Posttransplant Malignancies

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Transplantation and the use of immunosuppressive medications seem to increase the risk of some, but not all, types of malignancies. The incidence of colon, breast, prostate, and lung cancer does not seem to be increased in posttransplant recipients. The incidence of renal cell carcinoma is difficult to assess, however, does not appear to be greater in renal transplant recipients than what is found in the nontransplant end stage renal disease population.

The incidence of lymphomas, skin cancer, and Kaposi's sarcoma does appear to be significantly increased in posttransplant recipients.

Skin Cancer

Skin cancer occurs at a frequency up to twenty times greater in posttransplant recipients than in the general population. While basal cell carcinoma is more common in the general population, squamous cell carcinoma seems to occur more frequently in transplant recipients. In addition, melanoma occurs more frequently in transplant recipients. In general, whatever the type of skin malignancy that occurs, it tends to take a more aggressive course in the transplant recipient than in the nonimmunocompromised individual. Early detection and aggressive management should be incorporated in all long-term follow-up of transplant recipients. Sun exposure should be dissuaded and regular complete skin evaluations should be employed.

Kaposi's Sarcoma (KS)

Kaposi's sarcoma is not infrequent in the posttransplant period. It has recently been related to the presence of Herpes virus VIII. However, as of this writing, the casual relationship of HSV VIII and KS has not been totally established. KS usually presents as a bluish and often macular skin lesion. However, it may affect other sites including the oropharynx, lung, and other internal organs. KS may respond to decreased or cessation of immunosuppression, but at times may require either chemotherapy or radiotherapy.

Lymphoma

Most lymphomas posttransplant are B-cell lymphomas of the non-Hodgkin's type. The nomenclature of B-cell lymphoma in this setting is confusing and is often referred to as posttransplant lymphoproliferative disease (PTLD). Almost all cases of PTLD are related to infection with Epstein-Barr Virus (EBV). Patients initially seronegative for EBV who receive organs from donors serologically positive for EBV seem to be at highest risk for the development of PTLD.

As opposed to nontransplant lymphomas, PTLD is often extra-nodal and may first present as involvement of such disparate sites as the GI tract, lung, or kidney. The risk of PTLD also seems to be related to the degree and type of immuno-suppression. In particular, repeated anti-lymphocyte antibodies seem to incur a higher risk for development of PTLD. However, PTLD also seems to have a tendency to increase when very large doses of either Cyclosporine or Tacrolimus were used compared to lower doses of these agents that are now in common use.

Therapy for PTLD varies, occasionally a decrease in immunosuppressive medications may reverse the process. This option is most appropriate in vital organ transplants. Cessation of immunosuppression completely is also an option. Chemotherapy and radiotherapy can also be employed. The use of Acyclovir has also been advocated. Regardless of therapy, the prognosis for this entity is generally poor. Much discussion has been made of the clonality and presence of gene rearrangements, particularly as to guide therapy. Whether this distinction truly benefits patients remains to be seen.

Skeletal Complications

Renal transplantation is associated with several functional and structural abnormalities of the skeletal system. Some of these complications such as persistent hyperparathyroidism, aluminum-associated bone disease, B-2 microglobulin amyloidosis may be preexistent at the time of transplantation. Subsequent development of osteopenia, osteonecrosis and gout may cause additional skeletal problems. The most common posttransplant skeletal disorders are immunosuppression related bone disease, painful leg syndrome and avascular bone necrosis.

Osteoporosis is prevalent after renal transplantation and is characterized by decreased bone mineral density [BMD], fractures and skeletal pain. The most significant bone loss is noted during the early posttransplant period when corticosteroid dosage is high and seems to correlate directly with total amount of corticosteroid used. Additionally cyclosporine and persistent elevation of parathyroid hormone levels may exacerbate the bone loss after transplantation. The kidney-pancreas allograft recipients seem to be at an increased risk for fracture due to steroid induced osteopenia as compared to recipients of kidney alone. Treatment for - after transplantation is quite challenging since significant bone loss has already occurred. Current attempts to treat these patients include steroid withdrawal regimens, alendronate, calcium supplements and calcitonin.

Ten percent of renal transplant patients experience the painful leg syndrome during the posttransplant period. This is characterized by symmetrical pain in the knees and ankles during the first few months of the posttransplant period and the pain is relieved in a few weeks. Appearance of the syndrome coincides with the initiation of Cyclosporine therapy and may be relieved by addition of calcium channel blockers. Plain x-rays and bone scans do not help. MRI scans often show stress fractures. Pathogenesis of this syndrome is not known and there is no correlation with pretransplant hyperparathyroidism.

Prevalence of avascular necrosis of the hip in renal transplant patients is between 5% and 37%. This is a most disabling complication that develops between 6 months and 2 years in the posttransplant period. The patient often presents with pain on the affected side and is frequently severe enough to impede walking. Bilateral avascular necrosis of the hips is common and several other bones may also be affected in 30% of patients. This complication is directly due to steroids and there seems to be a relationship between the cumulative steroid dose and necrosis as well as other bone fractures. Diagnosis can be made with the currently available MRI technology. When patients develop severe symptoms surgical treatment often becomes necessary. There are many surgical approaches such as drilling of the femoral head and neck, free fibular grafting, cup arthro-plasty, hemiarthroplasty and cemented or cementless total hip arthroplasty.

Selected Readings

1. Cecka JM, Terasaki PI. The UNOS scientific renal transplant survey. In: Terasaki PI, Cecka JM, eds. Clinical Transplants 1994. Los Angeles: UCLA Tissue Typing Laboratory, 1995; 1-18.

2. Paul LC. Chronic renal transplant loss. Kidney Int 1995; 47:1491-1499.

3. Raisanen-Sokolowski A, Glysing-Jensen T, Mottram P et al. Sustained anti-CD4/ CD8 blocks inflammatory activation and intimal thickening in mouse heart allografts. Arterioscl Thromb Vasc Biol 1997; 17:2115-2122. Russell ME, Wallace AF, Hancock WW et al. Upregulation of cytokines associated with macrophage activation in the Lewis to F344 rat chronic cardiac rejection model. Transplantation 1995; 59(4):572-578.

Mhoyan A, Cramer DV, Baquerizo A et al. Induction of allograft nonresponsiveness following intrathymic inoculation with donor class I allopeptides. I. Correlation of graft survival with anti-donor IgG antibody subclasses. Transplantation 1997; 64:1665-1670.

Kerman RH, Susskind B, Kerman DH, Lam M et al. Anti-HLA antibodies detected in posttransplant renal allograft recipient sera correlate with chronic rejection. Transplant Proc 1997; 29:1515-1516.

Tullius SG, Tilney NL. Both alloantigen-dependent and-independent factors influence chronic allograft rejection. Transplantation 1995; 59:313. Brenner BM, Cohen RA. Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992; 3:162.

Almond PS, Matas A, Gillingham K et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993; 55:752-757.

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