Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders.
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Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders. Dr.Abhijit K Korane. INCIDENCE OF CANCER AFTER RENAL TRANSPLANT. The incidence of cancer in renal transplant recipients ranges from 2.3–31%.

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Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders.

Dr.Abhijit K Korane.


INCIDENCE OF CANCER AFTER RENAL TRANSPLANT. transplant Lymphoproliferative disorders.


  • The incidence of cancer in renal transplant recipients ranges from 2.3–31%.

  • The risk of de novo malignancies is increased in transplant recipients, with a relative risk 3–5 times that of the general population.

    (Andres A. Cancer incidence after immunosuppressive treatment

    following kidney transplantation. Crit Rev Oncol Hematol 2005;

    56: 71–85)


  • Data from the Collaborative Transplant Study ranges from 2.3–31%.

    (CTS) show an increase of at least 3-fold in the

    incidence of cancer compared with the

    expected incidence in general population.

  • Australia and New Zealand Dialysis and Transplant (ANZDATA) registry shows a standardized incidence ratio of 3.46 for all cancers reported in Australia and New Zealand between 1980 and 2005 in patients after a first transplant



Study that included of over 35,000 first time renal transplant recipients the cancer rates for,

  • colon, lung, prostate, stomach, esophagus, pancreas, ovary and breast, were roughly twofold higher.

  • melanoma, leukemia, hepatobiliary tumors, cervical and vulvovaginal tumors were approximately fivefold more common;

  • testicular and bladder cancers were increased approximately threefold; 15-fold more common. Finally,

  • KS, NHL and nonmelanoma skin cancers were encountered with over 20-fold increased frequency.

    (Penn, I. Cancers complicating organ transplantation. N Engl J Med 1990;323:1767.)


Defining Characteristics of transplant recipients the cancer rates for,

PTLD


PTLD refers not to a single disease but to a syndrome that includes a wide range of abnormal hyperplastic (inflammatory or reactive) and neoplastic lymphocyte growths, ranging from a benign self-limited form of lymphoproliferation to an aggressive, widely disseminated disease.


INCIDENCE OF PTLD includes a wide range of abnormal hyperplastic (inflammatory or reactive) and neoplastic lymphocyte growths, ranging from a benign self-limited form of lymphoproliferation to an aggressive, widely disseminated disease.


The disease occurs in around 1–10% of transplant recipients, is the most common malignancy in transplanted children, and is second only to squamous cell cancer in adults.

(Penn I. The problem of cancer in organ Transplant recipients: an

overview. Transplant Sci 1994;4:23–32.)


Over 50% of PTLD cases are associated with primary EBV infection and this accounts for the particular risk to paediatric transplant recipients.





Incidence in india
Incidence in India after transplant,

  • The overall incidence of malignancies in Indian transplant recipients is not known.

  • Less than 2% of primarily azathioprine-prednisolone treated transplant recipients developed cancers.

    (Sakhuja V, Jha V, Ghosh AK, Singh SK, Chugh KS. Low incidence of malignancies following renal transplantation in India. Nephrology 1995; 1:301)


Conclusions, from single centre studies, after transplant,

  • The overall incidence of malignancies is lower in contrast to the western countries,

    2. The skin cancer incidence is much lower,

    3. PTLD is the commonest malignancy in the Indian transplant population,

    4. Majority of PTLD is encountered after the first year.

    (Sakhuja V, Jha V, Ghosh AK, Singh SK, Chugh KS. Low incidence o malignancies following renal transplantation in India. Nephrology 1995; 1:301)


  • In analysis of 294 patients followed up for more than 6 months after transplantation six malignancies were noted in four patients, giving an incidence of 2%.

  • Among 157 of those who were followed up for more than 2 years, the incidence was 3.8%. Most of these patients were from the pre- CNI era.


More recent analysis, a total of 26malignancies months after transplantation six malignancies were noted in four patients, giving an incidence of 2%.

out of 1400 transplant patients, giving an

incidence of 1.4%. PTLD formed the largest

chunk, accounting for 19 cases (63.3%).


  • Pathophysiology months after transplantation six malignancies were noted in four patients, giving an incidence of 2%.


Most PTLDs are of B-cell origin months after transplantation six malignancies were noted in four patients, giving an incidence of 2%.

  • Early onset PTLDs are mainly regarded as EBV–driven lymphoproliferations that are frequently polyclonal or oligoclonal,

  • Late onset PTLDs are true monoclonal lymphoid malignancies that are not necessarily associated with EBV infection





Epstein barr virus
Epstein-Barr Virus from an EBV seropositive person to an EBV seronegative recipient.

