Post Transplant Malignancy – A Brief Review

Review Article

INTRODUCTION

Solid organs transplant is the only life saving modalityfor end stage disease of various organs. In past few decadesgreat advances have been made in the field of organtransplant. Availability of excellent infrastructure in leadinghospitals, advancement of surgical techniques, growingresearch and development of various safe options forimmunosuppression have lead to improvement in graftsurvival, increased life expectancy and morbidity free posttransplant life in recipients. This has resulted in notableincrease in number of solid organ transplants. Currentlysurvival rate of renal transplant recipients is 95% at 1 yearand about 90% at 5 years [1].

Recipients of solid organ transplant are exposed toprolonged immunosuppression which increases potentialrisk of post transplant malignancies (PTM). In addition,relatively older individuals are being considered fortransplants who carry inherent risk of malignancies. ThusPTM is now a major challenge in patients successfullytreated by organ transplantation. Compared to generalpopulation, several types of malignancies occur morecommonly in transplant recipients and are often moreaggressive with far worse prognosis [2].

In 1968, Starzl and Penn described the first case of PostTransplant Lymphoproliferative Disorder (PTLD). Pennestablished a voluntary Transplant Tumor Registry in 1969,which was posthumously renamed as Israel PennInternational Transplant Tumor registry (IPITTR) in honourof his life’s commitment to the study of transplantmalignancies [3].

INCIDENCE

Immunosuppressed allograft organ recipients have 3 to5 fold increase in cancer risk as compared to age matchedgeneral population [4]. The most common malignanciesencountered in post transplant recipients are non melanoticskin cancers (NMSC - upto 82 %), PTLD (upto 11%) andKaposi’s sarcoma (KS) (about 6%) [5-7]. Besides thesemalignancies, other tumors showing higher frequency arerenal cell carcinoma, in-situ carcinoma of uterine cervix,hepatobiliary carcinoma, anogential cancer andgastrointestinal tumors [8]. US Renal Data System(USRDS) database showed that incidence of commoncancers such as colon, lung, prostate and breast is two timeshigher in post transplant recipients as compared to agematched population, while the increase in incidence rangesfrom 3 fold for bladder and testicular malignancies, 15 foldfor kidney malignancies and 20 fold for lymphomas andNMSC [9].

Netherland study showed that skin malignancydeveloped in 53% of patients after renal transplant and 48%of this subsequently developed second malignancy. PTLDdeveloped in 11% of patients, of which 65% presented withlymphoma. Skin malignancies usually have goodprognosis, PTLD has variable prognosis and GITmalignancies have poor prognosis[6].

Post transplant malignancies are a problem forrecipients of all types of organ transplants. The risk ofPTLD being more after small bowel, heart and lungtransplant than renal and liver transplants [10]. Reportedincidence of cancer in renal transplant recipients is 2.3-

169 Apollo Medicine, Vol. 7, No. 3, September 2010

POST TRANSPLANT MALIGNANCY – A BRIEF REVIEW

Veena Malhotra, Sumaid Kaul and Deep Shikha Arora

Senior Consultants, Department of Histopathology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.

Correspondence to: Dr Veena Malhotra, Senior Consultant, Department of Pathology, Indraprastha Apollo Hospitals,Sarita Vihar, New Delhi 110 076, India

E-mail: veena_m@appollohospitals.com

Immunosuppressed allograft recipients have three to five folds increase in cancer risk as compared to agematched general population. The most common malignancies encountered are Non Melanotic Skin Cancer,Post Transplant Lymphoproliferative Disorder and Kaposi’s Sarcoma. Duration of immunosuppressivetherapy and/or type of immunosuppressive agents are important controllable factors which have an impact inthe development of tumors. Oncogenic viruses have an important role in the development of thesemalignancies.

Key words: Post transplant malignancy, Immunosuppressive agents.

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Review Article

31 % in published series [11]. Data from registry ofInternational Heart and Lung Transplantation (ISHLT)shows that amongst the heart transplant recipients, 3.1% ofsurviving patients develop some form of malignancy after 1year, which increased to 16.1% in 5 years survivors and26.2% in 8 years survivors. Data from lung transplantrecipients showed the same trend [12]. USRDS datashowed that in renal transplant recipients cumulativeincidence of cancer excluding NMSC is 3.3% at 1 year and7.5% at 3 years [13].

