30 Clin Pathol 1995;48:390-392

Epstein-Barr virus associatedlymphoproliferative disorder with fatalinvolvement of the gastrointestinal tract in an

infant

L X Pan, P Ramani, T C Diss, L N Liang, P G Isaacson

Department ofHistopathology,University CollegeLondon MedicalSchool, UniversityStreet, LondonWC1E 6JJL X PanT C DissJ N LiangP G Isaacson

Departnent ofHistopathology,Hospitals for SickChildren, GreatOrmond Street,London WCIN 3JHP Ramani

Correspondence to:Dr L X Pan.

Accepted for publication26 September 1994

AbstractA case of fatal Epstein-Barr virus (EBV)associated lymphoproliferative disorder isreported in an 11 month old female. Heavyinfiltrates of CD20 + and EBV EBERmRNA expressing lymphoid blasts were

found to cause a series of ulcers along theentire length of the gastrointestinal tractand there was an ileal perforation. Similarinfiltrates were also found in lymph nodes,spleen, and liver. Although blood pheno-typic analysis performed shortly beforeher death revealed a severe decrease in Tlymphocytes, neither the patient nor othermembers of her family had a history ofprimary or secondary immunodeficiency.EBV infection is common in children.However, such a fatal infection ofthe virushas not apparently been described pre-viously in infants without pre-establishedimmunodeficiency.(J7 Clin Pathol 1995;48:390-392)

Keywords: EBV, gastrointestinal tract, lympho-proliferation, infant.

Epstein-Barr virus (EBV) infection occurs

commonly in children. In infants, such in-fection is relatively rare and usually silent.'

Figure 1 EBV infected gut with a perforation in the terminal ileum and enlargedmesenteric lymph nodes.

In older children the infection tends to besymptomatic as a result of infectious mono-nucleosis, a benign self limiting lympho-proliferation. In patients with primary andsecondary immunodeficiencies, EBV infectionmay lead to fatal lymphoproliferative diseases,ranging from extensive polyclonal diffuselymphoid hyperplasia to monoclonal lymph-omas. "2

In this report, we describe an 11 month oldgirl who, despite having no history of im-munodeficiency, died from severe haem-orrhage, ulceration, and perforation of thegastrointestinal tract caused by extensive EBVassociated oligoclonal lymphoproliferatiion.

Case reportThe patient, an 11 month old female, presentedwith fever, diarrhoea, and generalised lymph-adenopathy over two weeks. Viral serology testson admission showed that serum IgG to EBVnuclear antigen (EBNA) was positive, whileEBV IgM to EBNA and EBV capsid antigen(VCA) were negative. Cytomegalovirus latextest was also negative. Total white blood cellcount was 6-6 x 10'/mm' and lymphocytecount was 2-05 x 103/mm'. The child de-veloped persistent abdominal distension, andcoffee ground nasogastric aspirates indicatedhaemorrhage. Chest x ray and abdominal x rayshowed free subdiaphragmatic air. The patientdied two weeks after presentation followingsevere peritonitis. Flow cytometric analysis ofblood lymphocytes performed 24 hours beforethe death showed CD2-14%, CD3-9%, CD4-1%, CD8-15%, CD16/56-3%, and CD19-71%, indicating a decrease in T lymphocytes,especially T4 (helper/inducer) and an increasein B lymphocytes.The patient was noted since birth to have

several dysmorphic features such as a triangularface, micrognathia, low set ears, and hypotonia.Chromosomal studies showed normal 46XXkaryotype. No specific syndrome could be iden-tified. Her elder sister (age three years) hadsimilar dysmorphic features, but neither thepatient nor other members of her family had ahistory of primary or secondary immuno-deficiency.Necropsy showed, in addition to generalised

lymphadenopathy, a series of ulcers along thewhole length of the gastrointestinal tract, witha perforation of the ileum (fig 1). There wasassociated peritonitis with 100 ml of purulentfluid in the abdominal cavity. The tonsils,spleen, and liver were not enlarged. There was

390

on 30 June 2019 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.48.4.390 on 1 A

pril 1995. Dow

nloaded from

EBV associated lymphoproliferative disorder in an infant

M R N A A B B|._ ... a s . ~~~~~~~~~~~~-----------

100-

Figure 2 Polymerase chain reaction (PCR) analysis of rearranged Ig VH gene showsoligoclonal patterns of the lymphoid lesions at two different sites of the gut (A and B;duplicated PCR reactions). M= Phi-X HinfI marker; R = Raji cell line monoclonalcontrol; N= negative control without DNA template.

4 ~~ j :.r

t: t t . :.am

w. ffi' v -i i

^,,dN'' e { , p

~ 0f<

* } 4# -e~~~9)

I B

oo 0

*S 41

A

fo 1p

C*'s.

_ 0.

f

ta

* Ww w

.g a *1'w

..* .A

4E. ..

0

IN*

*eV*-. .5

,V'

.'

A

f.

