy agents that are currently the

standard of care for systemic diffuse large-B-celllymphomas do not penetrate the central nervous

system, nor does rituximab, an anti-CD20 mono-clonal antibody that is an important additionalagent in treating this cancer. So we were left in

this case with a choice of high-dose methotrexateas a therapy that would penetrate into the central

Figure 3. Cytologic Preparation of a Sample of Cerebro-spinal Fluid.

There are large cells with vesicular nuclei and moderate-ly abundant, eccentrically placed cytoplasm (Papanico-

laou stain). These cells resemble the tumor cells on an

air-dried direct smear prepared from the patients ingui-nal lymph node (inset, WrightGiemsa stain).

Table 2. Common Features of Immunodeficiency-Associated Lymphoproliferative Disorders.

Defective T-cell function leading to decreased immuno-surveillance

Presence of the EpsteinBarr virus (EBV) in lymphomacells, with viral antigen expression pattern character-

istic of in vitro EBV-immortalized lymphoblastoidcell lines

Predilection for extranodal sites (especially the brain)

Potential to regress with restoration of T-cell function



7/7



nervous system and also affect the lymph-node

disease, or whole-brain radiation for palliation.Unfortunately, the patients neurologic status did

not improve, and she also had biochemical evi-dence of myocardial infarction after admission

to the intensive care unit. Serial CT scans and MRI

(Fig. 1B) showed rapid growth of the tumor. Inthe setting of her other medical problems and

advanced age it was thought that systemic che-motherapy was not an option. The family declined

radiation therapy and ultimately decided to with-

draw care. She died on the eighth hospital day.

Anatomical Diagnosis

Diffuse large-B-cell lymphoma, EBV-positive, as-

sociated with iatrogenic immunosuppression.No potential conflict of interest relevant to this article was re-

ported.

SLIDESETSFORTHECASERECORDSAVAILABLEINDIGITALFORMAT

Any reader of theJournal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is eligible to receive digital images,with identifying legends, of pertinent radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs. The images on the CD for each case are inboth PowerPoint and 300 dpi jpg format. For some cases, additional images that have not been selected for publication will be included on the CD. These images, whichillustrate the current cases in the Journal, are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber.Each year approximately 250 images from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the current subscription

year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone617-726-2974) or [email protected].

Images from individual cases may be obtained at a cost of $35 per case.

References

Keane J, Gershon S, Wise RP, et al.Tuberculosis associated with infliximab,a tumor necrosis factor neutralizingagent. N Engl J Med 2001;345:1098-104.

Persson PG, Karlen P, Bernell O, et al.Crohns disease and cancer: a population-based cohort study. Gastroenterology 1994;107:1675-9.

Bernstein CN, Blanchard JF, KliewerE, Wajda A. Cancer risk in patients with

inflammatory bowel disease: a population-based study. Cancer 2001;91:854-62.

Choi PM, Zelig MP. Similarity ofcolorectal cancer in Crohns disease and ul-cerative colitis: implications for carcinogen-esis and prevention. Gut 1994;35:950-4.

Ekbom A, Helmick C, Zack M, AdamiHO. Increased risk of large-bowel cancer inCrohns disease with colonic involvement.Lancet 1990;336:357-9.

Gillen CD, Andrews HA, Prior P, AllanRN. Crohns disease and colorectal cancer.Gut 1994;35:651-5.

Greenstein AJ, Mullin GE, StrauchenJA, et al. Lymphoma in inflammatory bow-el disease. Cancer 1992;69:1119-23.

Arseneau KO, Stukenborg GJ, Con-

nors AF Jr, Cominelli F. The incidence oflymphoid and myeloid malignancies amonghospitalized Crohns disease patients. In-flamm Bowel Dis 2001;7:106-12.

Lewis JD, Bilker WB, Brensinger C,Deren JJ, Vaughn DJ, Strom BL. Inflam-matory bowel disease is not associated withan increased risk of lymphoma. Gastroen-terology 2001;121:1080-7.

Bouhnik Y, Lemann M, Mary JY, et al.Long-term follow-up of patients withCrohns disease treated with azathioprine or6-mercaptopurine. Lancet 1996;347:215-9.