Pathogenesis

All human beings are continuously being exposed tocarcinogens or mutagens. These mutations are dealt with byimmune surveillance mechanism. Immunosuppressivetherapy resulting in lack of adequate immune surveillanceplays a key role in development of post transplantmalignancies. This is coupled with conventionalpredisposing factors for development of tumors. Commonrisk factors are increasing age of patient, cigarette smoking,exposure to ultraviolet light, total sun burden, latentoncogenic viruses, previous exposure to carcinogens andanalgesic abuse [14]. Geographical factors such aspredisposition to certain malignancies in some countries i.e.liver tumors in South East Asia and GI malignancies inJapan, also play a role. Genetic predisposition for certainmalignancies also contributes [15]. The duration ofimmunosuppressive therapy, and/or type ofimmunosuppressive agents are the important controllablefactors which have an impact on the development of PTM.

In development of post transplant malignanciespotentially oncogenic viruses play a major role. HumanHerpes Virus-8 (HHV8) is associated with Kaposi’ssarcoma, Human Papilloma Virus (HPV) 8 and 19 with skincancer, HPV58 with Bowen disease, Epstein Barr Virus(EBV) with PTLD, Hepatitis B and C virus withhepatocelullar carcinoma [16] . PTLD in particular isrelated to EBV with 98% of cases related with latent EBVinfection [17].

It has been suggested that duration and type ofimmunosuppressive agent used can affect cancer risk.Number of studies demonstrate that incidence of PTMincrease after the introduction of the calcineurin inhibitor(cyclosporin), whereas a few studies report no increase inthe risk of cancer [17-19]. An induction regimen thatcontains lymphocyte depleting antibodies such as OKT3and antithymocyte globulin is a well documented risk factorfor the development of PTLD [16]. Cyclosporin may causecancer progression through direct cellular effect and also byincreased expression of transforming growth factor B(TGF-B) [20]. In addition, a role for cyclosporin in

stimulating angiogenesis mediated by Vascular EndothelialGrowth Factor (VEGF) has also been demonstrated [20]. Invitro studies have suggested that cyclosporin inducesmalignancy by reduction in p53 induced apoptosis andsuppression of UV induced DNA repair [16]. Purineanalogues such as azathioprin, have also been used in posttransplant patients. Post transplant patients treated withPurine analogues have a much more rapid development ofskin cancer in comparison those treated with cyclosporine[16,21].

Potential role of newer immunosuppressive agents thatis proliferation signal inhibitors (PSIs), Siromulus andEverolimus, in prevention of PTM is increasingly beingevaluated. These new immunosuppressive agents have arole in prevention, modification and even treatment of posttransplant malignancies [14]. In addition toimmunosuppression, they have antiproliferative effect bytheir action on cell cycle. In vitro and vivo studies havedemonstrated that PSI’s can prevent growth of transformedcells, increase rate of apoptosis in tumor cells, decreaseangiogenesis and thus tumor progression [22-24].

Post Transplant Lymphoproliferative Disorder

(PTLD)

PTLD is that most common malignancy after skincancer in solid organ recipients [25]. It is more common inpediatric patients [26]. WHO has classified PTLD as; (i)Early lesion characterized by reactive plasmacytichyperplasia or infectious mononucleosis type picture; (ii)Polymorphic PTLD showing full range of B cell maturationfrom immunoblast to plasma cell, small to mediumlymphocytes and cells resembling centrocytes and (iii)Monomorphic PTLD which includes B cell neoplasms likediffuse large B cell lymphoma, Burkitt’s lymphoma, plasmacell myeloma, T cell lymphoma and Hodgkin’s lymphoma[27].

The relationship of PTLD with Epstein Barr Virus(EBV) is well recognized. Immunosuppressive drugs usedin post transplant period can lead to decrease in EBVspecific T cell surveillance and proliferation. Recipientswho are EBV negative and receive graft form EBV positiveindividuals are at highest risk for developing PLTD.

Early lesions are most often seen in children and youngadults and usually occur within the first year posttransplantation, while second and third group i.e.polymorphic and monomorphic PTLD are seen later posttransplantation [10]. In one study, relative risk oflymphomia in the first 6 months after transplant was 13.8which decreased to 3.46 between 2.5 to 3 years[17].Incidence of PTLD is between 5-20 % after heart, lung andsmall bowel transplant. However, the incidence after kidney

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transplant recipient is much lower i.e.1-3% as kidneytransplant recipients require relatively less severeimmunosuppressive treatment [16].

Vast majority of PTLD are host derived. However somecases can be derived from donor lymphocytes transplantedwithin the graft [28]. Sites of predilection for PTLD areextranodal. Trasplanted organ and digestive tract are mostfrequent sites [29]. CNS is frequently involved in up to 30%cases [30]. PTLD arising within one year of transplant isusually associated with EBV infection and commonlyinvolves graft. This may suggest permissive role of graftmicroenviorment in the pathogenesis [31].

