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Acute Lymphoblastic Leukemia in an Adult After Renal Transplantation

Solid organ transplant patients are at an increased risk of developing various types of malignancies including hematological ones. The mechanisms behind these malignant changes are multifactorial. These include immunosuppressive agents, pre-transplantation cancer recurrence in the recipient, and de novo cancer development. Acute lymphoblastic leukemia is a rare malignancy in renal transplant recipients. Here, we describe the case of an adult male patient who underwent renal transplantation for end-stage renal disease due to diabetes and hypertension. He developed high hyper-diploid acute lymphoblastic leukemia four months after transplantation. This case is unique due to the presence of the high hyper-diploid cytogenetics of the B-cell acute lymphoblastic leukemia (B-ALL) occurrence in an adult renal transplant recipient.


Introduction
Solid organ transplant recipients have an increased risk of developing cancer [1]. Several factors have been linked with the development of these cancers. These include immunosuppression, oncological viral infections (Epstein-Barr virus (EBV)), diminished immune surveillance of neoplastic cells, cancer already present in the transplanted tissue, and recurrence of cancer in the recipient [1]. The contributory effects of various immunosuppressive medications leading to the development of post-transplant cancer are not well understood.
The most common types of cancers that occur post-transplantation are skin cancers, non-Hodgkin's lymphoma, lung cancer, liver cancer, and renal cancer [1]. Post-transplant lymphoproliferative disorders (PTLD) also commonly occur. This is a group of lymphoid cancers that occur in transplant recipients such as infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin-type lymphoma [2]. Acute lymphoblastic leukemia (ALL) is not part of the PTLD spectrum. ALL is a rare hematological malignancy amongst other hematological disorders seen in posttransplant patients [1,3]. Just 2.2% of calculated cases of ALL were observed in post-solid organ transplantation cases per 100,000 populations [1]. ALL is very common in children. High hyper-diploid (51-67 chromosomes) B-cell ALL (B-ALL) in adults is rare [4].
Here, we describe a case of a 32-year-old male who underwent cadaveric renal transplantation. He developed high hyper-diploid ALL four months post-transplantation.

Case Presentation
A 32-year-old Hispanic male presented to the emergency department with abdominal distension, discomfort, constipation, bloating, urinary frequency, and urinary hesitancy for the past five days. He was found to have ascites. He had a history of end-stage renal disease and was on peritoneal dialysis for the past three years on daily basis. He underwent a deceased donor pediatric en bloc renal transplant four months prior to presentation due to end-stage renal disease. His immunosuppression consisted of tacrolimus, mycophenolate mofetil, and induction therapy with Campath-1H (alemtuzumab). He had good allograft function and excellent urine output until he started having these symptoms. He had a history of diabetes since childhood and was on insulin therapy. His diabetes led to diabetic nephropathy, retinopathy, and neuropathy. In addition, he had obesity and hypertension stable on antihypertensives. His family history was unremarkable and he never used alcohol, illicit drugs, and smoking. He had a history of hepatitis C virus (HCV) treatment, and his viral markers were negative. His vital signs were normal. Apart from ascites and diffuse lymphadenopathy, no other significant findings were noted on physical examination upon presentation.
His polymerase chain reaction (PCR) was negative for cytomegalovirus (CMV) and EBV. Cytologic evaluation of the cerebrospinal fluid was negative for leukemic blasts. Histologic evaluation paired with immunohistochemical stains on the transjugular core biopsy of the liver tissue revealed intact and viable liver parenchyma containing expanded portal triads with an atypical infiltrate of TdT-positive Blymphoblasts, consistent with porto-centric involvement by ALL.
The patient's marrow aspirate and biopsy showed hyper-cellular marrow with 100% cellularity effaced by B-ALL. The monomorphic population consisted of mononuclear cells with a blast-like morphology, scant basophilic cytoplasm, and absent Auer rods. The remainder of marrow elements, including granulocyte forms, were virtually absent with only rare erythroid precursors. Myeloid-to-erythroid (M:E) ratio is not relevant secondary to increased blast population. Bone marrow biopsy shows a complete replacement of the marrow elements by a monomorphic population of lymphoblasts of B-ALL ( Figure 1).

FIGURE 2: Transplant kidney biopsy showing lymphoblasts in the renal interstitium surrounding the glomeruli and tubules characteristics of Bcell acute lymphoblastic leukemia
The B-cells were strongly and diffusely positive for PAX5, TdT, and CD34. CD34 staining the tumor cells in the kidney is shown in Figure 3.

FIGURE 4: Electron microscopy of the transplanted kidney showing a lymphoblast (blue arrow) in the renal interstitium
Immunohistochemical stains were positive for CD10, CD19, CD34, TdT, PAX5, BCL2, and negative for CD3, CD20, CD4, CD8, EBER ISH, BCL6, MUM1, CD30, CD43. CD33 was weakly positive. Figure 5 shows a positive TdT stain in the kidney.  Since ALL is more common in children and rare post transplant, there was a high suspicion of a female child donor being the source of leukemia. Karyotyping performed on recipient marrow showed the following: 46, XY, add (9) (p13) [cp3]/53, idem, +2, +6, +21, +2 ~3m [cp2] /46, XY, which confirmed the source of ALL to be the recipient. Fluorescence in situ hybridization (FISH) showed trisomy of chromosome 6, tetrasomy of chromosome 21, trisomy of chromosomes 4, and deletion of the CDKN2A (p16) gene on chromosome 9 at 9p21. Extra copies of BCL2 and IGH fusion signal mean the presence of chromosome 18 and 14 abnormalities, respectively, were seen.
After discontinuing the immunosuppressive regimen, he underwent chemotherapy, and eventually lost his transplanted kidney.

Discussion
Transplant recipients are at a high risk of developing cancer [1]. The use of immunosuppressive agents, cancer recurrence in the recipient, cancer in the donor tissue, and de novo cancer development are a few mechanisms of cancer development. Cancer is one of the leading causes of death in renal transplant recipients [5]. These malignant changes depend on the intensity and duration of immunosuppressive therapy, but we don't know the contributory effects of various immunosuppressive medications on the development of post-transplant cancer. The average time reported in the literature to develop leukemia after renal transplantation is 11.8 +/-8.5 years [2,5]. This patient developed B-ALL four months after transplantation and immunosuppressive therapy. The cause of this rapid development of leukemia in this patient could be coincidental. The Hispanic population has a higher incidence of ALL because of polymorphisms in the ARID5B gene [6].