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Simultaneous development of Kaposi's sarcoma and lymphoma in a renal transplant recipient
Simultaneous Development of Kaposi’s Sarcoma and Lymphoma in a Renal Transplant Recipient Abdalla Sabeel, MD, Wajeh Qunibi, MD, FACP, Osman Alfurayh, MD, and Khalid Al Meshari, MD ● Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma are frequent complications of renal transplantation that usually occur as separate entities. We describe a young woman who simultaneously developed Kaposi’s sarcoma and lymphoma after kidney transplantation. Immunosuppression consisted of cyclosporine and prednisone with normal serum creatinine. Fifteen months after transplantation, she developed Kaposi’s sarcoma skin lesions, generalized lymphadenopathy, and asciitis. A lymph node biopsy showed both Kaposi’s sarcoma and lymphoma in the same tissue specimen with Epstein-Barr viral genomes within the tumor cells. Graft function remained normal. Cyclosporine was discontinued, and treatment with acyclovir was started, but the patient’s condition rapidly deteriorated, and she died. This is the first case in which both Kaposi’s sarcoma and lymphoma were present in the same biopsy specimen. After renal transplantation, more than one tumor can develop either simultaneously or in succession. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Kaposi’s sarcoma; lymphoma; renal transplantation.
A
LTHOUGH renal transplantation is the preferred treatment modality for patients with end-stage renal disease (ESRD), it has its own complications. One of the more serious complications is increased risk of developing cancer.1,2 In general, solid organ transplantation is associated with more than a 20-fold increase in the incidence of carcinoma, a 40-fold increase in the incidence of non-Hodgkin’s lymphoma, and a 400- to 500-fold increase in the incidence of Kaposi’s sarcoma (KS). Most posttransplantation lymphomas are of the non-Hodgkin’s type and constitute 22% of all posttransplantation tumors compared with only 5% in the general population.3 Conversely, KS accounts for 6% of posttransplantation tumors compiled in the Cincinnati Transplant Tumor Registry (CTTR). By contrast, KS is the most common tumor occurring in our renal transplant recipients, accounting for 65% of posttransplantation tumors.4 KS usually occurs as a separate entity in transplant recipients. However, it has at times been reported to occur in association with other primary malignancies. Penn5 reported that 3 of 58 transplant patients with KS had second primary malignancies, one each reticulum cell From the Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Received July 25, 1997; accepted as submitted August 29, 1997. Address reprint requests to Wajeh Y. Qunibi, MD, FACP, Lee County Kidney Center, P.O. Box 70, Ste 11 Pennington Gap, VA 24277. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3104-0021$3.00/0 706
sarcoma, carcinoma of the colon, and carcinoma of the thyroid.5 In another study, 2 of 35 Saudi Arabian renal transplant recipients with KS developed new primary tumors; one had nonHodgkin’s lymphoma of the colon, and the other had papillary carcinoma of the thyroid.6 In this report, we present the case of a young woman who simultaneously developed KS and lymphoma 15 months after renal transplantation. Both tumors were concomitantly present in a lymph node biopsy specimen. CASE REPORT A 30-year-old woman developed ESRD secondary to renal stones and chronic pyelonephritis and was maintained on hemodialysis for 2 years. In August 1995, she received a live nonrelated kidney transplant abroad. She had a smooth posttransplantation course and enjoyed good health and was maintained on cyclosporine 150 mg twice daily and 15 mg prednisone daily. Fifteen months after the transplantation, she presented to another hospital with fever, abdominal distention, and skin lesions on the upper and lower limbs. She had a lymph node biopsy, which was thought to have a granuloma. She was started on antituberculous medication but did not improve. She was then referred to our institution for further management. On examination, she was found to be pale and jaundiced. Pulse rate was 110 beats/min; blood pressure, 120/70 mm Hg; and temperature 38°C. She had generalized lymphadenopathy, ascitis, and spleenomegaly. Dark red nontender papules were seen over the upper limbs, trunk, and lower limbs. Laboratory investigations showed hemoglobin, 85 g/L; white blood cells (WBC), 3.2 ⫻ 109/L; platelets, 30 ⫻ 109/L; serum creatinine of 60 µmol/L; albumin, 20 g/L; alanine transaminase (ALT), 15 IU/L; aspartate transaminase (AST), 18 IU/L; alkaline phosphatase, 955 IU/L; and total bilirubin, 68 µmol/L. Viral studies for cytomegalovirus (CMV), hepatitis B virus; hepatitus C virus; Epstein-Barr
