Rejection Versus Posttransplantation Lymphoproliferative Disorder in a Renal Transplant Recipient

Clinical History 

A 56-year-old man presented in acute renal failure with a serum creatinine level of 8.1 mg/dL (618 μmol/L). He had received a living unrelated donor renal transplant 4.5 years before, with bilateral native nephrectomies, for autosomal dominant polycystic kidney disease. The graft was a 6-antigen mismatch, and he received basiliximab (anti–interleukin 2 receptor α) induction. His posttransplantation course was uncomplicated, except for subclinical acute cellular tubulointerstitial rejection (CCTT/Banff type I) on the 3-month surveillance biopsy specimen, which resolved with pulse steroid treatment. Maintenance immunosuppression consisted of triple therapy with tacrolimus (FK506), 3 mg twice daily; azathioprine, 200 mg/d; and prednisone, 10 mg/d. Serum creatinine level was slightly increased (2.2 mg/dL [168 μmol/L]) 1 month before presentation (baseline, 1.7 mg/dL [130 μmol/L]).

The patient had an extensive travel history and presented immediately on return from a trip to Asia for elective cosmetic surgery. While abroad, he experienced fever, chills, night sweats, malaise, and right suprascapular pain and received injections of unknown medications, presumably an antibiotic and a nonsteroidal anti-inflammatory. At presentation, laboratory data included negative or normal C3, C4, antinuclear antibody, rheumatoid factor, anti–glomerular basement membrane, hepatitis B and C, and polyoma BK viral study results, with a low-titer antineutrophil cytoplasmic antibody (1:20). Renal ultrasound showed a 15-cm allograft kidney. A concurrent chest computed tomographic scan showed numerous 2- to 5-mm pulmonary nodules, along with several poorly defined opacities in the left lower lobe, each 1 to 2 cm in diameter, and right lower lobe consolidation. There was mediastinal adenopathy and an 18-cm spleen. A renal allograft biopsy was performed on hospital day 1, followed 3 days later by a computed tomography–guided needle biopsy of the lung.

Kidney Biopsy 

The renal allograft biopsy specimen was remarkable for a diffuse, dense, mixed interstitial inflammatory cell infiltrate composed of lymphocytes, numerous eosinophils, fewer neutrophils, and very rare plasma cells. Lymphocytic tubulitis was readily identified. There were clustered vaguely spindle-shaped histiocytes suggestive of poorly formed granulomas and patchy zones of necrosis, some with accompanying hemorrhage. Fibrinoid change in adjacent small arteries also was seen; 1 was occluded by swollen endothelial cells and foamy debris. Venulitis was present, but there was no other evidence of arterial endothelialitis. Rare cells with large nuclei and irregular nuclear contours were seen in the background, along with rare interstitial mitotic figures (Fig 1A to C). Six sampled glomeruli were unremarkable.

View Large Image Download to PowerPoint

Figure 1. Histopathologic findings in kidney biopsy specimen. (A) Mixed inflammatory cell infiltrate with numerous eosinophils, eosinophilic tubulitis (arrows), and tubular injury. (B) Interstitial inflammatory infiltrate including large atypical cells. (Inset) Cells with (left) irregular nuclear contour and (right) macronucleolus. (C) Vascular findings at edge of necrosis: (∗) vessel with fibrinoid change, (arrowheads outline) artery with lumen occluded by flocculent material with lymphocytes, and (arrow) interstitial mitotic figure in histiocyte-rich area. (D) Immunohistochemical staining of serial sections shows the infiltrate is composed of a majority of (left) small CD3-positive T cells and (right, matched field) a minority of small CD20 positive B-cells. (E) Immunohistochemical staining of serial sections shows (left) CD30 stains clusters of cells, including large cells, whereas (right) PAX5 highlights few B cells, including (matched field) a rare cell with large nucleus. (F) Epstein-Barr virus (EBV) in situ hybridization highlights numerous infiltrating cells; positive signal is blue with red counterstain (original magnifications ×400).

The histopathologic differential diagnosis centered on a drug/hypersensitivity reaction, infection, rejection, PTLD, or Hodgkin lymphoma. Histochemical stains were negative for bacterial, mycobacterial, and fungal organisms; immunostains for BK polyoma virus and C4d were also negative. A panel of hematolymphoid markers showed that the infiltrate was composed of numerous CD3-positive T cells, with a minority of CD20- and/or PAX5-positive small and rare large B cells (Fig 1D and E). CD30 highlighted increased numbers of medium-sized immunoblasts, some in clusters (Fig 1E), but Reed-Sternberg cells or variants were not apparent on special studies, including CD15 staining. In situ hybridization for EBV encoded RNA (EBER-ISH) was strikingly positive, especially in CD30- and PAX5-labeled foci (Fig 1F). Gene rearrangement studies were attempted, but were unsuccessful. Based on the rare atypical lymphoid cells, zones of ischemic necrosis, and immunohistochemical profile, most notably EBV positivity, a diagnosis of PTLD (infectious mononucleosis–like) was favored.