Most of the PTLD are B cell type, T cell lymphomas areonly about 15% of these. T cell lymphomas tend to occurlate and affect extranodal sites. HTLV-1 virus has beenimplicated in pathogenesis of T cell lymphoma. [32].

Duration, degree and type of immunosuppressive agentused greatly influence development of PTLD. Introductionof triple therapy i.e. cyclosporin, OKT3 antibody andantithymocyte globulin is associated with increased risk[33]. There is higher risk of PTLD with tacrolimus thancyclosporin therapy in kidney transplant recipient [34].

Efforts have been made to identify patient at high risk ofdeveloping PTLD by monitoring EBV-DNA load. Nothreshhold values predictive of development of PTLD havebeen identified [35]. However, a rising trend of EBV- DNAin a particular patient may define patient at risk [36]. Serialraised IL-10 levels and a unique monoclonal serum proteinhas been identified in patients who developedPTLD [37,38]. Vaccine against EBV may provideprotection to post transplant patients [39].

Reduction in immunosuppression is first line oftreatment in the management of patients with PTLD.Complete regression of early lesions and polymorphicPTLD usually occurs as a result. No standard guidelinesexist, but decreasing cyclosporin/tacrolimus by 50% anddiscontinuing azathioprin or mycophenolate isrecommended [40]. Immunosuppression should be reducedto minimal possible safe level keeping in mind graftsurvival. Twenty five to 50% patients respond to reductionin immunosuppression alone. Beneficial effect of antiviralagents such as cyclovir is doubtful [25].

For last few years monoclonal antibody therapy(rituximab) directed against B cell receptor (CD20) hasbeen introduced in treatment of B cell PTLD with promisingresults [41-44]. Whether demonstration of CD20expression in biopsy is prerequisite for starting treatment isnot well established. When to start rituximab therapy isanother issue. Whether the treatment should be initiated

after absence of response to reduction inimmunosuppression treatment or simultaneously is stilldebated [29].

It is suggested that in monomorphic PTLD, startingrituximab at the same time as reducing immunosuppressionis a justified approach, which increases the chances ofcomplete remission [29]. In cases which are refractive tofirst line treatment by rituximab, it is yet unclear whetherextended treatment by rituximab is appropriate or whetherpolychemotherapy should be initiated. Because of higherrate of treatment related morbidity and mortality, use ofrituximab has become more common [45]. Case series havedescribed response rate with single agent rituximab ofaround 60% [45]. Finally, adoptive T-cell immunotherapy,via infusion of EBV- specific CTLs in patients with EBV-positive PTLD has shown promise [45].

PSIs have shown promising results in the treatment ofPTLD [46]. Data from centers in Europe of nineteen postrenal transplant patients with PTLD have been pooled. Inthese patients calcineurin inhibitor was withdrawn ineighteen and minimized in one with simultaneousconversion to PSIs. Concomitant CHOP was given in sixand rituximab in another six. Fifteen out of eighteen patientsshowed remission which was maintained for 6 to 56 months[46]. Radiation therapy is method of treatment for CNSlymphoproliferative disease [30].

Kaposi’s Sarcoma (KS)

The incidence of Kaposi’s Sarcoma (KS) in transplantpatients may be as high as 500 times than in healthyindividuals [7,47]. In renal transplants it is seen in upto 6%of recipients though recent data demonstrates a loweroverall incidence of 8.8 cases of KS per 1,00,000 personyears [5]. Prevalence of KS in transplant recipients dependson geographical location, ranging from 0.5% in westerncountries such as USA to 5.3% in Saudi Arabia. Majority ofcases occur in patient from Mediterranean, Jewish, Arabic,Caribbean or African ethnic groups [7,47]. The median timefrom transplantation to diagnosis of KS is about 1.5 years[48]. KS presents as cutaneous involvement in about 80%cases. Visceral involvement is seen in 20% cases. Lungs,GIT and lymphoid tissue can be involved [47, 49]. Thepathogenesis of KS is related to the use of immuno-suppressive drugs and subsequent viral infection [45].HHV-8 is implicated in the pathogenesis of tumordevelopment.

The first association of KS and HHV-8 was made whenvirus was isolated from KS tissue in AIDS patients [50].Various mechanisms may be involved in HHV-8 inducedtumor development. HHV-8 proinflammatory proteinsmight directly inhibit apoptosis and there by promote cell

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transformation [51]. The virus might also modulate themajor histocompatibity class 1 antigen presentationpathway making infected host cells invisible to cytotoxic Tlymphocyte surveillance [51]. Development of KS mayinvolve initial latent HHV-8 infection of endothelial cellsand subsequent conversion in spindle cells. This is followedby proliferative phase and expression of a lytic protein, viralG protein coupled receptor (vGPCD). In endothelial cellsvGPCR oncoprotein increases secretion of VEGF andplays a pivotal role in development of tumor [52 ].