American Journal of Kidney Diseases, Vol 31, No 4 (April), 1998: pp 706-709
KAPOSI’S SARCOMA AND LYMPHOMA IN A KIDNEY RECIPIENT
virus (EBV); and human immunodeficiency virus (HIV) were all negative. Ascitic fluid analysis did not show malignant cells or acid-fast bacilli. Bone marrow aspirate showed a moderately hypocellular marrow but no evidence of lymphoma or granuloma. Skin biopsy from the leg lesions was diagnostic of KS. An axillary excisional lymph node biopsy showed both KS and lymphoma, (Figs 1-3). In situ hybridization was positive for EBV. Upper gastrointestinal (GI) endoscopy showed lesions similar to those of the skin in the esophagus, stomach, and duodenum. Computed tomography (CT) of the chest showed mediastinal and hilar lymphadenopathy with bilateral pleural effusion but clear lung fields. CT of the abdomen showed extensive retroperitoneal lymphadenopathy, ascitis, and spleenomegaly. The liver was unremarkable. Cyclosporine was discontinued, and intravenous acyclovir was started. She also received appropriate antibiotics and parenteral nutrition, but her general condition deteriorated rapidly, and she was considered not suitable for chemotherapy. She died 5 weeks after hospitalization.
DISCUSSION
The increased incidence of KS and lymphoma after renal transplantation has been repeatedly documented over the years.2-4 In these patients, the incidence of KS varies between 0.4% and 5.3%.4 The incidence is even higher in patients treated with cyclosporine as compared with those treated with conventional immunosuppressive therapy (azathioprine or cyclosphosphamide and prednisone) (10% v 3% of all neoplasms).7,8 KS usually develops in the early months after transplantation, and in most cases the tumor is confined to the skin, but visceral involvement is also common, affecting the gastrointestinal tract
Fig 1. Photomicrograph of Kaposi’s sarcoma (lower right) and posttransplantation lymphoproliferative disorder (PTLD) (upper left) (original magnification ⴛ125).
707
(GIT), lymph nodes, and lungs.7,9 Cessation or reduction of immunosuppressive drugs results in complete remission of KS in most cases without compromising the graft function.9 However, the tumor usually recurs after reinstitution of immunosuppression.10 By contrast, patients with the aggressive type of KS that involves deep organs or lymph nodes have poor prognosis.9 In the patient presented here, the tumor has already involved the skin, GIT, lymph nodes, and possibly the lung at the time of diagnosis, and therefore her prognosis was considered poor from the outset. There also was not enough time for her to show remission after CsA was discontinued. Transplant recipients treated with cyclosporine also have higher incidence of lymphoma when compared with patients treated with conventional immunossuppressive therapy (26% v 11% of all neoplasms).7 More than 90% of these lymphomas are of the non-Hodgkin’s type, mainly originating from B lymphocytes.3 Both KS and non-Hodgkin’s lymphoma occurring in immunosuppressed patients are thought to have an infectious origin. B cells are known to be dually infected with both EBV and Kaposi’s sarcoma–associated herpes virus (KSHV). KSHV is strongly implicated in the pathogenesis of KS in HIV patients and renal transplant recipients.11 EBV is also known to play a unique role in the pathogenesis of B cell lymphoma. Cyclosporine
708
SABEEL ET AL
Fig 2. Photomicrograph of PTLD showing pleomorphic lymphoid cells. Large lymphoid cells with vesicular nuclei and prominent nucleoli (large arrows) as well as small lymphocytes (small arrows) are seen (original magnification ⴛ250).
inhibits the surveillance mechanism of cytotoxic T cells, thus allowing the development of EBVrelated lymphoproliferative disease.12 It is believed that the cumulative dose of immunosuppressive drugs, particularly when monoclonal or polyclonal antibodies are used, enhances the risk of lymphoma.7,8,13 Two clinical patterns of lymphoproliferative disorders were observed in organ transplant recipients. An early one occurring within 3 months posttransplantation that is potentially treatable, and a fatal one that has an insidious
Fig 3. Photomicrograph showing the spindle cells of Kaposi’s sarcoma forming vascular spaces (arrows) and extravasated red blood cells (original magnification ⴛ250).