Present DH, Rutgeerts P, Targan S, etal. Inflix imab for the treatment of fistulasin patients with Crohns disease. N Engl JMed 1999;340:1398-405.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Fraser AG, Orchard TR, RobinsonEM, Jewell DP. Long-term risk of malig-nancy after treatment of inflammatorybowel disease with azathioprine. AlimentPharmacol Ther 2002;16:1225-32.

Aithal GP, Mansfield JC. The risk oflymphoma associated with inflammatorybowel disease and immunosuppressivetreatment. Aliment Pharmacol Ther 2001;15:1101-8.

Connell WR, Kamm MA, Dickson M,Balkwill AM, Ritchie JK, Lennard-Jones

JE. Long-term neoplasia risk after azathi-oprine treatment in inflammatory boweldisease. Lancet 1994;343:1249-52.

Kinlen LJ. Incidence of cancer in rheu-matoid arthritis and other disorders afterimmunosuppressive treatment. Am J Med1985;78:44-9.

Farrell RJ, Ang Y, Kileen P, et al. In-creased incidence of non-Hodgkins lym-phoma in inflammatory bowel diseasepatients on immunosuppressive therapybut overall risk is low. Gut 2000;47:514-9.

Colombel JF, Loftus EV Jr, TremaineWJ, et al. The safety profile of infliximabin patients with Crohns disease: the Mayo

Clinic experience in 500 patients. Gastro-enterology 2004;126:19-31.

Brown SL, Greene MH, Gershon SK,Edwards ET, Braun MM. Tumor necrosisfactor antagonist therapy and lymphomadevelopment: twenty-six cases reported tothe Food and Drug Administration. Ar-thritis Rheum 2002;46:3151-8.

Ljung T, Karlen P, Schmidt D, et al.Infliximab in inflammatory bowel disease:clinical outcome in a population based co-hort from Stockholm County. Gut 2004;53:849-53.

dAmore F, Johansen P, Houmand A,Weisenburger DD, Mortensen LS. Epstein-Barr virus genome in non-Hodgkins lym-phomas occurring in immunocompetent

12.

13.

14.

15.

16.

17.

18.

19.

20.

patients: highest prevalence in nonlym-phoblastic T-cell lymphoma and correla-tion with a poor prognosis. Blood 1996;87:1045-55.

Jaffe ES, Harris NL, Stein H, Vard-iman JW. Pathology and genetics of tu-mours of haematopoietic and lymphoidtissues. Vol. 3 of World Health Organiza-tion classification of tumours. Lyon,France: IARC Press, 2001.

Knowles DM, Cesarman E, ChadburnA, et al. Correlative morphologic and mo-lecular genetic analysis demonstrates threedistinct categories of posttransplantationlymphoproliferative disorders. Blood 1995;85:552-65.

Cleary ML, Nalesnik MA, Shearer WT,Sklar J. Clonal analysis of transplant-asso-ciated lymphoproliferations based on thestructure of the genomic termini of theEpstein-Barr virus. Blood 1988;72:349-52.

Cleary ML, Warnke R, Sklar J. Mono-clonality of lymphoproliferative lesions incardiac-transplant recipients: clonal anal-

ysis based on immunoglobulin-gene re-arrangements. N Engl J Med 1984;310:477-82.

Dayharsh GA, Loftus EV Jr, SandbornWJ, et al. Epstein-Barr virus-positive lym-phoma in patients with inflammatorybowel disease treated with azathioprine or6-mercaptopurine. Gastroenterology 2002;122:72-7.

Wong NA, Herbst H, Herrmann K, etal. Epstein-Barr virus infection in colorec-tal neoplasms associated with inflamma-tory bowel disease: detection of the virusin lymphomas but not in adenocarcino-mas. J Pathol 2003;201:312-8.

Losco A, Gianelli U, Cassani B, Baldi-ni L, Conte D, Basilisco G. Epstein-Barr

virus-associated lymphoma in Crohns dis-ease. Inflamm Bowel Dis 2004;10:425-9.Copyright 2006 Massachusetts Medical Society.

21.

22.

23.

24.

25.

26.

27.


Documents

Linfoma Associado a Imunodeficiencia