hodgkin's disease occurring in a child after liver transplantation

Annals of Oncology 9: 673-676. 1998.1998 Kluwer Academic Publishers. Primed in the Netherlands.

Short report

Hodgkin's disease occurring in a child after liver transplantation

V. Conter,1 B. Tschiimperlin,1 B. Gridelli,2 A. Lucianetti,2 S. Ascani,3 D. Bauer,4 R. Burnelli,5

S. Poggi,3 V. Ramaccioni,2 M. Milani1 & S. A Pileri3

Clinica Pedialrica, Ospedale S. Gerardo di Monza, University of Milan; 2Centro Trapianti di Fegato, Ospedali Riunili ofBergamo; ^ServiziodiAnatomia Patologica e Sezione di Ematopatologia, Istituto di Emalologia ed Oncologia Medica 'L. e A. Seragnoli', Universita degli Studi ofBologna; 4Istituto di Anatomia Patologica, University of Milan, 5Oncoemalologia Pedialrica, Unita Complessa di Pediatria, Universita degliStudi of Bologna, Italy

Summary

Here we describe the case of a 14-year-old boy who underwentliver transplantation for post-Kasai biliary atresia when aged4. Antirejection treatment consisted of prednisone and cyclo-sporine. At the age of 11 years the patient developed leftcervical lymphadenopathy; the biopsy showed classical Hodg-kin's disease(HD) of the mixed cellularity (MC) type. Neo-plastic cells expressed CD30 and CD15, and were negative forCD45, CD20, CD3, CD43, and CD79a. Furthermore, theycarried the EBV-related products LMP1 and EBER1/2. Treat-ment consisted of three cycles of adriamycin, bleomycin, vin-blastine and DTIC (ABVD), followed by radiotherapy (2,000

cGys) on involved fields. At present, 42 months after the diag-nosis of HD, the patient is still in complete remission. This is,to the best of our knowledge, the first reported case of classicalHD following liver transplantation. The positivity of neoplasticcells for LMP1 and EBER1/2 indicates a possible role forimmunosuppression in the development of the tumor, andwhether a reduction in immunosuppression might have influ-enced the course of the disease is open to question.

Key words: Hodgkin's disease, immunohistochemistry, in situhybridization, liver transplantation, post-transplant lympho-proliferative disorder

Case report

In June 1987 a four-year-old boy affected by post-Kasaibiliary atresia underwent an orthotopic liver transplan-tation. Following surgery, an immunosuppressive therapywas administered with prednisone (initially) and cyclo-sporine A (CyA, continued). CyA blood levels rangedfrom 50 to 100 ug/ml.

At the age of 11 years the patient presented with leftlatero-cervical lymphadenopathy, in the absence of sys-temic symptoms. A biopsy was performed and the diag-nosis of mixed cellularity (MC) Hodgkin's disease (HD)was made. The clinical stage was IIA, since in additionto the primary site, the left pulmonary hilum was in-volved.

The patient was treated according to the Italian Asso-ciation of Pediatric Hematology and Oncology (AIEOP)MH '89 protocol. Treatment consisted of three ABVDcourses (adriamycin 25 mg/m2, bleomycin 10 mg/m2,vinblastine 5 mg/m2, DTIC 350 mg/m2 on days 1 and15 given q 4 wks [1]) and subsequent local radiotherapy(2,000 cGys over 11 days on involved fields). Rapid re-gression of the cervical lymphadenopathy was observed.No relevant side effects were observed.

At the beginning of chemotherapy CyA dose wasreduced from 5 to 4 mg/kg/day, since the blood levelwas 115 ug/ml. Two months later, the dose was further

reduced to 2 mg/kg/day because of increased drug levelsin the blood (280 ug/ml). Two months after chemo-therapy discontinuation, the patient presented with verylow CyA blood levels (27 ug/ml) and a moderate alter-ation of liver enzymes (ALT 151 U/l, normal range 8-41U/l), consistent with a diagnosis of initial rejection;immunosuppressive treatment was thus increased (7 mg/kg/day) with normalization of the liver enzymes. Thepatient is currently doing well and is free of disease 42months after the diagnosis of HD; CyA is given at adose of 2.5 mg/kg/day. Liver function test results arenormal.

Hislologicalfindings

The lymph node biopsy was fixed in 10% bufferedformalin and embedded in paraffin at 56 GC [2]. Four-um-thick sections were cut, mounted on sylane-coatedslides and stained with hematoxylin and eosin, Giemsa,and Gomori silver impregnation for reticulin fibres [3].Some of them were also used for immunohistochemistry,which was performed on a TechMate 500 machine(Dako, Denmark) by applying the APAAP technique[3] and the panel of antibodies listed in Table 1. Addi-tional sections were cut and mounted on electrically-charged slides (Dako, Denmark), for performance of insitu ibridization for EBER1/2 by fluorescein-labelled

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Table 1. Panel of antibodies employed for the study.