late onset.13 Penn7 found that KS presents at an average of 20 months after transplantation, while lymphoma presents at an average of 33 months.7 Later, he observed that the average time of appearance of lymphoma was 50 months in patients on conventional therapy but was reduced to 15 months when cyclosporine was used, and was further reduced to 7 months when OKT3 was added to the immunosuppressive regimen.3 In a previous study from our institution, Qunibi et al9 has shown that KS appeared at a mean of 15.6 months after renal transplantation. Our pa-
KAPOSI’S SARCOMA AND LYMPHOMA IN A KIDNEY RECIPIENT
tient did not receive monoclonal or polyclonal antibodies, and she presented with KS and lymphoma simultaneously 15 months after transplantation, which fits well in the time frame for the onset of both tumors.3,9 Extranodal involvement of lymphoma is a feature of non-Hodgkin’s lymphoma in organ transplant population, and in 20% of cases the allograft is affected by the lymphoma.3,7 Extranodal sites of lymphoma were not detected in this patient, and the allograft was not involved, because serum creatinine remained normal until a few days before her death. Histology of the lymph node was characteristic of lymphoma and immunohistochemistry-defined B cells being positive for CD19. In situ hybridization studies showed EBV genomes within the tumor cells. The first-line treatment of KS or lymphoma in transplant patients is reduction or cessation of immunosuppression that might result in complete or partial regression of tumor.3,4 Our patient deteriorated rapidly after cessation of cyclosporine and died within weeks. Chemotherapy was considered, but her general condition precluded the institution of this type of therapy. To our knowledge, this is the only case in the literature in which both KS and non-Hodgkin’s lymphoma were present in the same biopsy specimen. A second transplant recipient was previously reported to have developed concomitant KS and non-Hodgkin’s lymphoma in the colon.6 It is interesting that both patients are from Saudi Arabia. In conclusion, this patient illustrates the fact that more than one tumor can develop in immunosuppressed patients, either simultaneously or in succession. One therefore should be diligent in the care of these patients.
709
REFERENCES 1. Gray JR, Kasiske BL: Patient and renal allograft survival in the late posttransplant period. Semin Nephrol 12:343352, 1992 2. Brunner FP, Landaiz P, Selwood NH: Malignancies after renal transplantation: The EDTA-ERA registry experience. Nephrol Dial Transplant 10:74-80, 1995 3. Penn I: Immunosuppression: A contributory factor in lymphoma formation. Clin Transplant 6:214-219, 1992 4. Qunibi WY, Akhtar M, Sheth K, Ginn HE, Al-Furayh O, DeVol EB, Taher S: Kaposi’s sarcoma: The most common tumor after renal transplantation in Saudi Arabia. Am J Med 84:225-232, 1988 5. Penn I: Kaposi’s sarcoma in immunosuppressed patients. J Clin Lab Immunol 12:1-10, 1983 6. Al-Sulaiman M, Al Kader A: Kaposi’s sarcoma in renal transplant recipients. Transplant Sci 4:46-60, 1994 7. Penn I: The changing pattern of post-transplant malignancies. Transplant Proc 23:1101-1103, 1991 8. Penn I: Cancers in cyclosporine-treated vs azathioprinetreated patients. Transplant Proc 28:876-878, 1996 9. Qunibi WY, Barri Y, Alfurayh O, Almeshari K, Khan B, Taher S, Sheth K: Kaposi’s sarcoma in renal transplant recipients: A report on 26 cases from a single institution. Transplant Proc 25:1402-1405, 1993 10. Dontrelepont J, Pauw L, Gruber S, Dunn D, Qunibi W, Kinnaert P, Vereerstraeten P, Penn I, Abramowicz D: Renal transplantation exposes patients with previous Kaposi’s sarcoma to a high risk of recurrence. Transplantation 62:463-466, 1996 11. Kedda MA, Margolious L, Kew MC, Swanepoel C, Pearson D: Kaposi’s sarcoma-associated herpes virus in Kaposi’s sarcoma occurring in immunosuppressed renal transplant recipients. Clin Transplant 10:429-431, 1996 12. York LJ, Qualtiere LF: Cyclosporin abrogates virusspecific T-cell control of EBV-induced B-cell lymphoproliferation. Viral Immunol 3:127-136, 1990 13. Alfrey EJ, Friedman AL, Grossman RA, Perloff LJ, Naji A, Barker CF, Montone KT, Tomaszweski JE, Chmielewski C, Holland T, Zmijewski C, Dafoe DC: Two distinct patterns of post-transplantation lymphoproliferative disorders (PTLD): Early and late onset. Clin Transplant 6:246-248, 1992
A
