Post-transplant lymphoproliferative disorder (PTLD) occurs in ~5% of solid organ and hematopoietic stem cell transplant recipients. We report a unique presentation of PTLD in the bladder of a lung transplant recipient. Our patient was a 62-year- old female who received a bilateral lung transplant for chronic obstructive pulmonary disease. She presented with fever, left-sided ﬂank pain and foul-smelling urine consistent with urosepsis. An abdominal and pelvic computerized tomography revealed an irregular and nodular bladder wall thickening suspicious for urothelial neoplasm. Cystoscopy revealed multiple bladder masses and biopsy demonstrated non-Hodgkin lymphoma consistent with PTLD. She was treated with a reduction in immunosuppression followed by chemotherapy and achieved remission. PTLD in the lung transplant recipients has been described in the gut, respiratory tract, skin, liver and kidney but not in the bladder. This case highlights the need for maintaining a high clinical vigilance even when transplant recipients present with seemingly benign clinical complaints. INTRODUCTION CASE REPORT Post-transplant lymphoproliferative disorder (PTLD) is a known A 62-year-old female who was cytomegalovirus (CMV) negative complication following solid organ and hematopoietic stem cell and Ebstein–Barr virus (EBV) positive who received a bilateral transplantation. The incidence is estimated between 2.5 and lung transplant for severe chronic obstructive pulmonary dis- 8% in lung transplant recipients . The gastrointestinal and ease (FEV1 15%) with an uncomplicated course for 5 years post- respiratory tracts have been reported as common anatomical transplantation. She presented with a 24 h history of fever, locations for PTLD in lung transplant recipients . The main- left-sided ﬂank pain and foul-smelling urine. The patient also had stay of PTLD management remains reduction in immunosup- a history of hypertension. She had a 70-pack year history of pression while counterbalancing the risk of rejection. smoking cigarettes prior to transplantation. Immunosuppressive Rituximab has been successfully used in CD-20 positive PTLD medications at presentation included prednisone, tacrolimus and [1–3]. The ideal chemotherapeutic regimen for PTLD in lung prophylactic antimicrobial therapy included bactrim, valganciclo- transplant recipients is unclear [1, 3]. vir and itraconazole. Mycophenolate mofetil was discontinued Bladder PTLD has not been previously described in lung due to persistent leukopenia. Valganciclovir was continued due to transplant recipients. Here, we describe this rare presentation CMV viremia. Her physical examination was unrevealing. At pres- of bladder PTLD with seemingly benign symptoms. We also entation, her labs were notable for a leukocytosis (20 000 per highlight the key features of PTLD in lung transplant recipients. microliter with a high neutrophilic count of 18 150 per microliter) Received: June 16, 2017. Revised: September 17, 2017. Accepted: November 26, 2017 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx093/4924571 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Post-transplant lymphoproliferative disorder in a lung transplant recipient 77 and mild hyponatremia (122 milliequivalents per liter). Urinalysis DISCUSSION was positive for white blood cells, leukocyte esterase and nitrites. Here, we present a unique case of PTLD masquerading as a pri- Her clinical picture was suggestive of urosepsis. She was started mary bladder cancer in a lung transplant recipient. Our patient on vancomycin and piperacillin/tazobactam. Urine and blood did not have any prior symptoms of urgency, urinary incontin- cultures grew Escherichia coli within 48 h of incubation. Her anti- ence or any constitutional symptoms suggestive of malignancy microbial regimen was then de-escalated to ceftriaxone based prior to presentation. She was asymptomatic from bladder on culture sensitivities. Computed tomography (CT) of the PTLD until she developed E. coli urosepsis. Her diagnosis was abdomen and pelvis revealed a non-obstructing nephrolithiasis established due to a thorough work-up which included imaging, on the right and irregular, nodular thickening of the bladder cystoscopy, biopsy and a PET scan for staging. Our top differential wall that was suspicious for a neoplasm (Fig. 