0* *0

-.400 4k

4 4A

0

Figure 3 A: Haematoxylin and eosin stained tissue section showing heavy ixgut mucosa by lymphoid blasts. B: In situ hybridisation for EBV EBER mRlstrong signal in blast cells.

no evidence ofbronchopneumonia or

No gross congenital defects were no

internal organs.

Histological sections from the ulcers sampledfrom multiple sites of the gut showed a dom-inant population of monomorphic lymphoidblasts accompanied by few plasmacytoid cellsand small lymphocytes in the mucosa. In someareas, this infiltrate extended through themuscle layers into the serosa. In the enlargedlymph nodes from different sites of the body,these cells caused architectural effacement.Similar infiltration was also observed in theportal tracts of the liver, white pulp of thespleen, and perivascular sites of the kidney andlung.The infiltrating lymphoid blasts were pre-

dominantly CD20+ and showed focal evid-ence of light chain restriction but were mostlypolytypic. EBV latent membrane protein(LMP) was weakly positive in some of thesetransformed cells. Polymerase chain reaction(PCR) for detection of immunoglobulin generearrangement3 revealed an oligoclonal patternwhich varied in different sites of disease (fig2). In situ hybridisation for EBVEBERmRNA4showed a strong signal in virtually all the trans-formed blasts from lymphoid lesions of variousorgans (fig 3).

DiscussionThe clinical features of the patient indicatedan acute infection with severe involvement ofthe gastrointestinal tract. The results of theserologic tests after admission (IgM to VCA

<-* eiu, andEBNA negative and IgG to EBNA positive)\* suggested past infection with EBV.5 It is pos-

sible that the acute phase ofthis disease resultedfrom reactivation of past EBV infection.

Fatal EBV associated polyclonal lympho-C proliferative disorders have been described

mainly in patients with immunodeficiencies,oi.** such as patients with X linked lympho-

* proliferative syndrome (XLPS), severe com-bined immunodeficiency (SCID), or afterorgan transplantation.'2 In this patient, pheno-

4. typic analysis performed shortly before deathshowed a marked decrease in T lymphocytes.However, the lack of recurrent infections and

,* X family history of primary or secondary im-%* munodeficiencies does not support a pre-ex-

VA isting immunodeficiency. We cannot excludethe possibility that the decrease in T lymph-

5 ocytes in our patient represents a response* 5 secondary to overwhelming virus infection and

s terminal illness.67a-o The diagnostic problems presented by EBV- infection continue to be a concern for path-

ologists. In this case, features such as efface-4 ment of architecture of the lymphoid organs

and the dense and monomorphous infiltratecomposed predominantly of transformed

0. .lymphoid blasts made it difficult to distinguishthe disease from high grade B cell lymphoma.Using immunohistochemistry and PCR we

4iltration of were able to elucidate the oligoclonal nature ofNA showing this fatal lymphoproliferation. In situ hy-

bridisation enabled us to show that EBV in-skin rash. fection was the cause of the disease. Therefore,ted in the to avoid an erroneous diagnosis of malignancy

in similar lymphoproliferative disorders, it is

391

-i- %..ff-j% %,

L."a

V.- 0Ti .

a-a .-!p

V.

V",4*# i

.L .,i.. I

yp-

I>4

on 30 June 2019 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.48.4.390 on 1 A

pril 1995. Dow

nloaded from

Pan, Ramani, Diss, Liang, Isaacson

essential to correlate the clinicopathologicalfindings with molecular results.

1 Schuster V, Kreth HW. Epstein-Barr virus infection andassociated diseases in children. I. Pathogenesis, epi-demiology and clinical aspects. Eur Pediatr 1992;151:718-25.

2 Weisenburger DD, Purtilo DT. Failure in immunologicalcontrol of the virus infection: fatal infectious mono-nucleosis. In: Epstein MA, Achong BG, eds. The Epstein-Barr virus: recent advances. London: Heinemann, 1986:127-61.

3 Diss TC, Peng HZ, Wotherspoon AC, Isaacson PG, Pan L.Detection ofmonoclonality in low-grade B-cell lymphomas

using the polymerase chain reaction is dependent on primerselection and lymphoma type. Pathol 1993;169:291-5.

4 MacMahon EM, Glass JD, Hayward SD, Mann RB, BeckerPS, Charache P, et al. Epstein-Barr virus in AIDS-relatedprimary central nervous system lymphoma. Lancet 1991;338:969-73.

5 Schuster V, Kreth HW. Epstein-Barr virus infection andassociated diseases in children. H. Diagnostic and thera-peutic strategies. EurJ Pediatr 1992;151:794-8.

6 Tazawa Y, Nishinomiya F, Noguchi H, Takada G, Tsuchiya S,Sumazaki R, et al A case of fatal infectious mononucleosispresenting with fulminant hepatic failure associated withan extensive CD8-positive lymphocyte infiltration in theliver. Hum Pathol 1993;24:1135-9.

7 Abramowsky C. Immunodeficiency disorders. In: StockerJT,Dehner LP, eds. Pediatric pathology, Vol I. Philadelphia:Lippincott, 1992:372-4.

392

on 30 June 2019 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.48.4.390 on 1 A

pril 1995. Dow

nloaded from