LTHOUGH renal transplantation is the preferred treatment modality for patients with end-stage renal disease (ESRD), it has its own complications. One of the more serious complications is increased risk of developing cancer.1,2 In general, solid organ transplantation is associated with more than a 20-fold increase in the incidence of carcinoma, a 40-fold increase in the incidence of non-Hodgkin’s lymphoma, and a 400- to 500-fold increase in the incidence of Kaposi’s sarcoma (KS). Most posttransplantation lymphomas are of the non-Hodgkin’s type and constitute 22% of all posttransplantation tumors compared with only 5% in the general population.3 Conversely, KS accounts for 6% of posttransplantation tumors compiled in the Cincinnati Transplant Tumor Registry (CTTR). By contrast, KS is the most common tumor occurring in our renal transplant recipients, accounting for 65% of posttransplantation tumors.4 KS usually occurs as a separate entity in transplant recipients. However, it has at times been reported to occur in association with other primary malignancies. Penn5 reported that 3 of 58 transplant patients with KS had second primary malignancies, one each reticulum cell From the Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Received July 25, 1997; accepted as submitted August 29, 1997. Address reprint requests to Wajeh Y. Qunibi, MD, FACP, Lee County Kidney Center, P.O. Box 70, Ste 11 Pennington Gap, VA 24277. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3104-0021$3.00/0 706
sarcoma, carcinoma of the colon, and carcinoma of the thyroid.5 In another study, 2 of 35 Saudi Arabian renal transplant recipients with KS developed new primary tumors; one had nonHodgkin’s lymphoma of the colon, and the other had papillary carcinoma of the thyroid.6 In this report, we present the case of a young woman who simultaneously developed KS and lymphoma 15 months after renal transplantation. Both tumors were concomitantly present in a lymph node biopsy specimen. CASE REPORT A 30-year-old woman developed ESRD secondary to renal stones and chronic pyelonephritis and was maintained on hemodialysis for 2 years. In August 1995, she received a live nonrelated kidney transplant abroad. She had a smooth posttransplantation course and enjoyed good health and was maintained on cyclosporine 150 mg twice daily and 15 mg prednisone daily. Fifteen months after the transplantation, she presented to another hospital with fever, abdominal distention, and skin lesions on the upper and lower limbs. She had a lymph node biopsy, which was thought to have a granuloma. She was started on antituberculous medication but did not improve. She was then referred to our institution for further management. On examination, she was found to be pale and jaundiced. Pulse rate was 110 beats/min; blood pressure, 120/70 mm Hg; and temperature 38°C. She had generalized lymphadenopathy, ascitis, and spleenomegaly. Dark red nontender papules were seen over the upper limbs, trunk, and lower limbs. Laboratory investigations showed hemoglobin, 85 g/L; white blood cells (WBC), 3.2 ⫻ 109/L; platelets, 30 ⫻ 109/L; serum creatinine of 60 µmol/L; albumin, 20 g/L; alanine transaminase (ALT), 15 IU/L; aspartate transaminase (AST), 18 IU/L; alkaline phosphatase, 955 IU/L; and total bilirubin, 68 µmol/L. Viral studies for cytomegalovirus (CMV), hepatitis B virus; hepatitus C virus; Epstein-Barr
American Journal of Kidney Diseases, Vol 31, No 4 (April), 1998: pp 706-709
KAPOSI’S SARCOMA AND LYMPHOMA IN A KIDNEY RECIPIENT
virus (EBV); and human immunodeficiency virus (HIV) were all negative. Ascitic fluid analysis did not show malignant cells or acid-fast bacilli. Bone marrow aspirate showed a moderately hypocellular marrow but no evidence of lymphoma or granuloma. Skin biopsy from the leg lesions was diagnostic of KS. An axillary excisional lymph node biopsy showed both KS and lymphoma, (Figs 1-3). In situ hybridization was positive for EBV. Upper gastrointestinal (GI) endoscopy showed lesions similar to those of the skin in the esophagus, stomach, and duodenum. Computed tomography (CT) of the chest showed mediastinal and hilar lymphadenopathy with bilateral pleural effusion but clear lung fields. CT of the abdomen showed extensive retroperitoneal lymphadenopathy, ascitis, and spleenomegaly. The liver was unremarkable. Cyclosporine was discontinued, and intravenous acyclovir was started. She also received appropriate antibiotics and parenteral nutrition, but her general condition deteriorated rapidly, and she was considered not suitable for chemotherapy. She died 5 weeks after hospitalization.