EBV is an enveloped herpesvirus with a 172 kb double stranded DNA genome.


  • Core:- from an EBV seropositive person to an EBV seronegative recipient. single linear molecule of dsDNA .

  • Capsid:- Surrounding the core is an icosahedralcapsid with a 100 nm diameter constructed of 162 capsomeres.

  • Tegument:- Between the capsid and envelope. It consists of viral enzymes.

  • Envelope:- The envelope is the outer layer of the virion.


PRIMARY EBV INFECTION from an EBV seropositive person to an EBV seronegative recipient.



  • Primary EBV infection in vivo generally occurs at an early age and is usually asymptomatic.

  • Infection if acquired during adolescence result in infectious mononucleosis.

  • During the early stages of infectious mononucleosis extremely large numbers of EBV-infected B cells circulate in the blood, but they are all resting memory cells.


Resolution of the infection, age and is usually asymptomatic.

  • Infection by EBV is controlled by both cellular and humoral immune mechanisms.

  • Antibody limits the spread of infectious virus,

    and cytotoxic T cells destroy infected cells that express viral proteins.


The major targets for control of EBV by the immune system are memory cells that have initiated viral replication. By killing these cells and preventing the spread of infectious virus by antibody, the immune response reduces the level of infection



RISK FACTORS maintain a latent infection with the virus genome retained in host cells without production of infectious virions.


Risk factors associated with post transplant malignancy
Risk factors associated with post-transplant malignancy maintain a latent infection with the virus genome retained in host cells without production of infectious virions.


Primary EBV infection:- maintain a latent infection with the virus genome retained in host cells without production of infectious virions.

Analysis of 381 consecutive non-renal

transplant recipients at a US clinic, the risk of

PTLD was 24 times higher in EBV-seronegative

recipients than in those seropositive for EBV at

the time of transplantation.

(Walker RC, Marshall WF, Strickler JG et al. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis 1995; 20: 1346–1353)


Several single-center analyses have found that maintain a latent infection with the virus genome retained in host cells without production of infectious virions.

EBVseronegative patients experienced a 10-

76-fold greater incidence of PTLD when

compared with their seropositive counterparts

(Preiksaitis JK, Cockfield SM. Epstein-Barr virus and lymphoproliferative

disorders after transplantation. In: Bowden RA, Ljungman P, Paya CV, eds.

Transplant infections. Philadelphia:

Lippincott-Raven,1998:245–63. 12. Ellis D, Jaffe R, Green M, et al. Epstein-Barr

virus–related Disorders in children undergoing renal transplantation with

tacrolimus-based immunosuppression. Transplantation 1999; 68:997–1003.)


-Use of the monoclonal antibody OKT3, maintain a latent infection with the virus genome retained in host cells without production of infectious virions.

-Cytomegalovirus (CMV)-seropositive donor,

-Younger age at transplantation,

-Infection with hepatitis C,


Lower incidence of PTLD in Asia compared with maintain a latent infection with the virus genome retained in host cells without production of infectious virions.

Western countries and a lower incidence in

recipients from particular ethnic groups

including Arabic, Jewish, Black and

Mediterranean individuals


Immunosuppressive regimens and maintain a latent infection with the virus genome retained in host cells without production of infectious virions.

PTLD


No significant difference in the 5-year incidence of lymphoma or rate of lymphoma development between patients receiving ciclosporin ,( with or without azathioprine and steroids) and those receiving azathioprine and steroids only.

(Opelz G, Dohler B. Lymphomas after solid organ transplantation:a

collaborative transplant study report. Am J Transplant 2003; 4: 222–

230)



  • OKT3 and ATG appeared to increase the risk of lymphoma only in the first year after transplant, with a subsequent PTLD risk similar to that in patients who did not receive antibody therapy.

  • Induction therapy with anti-interleukin (IL) 2 antibodies was not associated with any increase in the risk of PTLD

    (Opelz G, Dohler B. Lymphomas after solid organ transplantation:a collaborative transplant

    study report. Am J Transplant 2003; 4: 222–230)


Opelz in the first year after transplant, with a subsequent PTLD risk similar to that in patients who did not receive antibody therapy. G, Dohler B. Lymphomas after solid organ transplantation:a collaborative transplant study report. Am J Transplant2004; 4: 222–230


Posttransplantation in the first year after transplant, with a subsequent PTLD risk similar to that in patients who did not receive antibody therapy. Lymphoproliferative Disorder Associated with OKT3 andDecreased Antiviral Prophylaxis in Pancreas Transplant RecipientsClinical Infectious Diseases 1998;26:596–600


