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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2002  |  Volume : 13  |  Issue : 2  |  Page : 126-130
Post Transplant Malignancy

Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia

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How to cite this article:
Al-Khader AA. Post Transplant Malignancy. Saudi J Kidney Dis Transpl 2002;13:126-30

How to cite this URL:
Al-Khader AA. Post Transplant Malignancy. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2022 Aug 7];13:126-30. Available from: https://www.sjkdt.org/text.asp?2002/13/2/126/33123
Malignancy arises in a post-transplant patient in three possible ways: recurrence of pre­existing malignancy, arising de novo or transmitted through donor kidney. The pathogenesis of de novo malignancy is multifactorial and includes direct effect of immunosuppressive drugs, development of oncogenic viruses, suppression of immune surveillance, chronic antigenic stimulation and possible genetic predisposition. [1]

The average duration for malignancy to develop is five years after transplantation but this differs according to the malignancy. Thus, it is 21 months for Kaposi sarcoma (KS), 69 months for epithelial cancer, 112 months for vulval and perineal cancer and is biphasic for lymphoma (in the first 12 months post-transplant and after five years). [2]

The incidence of development of cancer after transplantation is markedly increased in skin squamous carcinoma, non-Hodgkins lymphoma (NHL), KS and carcinoma of the cervix, vulva and perineum. [3] It is unchanged in cancers of lung, prostate, colon and uterus, [1] and is actually reduced in breast cancer (by 25-30%). [4]

The clinical tumor registry (CTR) of 10,813 malignancies in 10,151 patients (i.e. 6% of transplant patients) showed that skin cancer accounted for 4,079 followed by lymphoma (1,801) and KS (432). [3]

In general, the long-term use of immuno­suppressive therapy increases the risk of malignancy by 100 fold. [3] Also, the more the immunosuppression given, the higher is the risk for malignancy. [1] In the same context, there is higher incidence of malignancy in non-renal transplants because of increased immunosuppression. [5] It has been shown that CD4 lymphocytopenia is associated with increased risk of skin cancer. [6] Anti­lymphocyte globulin (ALG) increases the risk of Epstein Barr (EB) virus related post­transplant lymphoproliferative disorders (PTLD). [7],[8],[9],[10] Viral infection has been implicated in other post-transplant malig­nancies e.g. HHV8 in KS and papilloma virus in cervical carcinoma. [11],[12]

Climatic conditions can also influence the incidence. Skin cancer, for example, increases with the amount of exposure to sun as well as duration after transplant. [13],[14],[15] In fact, it is estimated to occur in 40-70% of patients after 20 years of transplantation. Skin cancer, the commonest in transplant patients as a whole, has some features that differ from skin cancer in the general population; it tends to have multiple sites, it occurs in younger age-group (30 years vs. 60 years), [16] it is more aggressive and recurrent and the squamous cell type is commoner than the basal cell carcinoma. [16]

Lymphoproliferative disorders are the second commonest type of malignancy. They account for 21% of all post-transplant malignancies in the west compared to 5.0% in the general population. [4] One percent of all the transplant population is likely to develop a lymphoma; a 30-50 fold increase in risk. [4] One of the clear associations for development of PTLD is the amount of immunosuppression given, particularly ALG and OKT3. In cardiac transplants for example, it occurs in 11% of patients treated with OKT3. [17] Other important features of post­transplant lymphoma is that it tends to be extra-nodal in 70% of the cases, it is mostly of the large cell B cell type (12.5% only are of T cell type) [18] and NHL accounts for 93% of the cases. [4],[19] It is postulated that B cell proliferation is induced by the EB virus by binding to the EB receptor on the cell surface (CD21). It has been shown that EBV MRNA is present in hepatocytes before PTLD occurs. An EBV-associated protein (LMPI) engages tumor necrosis factor (TNF) receptors leading to cell growth and transformation. [20],[21],[22] The usual "killer" cell reaction is subdued by immunosuppression. The PTLD can be of three types: benign polyclonal proliferation of the B cells (55% of the cases) with no malignant transfor­mation (the presentation of this type is similar to infectious mononucleosis (IM). [23]

The second type (30% of the cases), again with IM like picture, is due to EBV-induced polyclonal cell proliferation with early malignant transformation (clonal cyto­genetic abnormalities and IG gene re­arrangement). [23] The third type is of extra­nodal solid tumors (15%). Here, there is monoclonal B cell proliferation with malignant transformation. [23]

In the polyclonal type, the treatment is usually reduction of immunosuppression and administration of antiviral therapy (acyclovir). With this regimen, 44% had complete resolution and in 23%, impro­vement can be anticipated. [24] In the monoclonal type, the treatment includes radiation, chemotherapy and surgery; however, the mortality rate is high (80%). [25]

Other treatment strategies are being tried including immunotherapy with activated autologous killer cells and interleuken-2 treated cells with promising results. [26] Prevention can be enhanced by using acyclovir or gancyclovir prophylactically whenever OKT3 is given (0.5 vs. 3.9% historic incidence).