DISCUSSION
The increased incidence of KS and lymphoma after renal transplantation has been repeatedly documented over the years.2-4 In these patients, the incidence of KS varies between 0.4% and 5.3%.4 The incidence is even higher in patients treated with cyclosporine as compared with those treated with conventional immunosuppressive therapy (azathioprine or cyclosphosphamide and prednisone) (10% v 3% of all neoplasms).7,8 KS usually develops in the early months after transplantation, and in most cases the tumor is confined to the skin, but visceral involvement is also common, affecting the gastrointestinal tract
Fig 1. Photomicrograph of Kaposi’s sarcoma (lower right) and posttransplantation lymphoproliferative disorder (PTLD) (upper left) (original magnification ⴛ125).
707
(GIT), lymph nodes, and lungs.7,9 Cessation or reduction of immunosuppressive drugs results in complete remission of KS in most cases without compromising the graft function.9 However, the tumor usually recurs after reinstitution of immunosuppression.10 By contrast, patients with the aggressive type of KS that involves deep organs or lymph nodes have poor prognosis.9 In the patient presented here, the tumor has already involved the skin, GIT, lymph nodes, and possibly the lung at the time of diagnosis, and therefore her prognosis was considered poor from the outset. There also was not enough time for her to show remission after CsA was discontinued. Transplant recipients treated with cyclosporine also have higher incidence of lymphoma when compared with patients treated with conventional immunossuppressive therapy (26% v 11% of all neoplasms).7 More than 90% of these lymphomas are of the non-Hodgkin’s type, mainly originating from B lymphocytes.3 Both KS and non-Hodgkin’s lymphoma occurring in immunosuppressed patients are thought to have an infectious origin. B cells are known to be dually infected with both EBV and Kaposi’s sarcoma–associated herpes virus (KSHV). KSHV is strongly implicated in the pathogenesis of KS in HIV patients and renal transplant recipients.11 EBV is also known to play a unique role in the pathogenesis of B cell lymphoma. Cyclosporine
708
SABEEL ET AL
Fig 2. Photomicrograph of PTLD showing pleomorphic lymphoid cells. Large lymphoid cells with vesicular nuclei and prominent nucleoli (large arrows) as well as small lymphocytes (small arrows) are seen (original magnification ⴛ250).
inhibits the surveillance mechanism of cytotoxic T cells, thus allowing the development of EBVrelated lymphoproliferative disease.12 It is believed that the cumulative dose of immunosuppressive drugs, particularly when monoclonal or polyclonal antibodies are used, enhances the risk of lymphoma.7,8,13 Two clinical patterns of lymphoproliferative disorders were observed in organ transplant recipients. An early one occurring within 3 months posttransplantation that is potentially treatable, and a fatal one that has an insidious
Fig 3. Photomicrograph showing the spindle cells of Kaposi’s sarcoma forming vascular spaces (arrows) and extravasated red blood cells (original magnification ⴛ250).