Lymphoproliferative in the first year after transplant, with a subsequent PTLD risk similar to that in patients who did not receive antibody therapy. Disorders After Renal Transplantationin Patients Receiving Triple or Quadruplelmmunosuppression J. Am. Soc. Nephrol. 1992; 2:5290-5294


Robson R, Cecka JM, Opelz G, Budde M, Sacks S. Prospective registry-based

observational cohort study of the long-term risk of malignancies in rena

transplant patients treated with mycophenolate mofetil. Am J Transplant 2005;

5: 2954–2960

  • Tacrolimus was also associated with an increased risk of PTLD,

  • Anti-IL-2 antibodies and sirolimus not associated with an increased risk of PTLD

  • Azathioprine and MMF were associated with a reduced risk of PTLD.


In a transplant centre in Denmark, including registry-based

667 patients, showed no increase in the

incidence of PTLD after the introduction of

CsA, OKT3 or ATG. MMF was associated with a

decrease in the incidence of PTLD.

(Birkeland SA, Hamilton-Dutoit S. Is Posttransplant lymphoproliferative disorder

(PTLD) caused by any specific immunosuppressive drug or by the

transplantation per se? Transplantation 2003; 76: 984–988)


Classification Systems registry-based


Frizzera registry-based G, Hanto DW (1981)recognized 4 categories of posttransplantation lymphoid growths:

1) Normal reactive hyperplasia,

2) True lymphomas,

3) Polymorphic diffuse B-cell hyperplasia,

4) Polymorphic B-cell lymphoma.


Nalesnik MA, Jaffe R (1988) registry-based subdivided PTLD into 2 major categories,

1) Polymorphic PTLD, including polymorphic diffuse B-cell hyperplasia and polymorphic B-cell lymphoma, and

2)Monomorphic PTLD, including immunoblastic sarcoma and other forms of lymphoma.


American Society of Hematopathology (1997), registry-based

1)Early lesions,

-infectious mononucleosis,

-plasma cell hyperplasia.

2)Polymorphic category,

3) Monomorphic category,

various B-, T-, and natural killer (NK) lymphocyte neoplasms.

4)Miscellaneous,

Hodgkin-like lymphom, plasmacytoma, multiple myeloma.



Staging of PTLD. registry-based

ANN ARBOR STAGING WITH COSTWALDS MODIFICATION


Staging of PTLD. registry-based

  • Although no staging system currently exists for PTLD, it is recommended that the Ann Arbor staging classification system with Cotswold’s modifications that is used to stage non-Hodgkin’s lymphomas be applied to PTLD.


Principal stages, registry-based

  • Stage I indicates that the cancer is located in a single region, usually one lymph node and the surrounding area.

  • Stage II indicates that the cancer is located in two separate regions, an affected lymph node or organ within the lymphatic system and a second affected area, and that both affected areas are confined to one side of the diaphragm


  • Stage III registry-based indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen.

  • Stage IV indicates diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs.


  • A registry-based or B: the absence of constitutional (B-type) symptoms is denoted by adding an "A" to the stage; the presence is denoted by adding a "B" to the stage.

  • E: is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue.

  • X: is used if the largest deposit if >10 cm large ("bulky disease"), or whether the mediastinumis wider than 1/3 of the chest on a chest X-ray.


Clinical Presentation registry-based


Posttransplantation lymphoproliferative disorders may present as symptoms from localized or systemic involvement or in the asymptomatic patient incidental to other clinical or radiographic findings.


Time to Onset present as symptoms from localized or systemic involvement or in the asymptomatic patient incidental to other clinical or radiographic findings.

  • PTLD can present as early as less than a month to as late as several years after transplantation.

  • In general, however, PTLD is remarkable for a short posttransplantation time of onset.


The time of onset is shorter in cyclosporine- and tacrolimus-treated patients than in the precyclosporine era.

(Mihalov ML, Gattuso P, Abraham K, et al. Incidence of post-transplant

malignancy among 674 solid-organ-transplant recipients at a single center.

Clin Transplant. 1996;10:248-255.)


47% of cases occur within 6 months, tacrolimus-treated patients than in the precyclosporine era.

62% within 1 year,

90% within 5 years following transplantation.

Posttransplantation Lymphoproliferative Disorders. Michael Nalesnik, MD, Anthony J. Demetris, MD, John J. Fung, MD, PhD, Parmjeet Randhawa, MD, Adriana Zeevi, PhD



Clinical Manifestations than those that do contain the virus. include,

(1) An infectious mononucleosis-like syndrome with or without generalizedlymphadenopathy,

(2) One or more nodal or extranodal tumors,

(3) A fulminant and disseminated presentation with sepsis.