In a study comparing EBV-induced (21 patients) with non-EBV induced PTLD (11 patients), it was found that there was a significant difference in the time of presen­tation post-transplant (18.2 months versus 77.5 months respectively (P = 0.02)) and in mean patient survival (37 months versus 1 month respectively (P = < 0.01). The pre­transplant EB serostatus could be important, as the risk for developing PTLD is 10.5% in seronegative adult patients compared to 0% in EBV seropositive patients. [17]

The importance of immunosuppression in the development of PTLD is shown by its higher incidence in cardiac transplant recipients, who receive higher dose of immunosuppression, as well as in patients in the first year post-transplant (falling by 80% thereafter). [1] Also, the use of OKT3 in a cumulative dose in excess of 75 mg increases the risk to 35.7% as compared to 6.2% with a cumulative dose less than 75 mg. [27]

A difference in the incidence of PTLD has been noticed depending on the type of trans­plant, being highest (19%) in intestinal transplant recipients and lowest in kidney transplant recipients (0.9%) with the inci­dences in heart and lung transplant recipients being 3.4% and 7.9% respectively. [28]

When assessing prospective recipients with pre-existing malignancy, the general advice is to wait for two years after complete cure before transplantation is carried out. However, a wait of five years is needed in patients with malignant melanoma, extensive colonic cancer and breast cancer. [29] With regard to transmission of malignancy through donor organs, the tumor registry [30] has reported 270 recipients of organs from donors with malignancy of whom 117 (43%) showed transmission; 45 involved allografts (29 from kidney carcinoma), six involved adjacent structures and in 66 there was distant metastasis. [31]

In only one out of 16 contralateral kidney donations, from a donor with carcinoma of the kidney, was there a development of cancer after 55 months of follow-up. [31] In nine kidney transplants, after a wide excision of small cancer, there was no recurrence after 79 months of follow-up. [31]

The general advise, therefore, is that organs from donors with malignancy should not be used except when it is low-grade skin malignancy, carcinoma-in-situ, primary brain tumor or documented 5-year cure (which should be extended to 10 years in case of breast and colon cancers and malignant lymphoma).

In recipients with pre-existing malignancy (there were 129 cases in the CTR registry), the overall recurrence rate was 21%. [32] The chance of recurrence progressively decreases with the period between cure and trans­plantation (55%, 33% and 13% in 2, 2-5 and >5 year periods respectively after cure). [32] Therefore, to reduce chances of post-transplant malignancy, the advise is less immunosuppression, less exposure to the sun, frequent clinical examination, reduction or cessation of immunosupp­ression and use of prophylactic acyclovir in high-risk patients e.g., when OKT3 is given.

In our experience, we have reported 48 cases of malignancy in 730 patients (6.5% of total transplant patients) over 5.3 years mean follow-up period. [33] The vast majority (75%) were due to KS. We had one kidney cancer, two each of hepatoma and thyroid cancer, one each of urinary bladder and uterine cancer.

Since this earlier report, we have had an additional 11 cases of KS, one case of hepatoma, two cases of medullary carcinoma of the thyroid, three cases of lymphoma and one case of colonic cancer (unpublished data).

Overall, we had 48 cases of KS over a 20­year period of follow-up of patients. We have developed a grading system for KS depending on the extent of involvement (I to IV) and, presence or absence of associated infection of malignancy (A or B). [34] Depending on the grading, the approach to treatment is reduction or cessation of immunosuppressive therapy. Chemotherapy is only used in fulminant KS and in those with pulmonary involvement, which carries a bad prognosis. [35],[36]

With this regime, we obtained a 73.7% regression rate (with functioning graft in 53.6% and non-functioning graft in 46.4%) and a mortality rate of 15.8%. Children and patients with lung involvement carried the worst prognosis. [37] Children also have a different type of presentation with lack of skin involvement, presence of pyrexia and extensive lymphatic involvement [37] as well as lung involvement. The progression is rather rapid. Radiotherapy has a place when the KS is associated with pain or mass effect. We have also noted that KS recurs in the same sites after reintroduction of immunosuppression [38],[39] and cyclosporin is more kaposigenic than azathioprine.