A needle core biopsy specimen of the lung showed different pathological features: extensive necrosis and sheets of lymphoid cells of variable size and nuclear morphological characteristics, including numerous large cells with atypical nuclei (Fig 2A). In addition, an angiocentric pattern was noted, with lymphocytes infiltrating the full thickness of the wall of the arteries (not shown). By immunohistochemical staining, CD20 labeled the majority of lymphocytes (B cells; Fig 2B), including medium to large cells and necrotic cells. CD30 stained a subset of large B cells, and CD3 showed admixed T cells. Again, EBER-ISH was positive. Molecular studies showed a clonal B-cell population. Histological, immunohistochemical, and molecular findings were diagnostic of monomorphic PTLD, diffuse large B-cell lymphoma, with a lymphomatoid granulomatosis-like pattern.8, 9

View Large Image Download to PowerPoint

Figure 2. Histopathologic findings in lung biopsy and allograft nephrectomy specimens. (A) Lung with dense monomorphic lymphoid infiltrate effaces pulmonary architecture. (B) CD20 staining shows B-cell phenotype. (C) Allograft nephrectomy with (lower left) glomerular ischemia, (upper right) prominent oxalate crystals, tubular atrophy, interstitial fibrosis, and non-atypical lymphocytes. (D) Chronic allograft arteriopathy with scant lymphoid infiltrate (original magnification: [A-C] ×400; [D] ×200).

Clinical Follow-up 

On transfer, the patient had sepsis caused by Klebsiella species and colitis caused by Clostridium difficile, and hematologic studies showed neutrophilia (90% on differential), anemia (hematocrit, 28.7%), and thrombocytopenia (platelets, 78.0 K/μL); atypical lymphocytes were not seen. He had underlying cardiac ischemia and ejection fraction of 18% on echocardiogram and was tolerating hemodialysis poorly. Initially, therapy consisted of a decrease in immunosuppression followed by single-agent rituximab given his comorbidities (375 mg/m2/wk for 4 weeks,10, 11 with prednisone, 10 mg/d, and tacrolimus, 0.5 mg twice weekly [target serum levels, 3 to 5 ng/mL]). In addition, the patient developed an acute abdomen and underwent sigmoid resection for ruptured diverticulitis. The patient recovered from these acute events and was discharged home on dialysis therapy 1 month after presentation. Maintenance rituximab was administered every 3 months.

EBV serological test samples drawn during hospitalization were consistent with late convalescence of a primary infection (Table 1). Review of transplantation data showed the patient was EBV- and cytomegalovirus-naïve at that time; the donor was also cytomegalovirus negative, with unknown EBV status.

Table 1. Epstein-Barr Virus Test Results

		Index Value at Renal Transplantation (2002)	Index Value During Hospital Admission (2007)
	Viral capsid antigen IgG	0.54	12.15
	Viral capsid antigen IgM	0.00	0.15
	Nuclear antigen, IgG	0.36	0.95
	Early (D) antigen, IgG	0.12	1.87

Note: Interpretation: index values 0 to 0.90 indicate negative; 0.91 to 0.99, equivocal; and greater than 1.00, positive. Abbreviation: IgG, immunoglobulin G; IgM, immunoglobulin M.

Computed tomographic scan at discharge showed resolution of the small lung nodules and decrease in size of the opacities. Three months later, the lung nodules had resolved completely; however, allograft kidney function did not recover, and a graft nephrectomy was performed 5 months after the initial presentation. The patient remains in remission 11 months after the initial presentation.

Histopathologic evaluation of the allograft nephrectomy showed diffuse interstitial fibrosis and tubular atrophy with numerous calcium oxalate crystals. There was no acute rejection, but there were focal loose collections of small non-atypical lymphocytes (Fig 2C and D). Lymphocytes were EBER-ISH negative (not shown), and there was no evidence of PTLD. Several arteries contained luminal or intimal cholesterol clefts. Arteries showed marked fibrous intimal hyperplasia with concentric intimal smooth muscle, consistent with chronic allograft arteriopathy/chronic vascular rejection, but no endothelialitis. Glomeruli showed ischemic features and mesangial sclerosis, with 12% global glomerulosclerosis.