Clone

Ber-H2C3D-12B11 +PD7/26L26JCB117DF-T1PolyCS1-4EBV (oligonucleotide probe)

Specificity

CD30CD15CD45CD20Cd79aCD43CD3LMPEBER

Source

DakoDakoDakoDakoProf. MasonDakoDakoDakoDako

probes, revealed by anti-fluorescein-specific antibodiesand the immunoalkaline phosphatase technique (Dako,Denmark).

The normal lymph node structure was diffusely effacedby a growth consisting of small lymphocytes, plasma cells,eosinophils, macrophages, and typical Hodgkin's andReed-Sternberg cells (HRSCs, Figure 1). No nodularity,sclerosis, 'mottled appearance', immunoblasts, plasma-cytoid differentiation or necrosis were observed.

At immunohistochemistry, HRSCs strongly expressedthe following molecules: CD30, CD15, and LMP1 (Fig-ure 2). On the other hand, they turned out to be negativefor the leukocyte-common antigen/CD45, as well as forEBNA2, CD3, CD20, CD43, and CD79a antigens.

In situ hybridization revealed a clear positivity forHRSCs for EBER1/2 (Figure 3).

According to the histological, immunohistochemicaland in situ hybridization findings, a common HD of theMC type (R.E.A.L.) was diagnosed.

Comments

About 2% to 10% of the patients who undergo liver,heart or lung transplantation may develop PT-LPDs [4].As shown by molecular and in situ hybridization studies[5, 6], these LPDs are related to EBV infection, probably

Figure 2. Hodgkin's and Reed-Sternberg cells strongly express theCD30 molecule both at the cytoplasmic membrane and paranuclearlevel (APAAP technique, Ber-H2 monoclonal antibody, Gill's hema-toxylin counterstain, x570).

Figure 1. Typical Hodgkin's and Reed-Sternberg cells, consisting ofsmall lymphocytes, eosinophils, plasma cells, and macrophages (hem-atoxylin and eosin, x520) in a cellular "milieu'.

Figure 3. Detection of the small RNAs EBER 1 and 2 in the tumouralcells by in situ hybridization (fluorescein-labelled specific probes, immu-noalkaline phosphatase technique, Gill's nuclear counterstain, x510).

due to immunosuppression which inhibits normal anti-viral immune mechanisms.

It has also been shown that some PT-LPDs canregress after reduction of immunosuppressive therapy,thereby challenging their malignant nature [7]. On clin-ical grounds, two forms of PT-LPDs can be recognized[8]. One of these mimics infectious mononucleosis, anddevelops in children and young adults, usually EBV-sero-negative at the time of transplantation and heavilyimmunosuppressed after the graft. The other presentswith a tumor syndrome and occurs in older patientsseveral years after the graft.

HD is a lymphoid neoplasm which usually occursin immunocompetent patients. In the past few years,several reports have pointed to a possible relationshipbetween its pathogenesis and EBV infection. In fact, ithas been shown that: i) a monoclonal EBV genome isfrequently detected in HD, and ii) HRSCs can containboth EBV DNA and EBERs and can express LMP1 inthe absence of EBNA2 and lytic antigens [5]. The latterphenotypic profile corresponds to a type II latencypattern, identical to the one found in nasopharyngeal


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carcinoma, a typical EBV-related tumor [5]. This obser-vation, along with the transforming capacity of LMP1 invitro, has supported the possibility of a role for EBV inthe development of HD [9]. Such an assumption, how-ever, does not apply to all HD cases, as EBV positivityin HD appears to correlate with geographic location andcultural, genetic and/or socio-economic factors [10]. InWestern countries, EBV is detected in about 90% of MCcases and in 40%-50% of the nodular sclerosis ones, butis not found in lymphocyte-predominant HD [5, 9, 10].Although only rarely, HD can also occur in immuno-compromised patients: it has been reported amongHIV+ drug-addicts in Italy and Spain [11], in a few renaltransplant recipients and in only one case after livertransplantation, in which, however, the diagnosis of'true HD' was challenged [12].

The case herein described, which to our knowledge isthe first to be reported of classical HD following livertransplantation, seems to satisfy all of the criteria for adiagnosis of common HD of the MC type. Clinicallythis patient presented with HD stage IIA seven yearsfollowing liver transplantation: this pattern does notcorrespond to the mononucleosis-like form of PT-LPDmore often observed in children and young adults [7].

With respect to the treatment, immunosuppressioncould have only favoured an event (i.e., EBV integrationin the genome of lymphoid elements and their neoplastictransformation) which seems to represent an integralpart of the natural history of MC-HD in most instances.In light of this, conventional chemo- and radiotherapyfor HD were administered, which yielded excellent re-sults, suggesting that PT-HD should be treated like HDoccurring in immunocompetent patients. Whether ornot withdrawal of immunosuppression - as commonlyattempted in conventional PT-LPDs [8] - would haveinduced regression of the disease in the present caseremains an open issue. However, it can be ethicallyquestionable to decrease immunosuppression and tomonitor the course of the disease before starting chemo-therapy, when the outcome of HD is indeed favourableby application of standard protocols [1]. The response toconventional therapy for HD in our patient was in factexcellent, with exactly the same tolerance and toxicity asin immunocompetent children.