   References Top

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2.Stewart T, Tsai SC, Grayson H, Henderson R, Opelz G. Incidence of de-novo beast cancer in women chronically immuno­suppressed after organ transplantation. Lancet 1995;346:796-8.  Back to cited text no. 2  [PUBMED]  
3.Penn I. The changing pattern of post transplant malignancies. Transplant Proc 1991;23:1101-3.  Back to cited text no. 3  [PUBMED]  
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19.Penn I, Porat G. Central nervous system lymphomas in organ allograft recipients. Transplantation 1995;59:240-4.  Back to cited text no. 19  [PUBMED]  
20.Mosialos G, Birkenbach M, Yalamanchili R, et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 1995;80:389-99.  Back to cited text no. 20  [PUBMED]  
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22.Liebowitz D. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients. N Engl J Med 1998;338:1413-21.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproli­ferative disorders occurring in the setting of cyclosporine A-prednisone immunosup­pression. Am J Pathol 1988;133:173-92.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Paya CV, Fung JJ, Nalesnik MA, et al. Epstein-Barr virus-induced post transplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Transplantation 1999;68:1517-25.  Back to cited text no. 24    
25.Penn I. Immunosuppression and lympho­proliferative disorders. PRO/COM, Univer­sity of Cincinnati Medical Center 1992.  Back to cited text no. 25    
26.Nalesnik MA, Rao AS, Furukawa H, et al. Autologous lymphokine-activated killer cell therapy of Epstein-Barr virus-positive and negative lymphoproliferative disorders arising in organ transplant recipients. Transplantation 1997;63:1200-5.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lympho­proliferative disorder after immunosup­pression with the monoclonol antibody OKT3 in cardiac transplant recipients. N Engl J Med 1990;323:1723-8.  Back to cited text no. 27  [PUBMED]  
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31.Penn I. Transmission of cancer from organ donors. Ann Transplant 1997;2(4):7-12.  Back to cited text no. 31    
32.Testa G, Klintmalm GB. Liver transplan­tation for primary and metastatic liver cancers. Ann Transplant 1997;2(4):19-21.  Back to cited text no. 32    
33.Abdalla A, Rassoul Z, Abdur Rehman M, Mousa D, Al-Sulaiman M, Al-Khader AA. Post renal transplantation malignancies - local experience and review of literature. Saudi Med J 1995;16:235-7.  Back to cited text no. 33    
34.Al-Khader AA, Al-Sulaiman M, Al-Hasani M, Haleem A. Posttransplant Kaposi sarcoma: staging as a guide to therapy and prognosis. Nephron 1988;48:165.  Back to cited text no. 34    
35.Gunawardena KA, Al-Hassani MK, Haleem A, Al-Sulaiman MH, Al-Khader AA. Pulmonary Kaposi sarcoma in renal transplant recipients. Thorax 1988;43(8):653-6.  Back to cited text no. 35    
36.Shaheen FA, Al-Sulaiman MH, Ramprasad KS, Al-Khader AA. Kaposi's sarcoma in renal transplant recipients. Ann Transplant 1997;2(4):49-58.  Back to cited text no. 36    
37.Al-Sulaiman MH, Mousa DH, Rassoul Z, Abdalla AH, Abdur Rehman M, Al-Khader AA. Transplant related Kaposi sarcoma in children. Nephrol Dial Transplant 1994;9:443­5.  Back to cited text no. 37  [PUBMED]  [FULLTEXT]
38.Al-Sulaiman MH, Mousa DH, Dhar JM, Al-Khader AA. Does regressed post­transplantation Kaposi's sarcoma recur following reintroduction of immunosup­pression? Am J Nephrol 1992;12:384-6.  Back to cited text no. 38  [PUBMED]  
39.Al-Sulaiman MH, Al-Khader AA. Kaposi's sarcoma in renal transplant recipients. Transplant Sci 1994;4:46-60.  Back to cited text no. 39  [PUBMED]  

Correspondence Address:
Abdullah Ahmed Al-Khader
Director of Renal Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 17660650

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