Infectious mononucleosis-like syndrome than those that do contain the virus.

  • A mononucleosis syndrome may occur early after transplantation, particularly in association with a primary EBV infection.

  • This presentation is particularly common in the pediatric population, and indeed, in some cases it is infectious mononucleosis.

  • Otolaryngologic symptoms and findings are often the first manifestation of PTLD in children.



  • A PTLD that occurs later is more likely to be circumscribed anatomically and to be associated with a more gradual clinical course.

  • Extranodal disease with visceral involvement is common with gastrointestinal, pulmonary, or central nervous system (CNS) symptoms.

  • Lymphadenopathy is painless, and atypical lymphocytes may or may not be present in the white blood cell differential count.


The allograft can also be involved. anatomically and to be associated with a more gradual clinical course.

  • The frequency of involvement varies according to the specific type of allograft.

  • PTLDs that arise in lung or intestinal transplant recipients involve those allografts in up to 80% of cases.

  • Liver and kidney, involve the allograft in about one third of cases.

  • The transplanted heart is only rarely involved with these tumors.


DIAGNOSIS OF PTLD anatomically and to be associated with a more gradual clinical course.


Clinical Diagnosis, anatomically and to be associated with a more gradual clinical course.

  • Awareness of this syndrome.

  • Isolated or systemic lymphadenopathy that suddenly appear should include PTLD in the differential diagnosis.

  • Abdominal pain, particularly with evidence of intestinal bleeding, raises the possibility of PTLD in the GI tract.

  • Persistent headaches or CNS symptoms suggest localization to the brain.

  • Upper respiratory tract infections that may be associated with lymphadenopathy or that do not resolve after a course of antibiotics should raise a suspicion of PTLD.


Primary EBV infections:- anatomically and to be associated with a more gradual clinical course.

can be detected by seroconversion, with

development of antiviral capsid antigen IgM

and IgG antibodies and anti–early antigen and

anti–Epstein-Barr nuclear antigen (EBNA)

antibodies


Pitfalls of serological tests anatomically and to be associated with a more gradual clinical course. :-

  • Transplant patients can fail to produce detectable anti-EBNA- 1 antibodies in the setting of primary infection,

  • Patients who are seropositive before transplantation can have falling anti-EBNA-1 titers associated with higher EBV loads and the development of PTLD


Pathologic examination of tissue is currently the gold standard for PTLD diagnosis.

Biopsy of lymph nodes and sites of extranodal involvement (ie, organs, bone marrow) is the definitive diagnostic test.


Biopsy specimens are analyzed for massive infiltration of B cells and plasma cells and may be subjected to in situ hybridization or immunostaining for detection of EBV


Monomorphic post transplant lymphoproliferative disorder
Monomorphic cells and plasma cells and may be subjected to in situ hybridization or immunostaining for detection of EBV post-transplant lymphoproliferativedisorder


PREVENTION OF PTLD, cells and plasma cells and may be subjected to in situ hybridization or immunostaining for detection of EBV


PREVENTION OF PTLD, cells and plasma cells and may be subjected to in situ hybridization or immunostaining for detection of EBV

  • Patients who are at high risk for the development of PTLD should be identified before transplantation.

  • EBV infection is a significant risk factor for PTLD development, EBV serostatus should be determined for all potential transplant recipients.



  • Aggressive supplemental immunosuppression should be used only in the presence of biopsy-proven acute rejection.

  • Because PTLD frequently presents with allograft dysfunction, it is important distinguish early PTLD from rejection before more potent antirejection therapy is started.



  • Comparisons of the incidence of PTLD in patients receiving and not receiving acyclovir or ganciclovir prophylaxis suggest that either prophylactic antiviral drug may be of some benefit however, PTLD has also been documented in patients receiving ganciclovir or acyclovir prophylaxis.

    (Keay S, Oldach D,Wiland A, et al. Post-transplant lymphoproliferative disorder

    associated with OKT3 and decreased antiviral prophylaxis in pancreastransplant

    recipients. Clin Infect Dis 1998; 26:596–600.)


Posttransplantation and not receiving acyclovir or ganciclovir prophylaxis suggest that either prophylactic antiviral drug may be of some benefit however, PTLD has also been documented in patients receiving ganciclovir or acyclovir prophylaxis.Lymphoproliferative Disorder Associated with OKT3 andDecreased Antiviral Prophylaxis in Pancreas Transplant RecipientsClinical Infectious Diseases 1998;26:596–600


Monitoring of EBV load and not receiving acyclovir or ganciclovir prophylaxis suggest that either prophylactic antiviral drug may be of some benefit however, PTLD has also been documented in patients receiving ganciclovir or acyclovir prophylaxis.