late onset.13 Penn7 found that KS presents at an average of 20 months after transplantation, while lymphoma presents at an average of 33 months.7 Later, he observed that the average time of appearance of lymphoma was 50 months in patients on conventional therapy but was reduced to 15 months when cyclosporine was used, and was further reduced to 7 months when OKT3 was added to the immunosuppressive regimen.3 In a previous study from our institution, Qunibi et al9 has shown that KS appeared at a mean of 15.6 months after renal transplantation. Our pa-
KAPOSI’S SARCOMA AND LYMPHOMA IN A KIDNEY RECIPIENT
tient did not receive monoclonal or polyclonal antibodies, and she presented with KS and lymphoma simultaneously 15 months after transplantation, which fits well in the time frame for the onset of both tumors.3,9 Extranodal involvement of lymphoma is a feature of non-Hodgkin’s lymphoma in organ transplant population, and in 20% of cases the allograft is affected by the lymphoma.3,7 Extranodal sites of lymphoma were not detected in this patient, and the allograft was not involved, because serum creatinine remained normal until a few days before her death. Histology of the lymph node was characteristic of lymphoma and immunohistochemistry-defined B cells being positive for CD19. In situ hybridization studies showed EBV genomes within the tumor cells. The first-line treatment of KS or lymphoma in transplant patients is reduction or cessation of immunosuppression that might result in complete or partial regression of tumor.3,4 Our patient deteriorated rapidly after cessation of cyclosporine and died within weeks. Chemotherapy was considered, but her general condition precluded the institution of this type of therapy. To our knowledge, this is the only case in the literature in which both KS and non-Hodgkin’s lymphoma were present in the same biopsy specimen. A second transplant recipient was previously reported to have developed concomitant KS and non-Hodgkin’s lymphoma in the colon.6 It is interesting that both patients are from Saudi Arabia. In conclusion, this patient illustrates the fact that more than one tumor can develop in immunosuppressed patients, either simultaneously or in succession. One therefore should be diligent in the care of these patients.
709
REFERENCES 1. Gray JR, Kasiske BL: Patient and renal allograft survival in the late posttransplant period. Semin Nephrol 12:343352, 1992 2. Brunner FP, Landaiz P, Selwood NH: Malignancies after renal transplantation: The EDTA-ERA registry experience. Nephrol Dial Transplant 10:74-80, 1995 3. Penn I: Immunosuppression: A contributory factor in lymphoma formation. Clin Transplant 6:214-219, 1992 4. Qunibi WY, Akhtar M, Sheth K, Ginn HE, Al-Furayh O, DeVol EB, Taher S: Kaposi’s sarcoma: The most common tumor after renal transplantation in Saudi Arabia. Am J Med 84:225-232, 1988 5. Penn I: Kaposi’s sarcoma in immunosuppressed patients. J Clin Lab Immunol 12:1-10, 1983 6. Al-Sulaiman M, Al Kader A: Kaposi’s sarcoma in renal transplant recipients. Transplant Sci 4:46-60, 1994 7. Penn I: The changing pattern of post-transplant malignancies. Transplant Proc 23:1101-1103, 1991 8. Penn I: Cancers in cyclosporine-treated vs azathioprinetreated patients. Transplant Proc 28:876-878, 1996 9. Qunibi WY, Barri Y, Alfurayh O, Almeshari K, Khan B, Taher S, Sheth K: Kaposi’s sarcoma in renal transplant recipients: A report on 26 cases from a single institution. Transplant Proc 25:1402-1405, 1993 10. Dontrelepont J, Pauw L, Gruber S, Dunn D, Qunibi W, Kinnaert P, Vereerstraeten P, Penn I, Abramowicz D: Renal transplantation exposes patients with previous Kaposi’s sarcoma to a high risk of recurrence. Transplantation 62:463-466, 1996 11. Kedda MA, Margolious L, Kew MC, Swanepoel C, Pearson D: Kaposi’s sarcoma-associated herpes virus in Kaposi’s sarcoma occurring in immunosuppressed renal transplant recipients. Clin Transplant 10:429-431, 1996 12. York LJ, Qualtiere LF: Cyclosporin abrogates virusspecific T-cell control of EBV-induced B-cell lymphoproliferation. Viral Immunol 3:127-136, 1990 13. Alfrey EJ, Friedman AL, Grossman RA, Perloff LJ, Naji A, Barker CF, Montone KT, Tomaszweski JE, Chmielewski C, Holland T, Zmijewski C, Dafoe DC: Two distinct patterns of post-transplantation lymphoproliferative disorders (PTLD): Early and late onset. Clin Transplant 6:246-248, 1992