These findings differ sharply from the experiencereported for HD in patients with Acquired ImmuneDeficiency Syndrome (AIDS), in whom HD is usuallyassociated with symptoms (mostly fever), advanced stagesand very poor response to therapy and poor outcome[14]. It is worthwhile emphasizing in this regard thatpatients with AIDS, unlike transplanted patients under-going immunosuppressive treatment, usually presentwith very marked reduction of T-helper lymphocytes.Impairment of immunological competence in trans-planted patients is less severe, and depends on theimmunosuppressive treatment used. At diagnosis of hisHD, our patient presented with a mild reduction of T4lymphocytes (365/ul) and a modest decrease in T4/T8lymphocyte ratio (0, 5).

A further aspect to be considered is the interactionbetween chemotherapy and CyA. This experience sug-gests that chemotherapy may reduce the clearance of thedrug. On the other hand, increased levels of CyA coulddecrease drug resistance in neoplastic cells and/or in-crease chemotherapy-related toxicity [13]. CyA dosesshould thus be carefully adjusted to blood levels, takinginto account also that very low blood levels could lead toa rejection of transplanted liver. Immunosuppressivetherapy may therefore need to be reduced, but shouldnot be discontinued. A careful monitoring of blood levelsis thus mandatory during chemotherapy treatment.

Acknowledgements

This paper was supported by grants from A.I.R.C.(Milan), M.U.R.S.T. (Rome) and Comitato M. L. Vergaper lo Studio e la Cura delle Leucemie.

References

1. Vecchi V, Pileri S, Burnelli R et al. Treatment of pediatric ageHodgkin disease tailored to stage, mediastinal mass, and age.Cancer 1993; 72: 2049-57.

2. Falini B, Pileri S. Martelli MF. Histological and Immunohisto-logical Analysis of Human Lymphoma. New York: CRC Press1989:9- 351-419.

3. Cordell JL, Falini B, ErberWN et al. Immunoenzymatic labellingof monoclonal antibodies using immune complexes of alkalinephosphatase and monoclonal anti-alkaline phosphatase (APAAPcomplexes). J Histochem Cytochem 1984; 32: 219-29.

4. Opelz G, Henderson R. Incidence of non-Hodgkin's lym-phoma in kidney and heart transplant recipients. Lancet 1993;342: 1514-6.

5. Anagnostopoulos I, Hummel M. Epstein-Barr virus in tumours.Histopathology 1996; 29: 297-315.

6. Delecluse HJ, Kremmer E, Rouault JP et al. The expression ofEpstein-Barr virus latent proteins is related to the pathologicalfeatures of post-transplant lymphoproliferative disorders. Am JPatholl995; 146: 1113-20.

7. Starzl TE, Nalesnik MA, Porter KA et al. Reversibility of lym-phomas and lymphoproliferative lesions developing under cyclo-sporin-steroid therapy. Lancet 1984; 1: 583-7.

8. Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Ep-stein-Barr virus, immunodeficiency, and B cell lymphoprolifera-tion. Transplantation 1985; 39: 461-72.

9. Herbst H, Dallenbach F, Hummel M et al. Epstein-Barr viruslatent membrane protein expression in Hodgkin's and Reed-Sternberg cells. PNAS 1991: 88: 4766-70.

10. Leoncini L, Spina D, Nyong'o A et al. Neoplastic cells of Hodg-kin's disease show differences in EBV expression between Kenyaand Italy. Int J Cancer 1996; 65: 781-4.

11. Tirelli U, Lazzann A, Alessi E et al. Malignant tumors with HIVinfection: a report of 580 cases. J Clin Oncol 1989; 7: 1582-3.

12. Nalesnik MA, Randhawa P, Demetris AJ et al. Lymphomaresembling Hodgkin disease after posttransplant lymphoprolifer-ative disorder in a liver transplant recipient. Cancer 1993; 72:2568-73.

13. Colombo T, Zucchetti M, D'lncalci M. Cyclosporin A markedlychanges the distribution of doxorubicin in mice and rats. JPharmacol Ther 1994; 269: 22-7.

14. Ree HJ, Strauchen JA, Khan AA et al. Human immunodeficiencyvirus-associated Hodgkin's disease. Clinicopathologic studies of24 cases and preponderance of mixed cellularity type character-


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ized by the occurrence of fibrohistiocytoid stromal cells. Cancer Correspondence to:1991; 67 (Mar 15): 1614-21. V. Conter, MD

15. Unger PD, Strauchen JA. Hodgkin's disease in AIDS complex Clinica Pediatncapatients. Report of four cases and tissue immunologic marker Ospedale San Gerardo di Monzastudies. Cancer 1986; 58 (Aug 15); 821-5. Via Donizetti 106

20052 Monza, ItalyReceived 21 November 1997; accepted 7 April 1998. E-mail: masera(S;xquasar.it


hodgkin's disease occurring in a child after liver transplantation

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