The monitoring of EBV load in patients who are at high risk for PTLD is a promising technique that would permit preemptive treatment in the form of reduction of immunosuppression and/or the use of antiviral agents.


MANAGMENT risk for PTLD is a promising technique that would permit preemptive treatment in the form of reduction of immunosuppression and/or the use of antiviral agents.


Reduction of Immunosuppression risk for PTLD is a promising technique that would permit preemptive treatment in the form of reduction of immunosuppression and/or the use of antiviral agents.


The most important initial strategy in the management of PTLD is to reduce and even to discontinue immunosuppressive therapy, with regression evident in 23%–50%.

(Starzl TE, Nalesnik MA, Porter KA, et al. Reversibility of lymphomas and

lymphoproliferative lesions developing under cyclosporine-steroid therapy.

Lancet 1984; 1:584–7.)

( Swinnen LJ, Mullen GM, Carr TJ, et al. Aggressive treatment for

postcardiac transplant lymphoproliferation. Blood 1995; 86:3333–4.)


How should immunosuppression be reduced? PTLD is to reduce and even to discontinue immunosuppressive therapy, with regression evident in 23%–50%.

  • Should it be withdrawn or reduced in a stepwise manner?

  • There are limited data to suggest that high EBV loads are immunosuppressive, and rejection events are highly unlikely if the patient’s virus load remains above specific levels.


Treatment of EBV-associated PTLD, PTLD is to reduce and even to discontinue immunosuppressive therapy, with regression evident in 23%–50%.

  • Antiviral drugs,

  • Immunoglobulin therapy,

  • IFN-alpha.


4. Monoclonal malignancies:-chemotherapy CHOP( PTLD is to reduce and even to discontinue immunosuppressive therapy, with regression evident in 23%–50%.cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide

plus prednisone.

5.Radiotherapy may be useful for central nervous system involvement and localized disease.

6. Cellular immunotherapy.


IFN-a:- PTLD is to reduce and even to discontinue immunosuppressive therapy, with regression evident in 23%–50%.

Has both antiviral and antiproliferative activity

The association of T-helper cell type 2 cytokine

Responses with PTLD, and their disappearance

after PTLD resolution, lends support to the use

of IFN-a for treatment of this disorder.

(Faro A. Interferon-alpha and its effects on post-transplant lymphoproliferative

disorders. Springer Semin Immunopathol 1998; 20:425–36.)


Conversion to proliferation signal inhibitors (PSIs) PTLD is to reduce and even to discontinue immunosuppressive therapy, with regression evident in 23%–50%.

PSIs inhibit tumour growth and progression; therefore, they may have the potential to prevent malignancy in this at-risk population.


  • Everolimus has found to have an inhibitory effect on the growth of PTLD cell lines while delaying the progression, and inducing regression, of established tumours in an in vivo experimental model.

  • Sirolimus also has a potent anti-proliferative effect on in vitro PTLD-derived cell lines and has been shown to inhibit the growth of solid tumours in a mouse model of PTLD.


Efficacy and safety of growth of PTLD cell lines while delaying the progression, and inducing regression, of established tumours in an in vivo experimental model.rituximab in B-cell post-transplantation lymphoproliferativedisorders: results of a prospective multicenter phase 2 studyBLOOD, 15 APRIL 2006 VOLUME 107, NUMBER 8

  • Fortysix patients were included.

  • Treatment consisted of 4 weekly injections of rituximab at 375mg/m2.

  • The overall survival rate at 1 year was 67%. Conclude that rituximab is effective and safe in PTLD, with stable responses at 1 year.


Cellular immunotherapy. growth of PTLD cell lines while delaying the progression, and inducing regression, of established tumours in an in vivo experimental model.


  • In allogeneic HST patients, there is another option for both prevention and treatment: cellular or adoptive immunotherapy.

  • Treatment with unselected donor mononuclear cells resulted in high response rates, but carried a significant risk of GVHD.

  • However, over 90% of patients may respond to DLI.

    (Rooney CM, Smith CA, Ng CY et al. Use of gene-modified virus-specific T lymphocytes to

    control Epstein–Barr-virusrelated lymphoproliferation. Lancet 1995; 345: 9–13.)


THANK YOU. prevention and treatment: cellular or adoptive immunotherapy.


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