Immunosuppresion is the key contributing factor fordevelopment of tumors. Use of cyclosporin as animmunosuppressive drug in post transplant patients isassociated with a higher incidence of Kaposi’s sarcoma.[47]. Reduction or discontinuation of immunosuppresssionis the first line treatment for KS.

Conversion of cyclosporin to low therapeutic doses ofmycophenolate mofetil can lead to regression of KS [53].PSIs (sirolimus and everolimus) through specific effect onVGEF may provide advantage of both immunosuppressiveand antineoplastic activity [54]. PSIs impair VEGFproduction and limit response of endothelial cells to VEGFin animal models [54, 55]. Recurrence after reduction orchange in immunosuppresion has been treated bychemotherapy, Anthracycline based chemotherapy is theusual line of treatment [45]. Paclitaxel has also shownsuccess in two phase II trials [56]. Imatinib (C-kit inhibitor)and antiangiogenic agents like bevacizumab may also havea role in treating KS [56-58].

NON MELANOTIC SKIN CANCER

Non melanotic skin cancer (NMSC) affects largenumber of organ transplant patients. Basal cell carcinoma(BCC) and squamous cell carcinoma (SCC) account formore than 90% of NMSC in transplant recipients [7].Squamous cell carcinoma is the most common form of skincancer in these patients occurring at an incidence 65- 250times greater than general population while incidence ofBCC is increased 10 fold after transplant [7]. This indicatesthat normal ratio of 4:1 of BCC to SCC is reversed intransplant recipients [7,59].

Overall cumulative incidence of NMSC aftertransplantation ranges from 2-24% after 5 years and 7-33 %after 10 years [60]. Lifelong immunosuppression is the mostimportant factor in the pathogenesis of NMSC. In addition,UV exposure, HPV infection, and genetic factors also play arole. Mutations of p53 and proto-oncogenes may occur [7].

Fair skinned people living in countries with hot climateand high ultra violet exposure are more at risk of developingpost transplant NMSC [61]. Ultraviolet radiations, in

addition to its role as mutagen, have immunosuppressiveproperties in the skin [7, 60]. Older age, male sex, presenceof permalignant lesions such as actinic keratosis andcigarette smoking has also been associated with SCC andBCC [60].

Transplant recipients should be warned about sunexposure. Studies have demonstrated beneficial effect ofsystemic retinoid chemoprophylaxis in transplant recipients[45, 62]. However, a rebound effect with higher incidence ofNMSC after discontinuation of therapy is also reported.Standard therapy for NMSC includes Mohs’ micrographicsurgery, superficial ablative therapy, cytotherapy andphotodynamic therapy along with attenuation ofimmunosuppresion [63].

Consensus guidelines for immunosuppressionreduction have been developed [64]. Extent ofimmunosuppression and type of immunosuppressive agentsused may play a critical role. A recent study indicated thatincidence NMSC increased from 19% at less than 5 years to47% after more than 20 years of immunosuppressivetherapy [65]. A study in liver transplant receipient showedmycophenolate mofetil (MMF) was associated withincreased risk of NMSC although this risk didn’t remainafter multivariate anlaysis [66], PSIS like sirolimus havepotential for reducing the incidence of NMSC [67].Compared with 5% incidence of NMSC in cyclosporintreated patients, no malignancies were observed in patientsreceiving sirolimus as base therapy [68]. Thus cyclosporinfree sirolimus based immunotherapy may reduce incidenceof post transplant skin malignancy.

CONCLUSION

• Allograft organ recipients have three to five foldsincrease in cancer risk as compared to age matchedgeneral population.

• Post transplant immunosuppressive therapy resultingin impaired cancer surveillance and facilitating theaction of oncogenic substances including oncogenicviruses are key factors in pathogenesis.

• The most common malignancies encountered in posttransplant recipients are NMSC (upto 82%), PTLD(upto 11%) and KS (upto 6%).

• PTLD has been classified by WHO as (i) early lesioncharacterized by infectious mononucleosis typepicture or plasma cell proliferation, (ii) polymorphicPTLD and; (iii) monomorphic PTLD. EBV hasimportant role in causing PTLD.

• Prevention of post transplant malignancies byjudicious use of immunosuppressive agents and early

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detection is important.

• Early lesions of PTLD regress by withdrawingimmunosuppressive agents.

• Newer agents like PSIs have been shown to havesimultaneous immunosuppressive and antitumorproperties and may play a promising role inmanagement of post transplant patients.

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