1A). Our differen- did not include PTLD. Surprisingly, biopsy of the bladder masses tial diagnosis included urothelial malignancy, followed by less revealed PTLD. Our case highlights the need for maintaining a common non-urothelial malignancy (e.g. squamous cell carcinoma, high clinical vigilance when managing transplant patients, even adenocarcinoma and small cell carcinoma), and non-epithelial when they present with seemingly benign complaints. tumors (e.g. lymphoma, sarcoma) with a superimposed bacter- PTLD is a well-known complication seen in patients who ial infection. have undergone solid organ or hematopoietic stem cell trans- A cystoscopy conﬁrmed multiple bladder masses. Biopsies plantation. ‘Early’ PTLD occurs within 1 year of transplantation revealed a non-epithelial malignancy with diffuse monomorphic and ‘late’ occurs beyond the ﬁrst year [1, 4]. Approximately, 5% cells. The histopathology was negative for EBV, positive for of lung transplant patients remain at risk of developing PTLD lymphoma markers CD-10, B-cell lymphoma 6 protein (BCL-6) [1, 5]. Intrathoracic PTLD occurs most frequently in lung trans- and multiple myeloma oncogene 1 (MUM1); and positive for CD- plant recipients with early disease, whereas extra-thoracic dis- 20 (indicative of B-cell origin), oncogene c-MYC (40%) and had a ease tends to occur later (the gastrointestinal tract being the high expression of cell proliferation marker Ki-67 (Fig. 2). These most common site) . However, bladder PTLD has not been histopathology ﬁndings in conjunction with the patient’shistory previously described in lung transplant recipients. of lung transplantation supported the diagnosis of diffuse large PTLD is a consequence of abnormal B-cell proliferation; and B-cell lymphoma consistent with PTLD. based on B-cell clonal morphology is categorized as mono- Peri-transplant tests were notable for both the donor and morphic or polymorphic. The abnormal B-cell proliferative recipient being positive for EBV. The patient was treated with response is classically seen in conjunction with EBV infection, ganciclovir/valganciclovir following transplantation and main- ranging from benign infectious mononucleosis-like illness and tained an undetectable serum EBV level until this presentation. polyclonal hyperplasia to aggressive malignant lymphomas. EBV-encoded RNA (EBER) in situ hybridization was found to be Although, EBV is thought to be central to the pathogenesis of negative on bladder biopsy tissue samples, but serum levels PTLD, PTLD cases associated with EBV have decreased while were now detectable (1009 IU/ml). EBV-negative PTLD cases have proportionally increased over After conﬁrming the diagnosis of PTLD, a whole-body posi- time from 10 (1990–1995) to 48% (2008–2013) [3, 6]. EBV status tron emission tomography (PET) scan was performed, which does not affect treatment responsiveness and does not impact revealed an FDG-avid pre-vascular anterior mediastinal lymph survival post-treatment . In our case, although both the node consistent with Stage IV PTLD (Fig. 1B). Our management donor and recipient were EBV-positive, her pathology was strategy was 2-fold: a safe reduction in the immunosuppressive negative for EBER in situ hybridization supporting a diagnosis of therapy to treat PTLD while preventing transplant rejection, fol- EBV-negative PTLD. lowed by chemotherapy with an intention to cure. We decreased Currently, there are no clinical trials that assess the treat- her tacrolimus to target serum levels between 4–6ng/ml instead ment of PTLD exclusively in post-lung transplant recipients. of 6–8 ng/ml, and she was treated with six cycles of rituximab- Both EBV-positive and EBV-negative PTLD respond to a reduc- cyclophosphamide, hydroxydoxorubicin, vincristine and prednis- tion in immunosuppression, which remains ﬁrst-line therapy one (R-CHOP). Post-treatment imaging revealed a reduction in . Observational cohorts and Phase II studies support the use bladder wall thickness (Fig. 3), and resolution of bladder masses of R-CHOP  and rituximab monotherapy has been shown to were conﬁrmed on cystoscopy. Post-treatment PET scans revealed cause remission in CD-20 positive B-cell PTLD [7–11]. resolution of all FDG-avid lesions (Fig. 4). Figure 1: This ﬁgure shows the pre-treatment imaging (A) CT scan of the abdomen and pelvis with bladder wall thickening (yellow arrows) and (B) PET scan with pre- vascular avid lymph node (SUV:14) for staging pre-treatment (yellow arrow). Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx093/4924571 by Ed 'DeepDyve' Gillespie user on 16 March 2018 78 H.S. Grewal et al. Figure 2: The H&E (A) section showed a diffuse sheet of monomorphic large B-cells expressing CD-20 (B) and CD-10 (C) with a high Ki-67 (D) proliferation fraction (>90%) Figure 3: CT scan of the abdomen and pelvis pre-treatment image with yellow arrows (A) and post-treatment image with blue arrows (B) showing the resolution of the bladder wall thickening. Figure 4: PET scan image of the anterior chest pre-vascular lymph node pre-treatment with yellow arrow (A) and post-treatment image with blue arrow (B) showing resolution of the PET avid lymph node. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx093/4924571 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Post-transplant lymphoproliferative disorder in a lung transplant recipient 79 4. Thomas de Montpréville V, Le Pavec J, Le Roy Ladurie F, ACKNOWLEDGEMENTS Crutu A, Mussot S, Fabre D, et al. Lymphoproliferative disor- We thank the Respiratory Institute, the Lung Transplant team ders after lung transplantation: clinicopathological charac- and the Pathology and Laboratory Medicine Institute at the terization of 16 cases with identiﬁcation of very-late-onset Cleveland Clinic for their support. forms. Respiration 2015;90:451–9. 5. Wudhikarn K, Holman CJ, Linan M, Blaes AH, Dunitz JM, CONFLICT OF INTEREST STATEMENT Hertz ME, et al. Post-transplant lymphoproliferative disor- ders in lung transplant recipients: 20-yr experience at the None declared. University of Minnesota: PTLD in lung transplant recipients. Clin Transplant 2011;25:705–13. FUNDING 6. Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, et al. The impact of EBV status on characteris- None. tics and outcomes of post-transplantation lymphoprolifera- tive disorder: EBV status in PTLD. Am J Transplant 2015;15: ETHICAL APPROVAL 2665–73. Not required. 7. Knoop C, Kentos A, Remmelink M, Garbar C, Goldman S, Feremans W, et al. Post-transplant lymphoproliferative dis- orders after lung transplantation: ﬁrst-line treatment with CONSENT rituximab may induce complete remission. Clin Transplant Written consent was obtained from the patient. 2006;20:179–87. 8. Cook RC, Connors JM, Gascoyne RD, Fradet G, Levy RD. GUARANTOR Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplant- Drs Harpreet Singh Grewal MD and Atul C. Mehta. ation. Lancet 1999;354:1698–9. 9. Oertel SHK, Verschuuren E, Reinke P, Zeidler K, Papp-Váry REFERENCES M, Babel N, et al. Effect of Anti-CD 20 antibody Rituximab in patients with post-transplant lymphoproliferative disorder 1. Kremer BE, Reshef R, Misleh JG, Christie JD, Ahya VN, Blumenthal NP, et al. Post-transplant lymphoproliferative (PTLD): post-transplant lymphoproliferative disorder (PTLD). Am J Transplant 2005;5:2901–6. disorder after lung transplantation: a review of 35 cases. J Heart Lung Transplant 2012;31:296–304. 10. Blaes AH, Peterson BA, Bartlett N, Dunn DL, Morrison VA. Rituximab therapy is effective for posttransplant 2. Kumarasinghe G, Lavee O, Parker A, Nivison-Smith I, Milliken S, Dodds A, et al. Post-transplant lymphoproliferative disease lymphoproliferative disorders after solid organ trans- plantation: results of a phase II trial. Cancer 2005;104: in heart and lung transplantation: deﬁning risk and prognos- tic factors. J Heart Lung Transplant 2015;34:1406–14. 1661–7. 11. Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM, 3. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al. Sequential treatment with rituximab followed by CHOP Vandenberghe P, et al.Efﬁcacy and safety of rituximab in B- cell post-transplantation lymphoproliferative disorders: chemotherapy in adult B-cell post-transplant lymphoproli- ferative disorder (PTLD): the prospective international multi- results of a prospective multicenter phase 2 study. Blood 2006;107:3053–7. centre phase 2 PTLD-1 trial. Lancet Oncol 2012;13:196–206. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx093/4924571 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Oxford Medical Case Reports – Oxford University Press
Published: Mar 1, 2018
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