Post-transplant Lymphoproliferative Disorder - Case Presentation - Alison Jazwinski, MD Flinders Medical Center Adelaide, South Australia

Patient 43 yo male HPI: Sent to FMC with persistently elevated liver enzymes on routine lab check (ALT 971, AST 521) On admission reported taking 2 Paracetamol tablets every 2 hours for a headache Denied abdominal pain, melena/hematemesis, vomiting, diarrhea Also denied numbness, weakness, difficultly swallowing or speaking

Patient PMH: Protein C deficiency Budd-Chiari Syndrome resulting in liver transplant 11/2007 Medications Tacrolimus 7mg bid Clonidine 100mg bid Propanolol 40mg bid Warfarin

Physical Exam Vitals: BP 130/78, HR 80, RR 16, temp 36.8 Gen: well appearing male in NAD HEENT: no scleral icterus, MMM Neck: no lymphadenopathy CV: RRR no M/R/G Lungs; CTAB no W/R/R Abdomen: soft, mildly TTP RUQ, no rebound/guarding, NABS Extrem: no edema Neuro: CN II-XII intact, strength 5/5 all muscle groups, reflexes 2+ throughout, gait normal, sensation intact to light touch, pinprick, vibration

Admission Labs Na 141 K 4.0 Cl 105 Bicarb 25 Urea 6.2 (WNL) Cr 103 (WNL) Hb 127g/L Hct 37 WBC 5.6 Platelets 108 Total prot 76g/L (WNL) Albumin 43g/L (WNL) Alk phos 165U/L ALT 332U/L AST 58U/L Bili 14umol/L (WNL) Paracetamol <10 Tacrolimus 7.7

Patient LFT abnormalities thought to be related to Paracetamol over-use. He was using it for a headache… why did he have a headache? Further evaluation revealed…

Head CT

28mm ring enhancing mass in right temporal lobe with moderate surrounding vasogenic edema. There is 6mm midline shift and effacement of overlying cerebral sulci.

Brain MRI

Solitary, thick walled ring enhancing lesion in right temporal lobe measuring 2.8cm x 2.3 cm x 1.8cm associated with extensive vasogenic edema and adjacent mass effect. Appearances are indeterminate, could represent a cerebral abscess however a high-grade glioma or solitary metastasis may also give this appearance. When spectroscopy was added, the findings were keeping with a high grade primary cerebral neoplasm such as a GBM.

Differential Diagnosis Infection Bacterial abscess Cryptococcus Toxoplasma Malignancy Lymphoma Primary CNS tumor Metastatic disease

Further steps Patient was initiated on dexamethasone and loaded with phenytoin for seizure proph CT chest/abdomen/pelvis negative for source of primary malignancy On to surgery with resection Cultures sent for AFB, cryptococcus, toxoplasma, and bacterial culture, all returned negative

Histology Features most in keeping with an EBV driven post-transplant lymphoproliferative disorder with no convincing monoclonality identified on immunoperoxidase stains and associated with considerable tissue necrosis

PTLD Mostly large cell lymphomas Most B cell type Extranodal involvement in 30-70% Appears to be related to EBV inducing B cell proliferation in setting of chronic immunosuppression PTLD cells are of host origin in the majority of cases Transplantation 2006;81:888 Transplantation 1990;49:1080

Putative Checkpoints in the EBV Life Cycle That Might Give Rise to Lymphoma N Engl J Med 350:1328, March 25, 2004

Forms of Disease Benign polyclonal lymphoproliferation (55%) Infectious mono-type illness Develops 2-8 weeks after immunosuppression initiated Polyclonal B cell proliferation with normal cytogenetics Polyclonal lymphoproliferation with early malignant transformation (30%) Localized solid tumors (15%) Monoclonal B cell proliferation with malignant cytogenetic abnormalities Am J Pathol 1988; 133:173

Areas of Involvement Gastrointestinal tract Lungs Skin Liver CNS (20-25%) Allograft lesions (20-25%) Transplantation 1995; 59:240

Treatment Approaches Reduction in immunosuppression Antiviral agents Chemotherapy Immune globulin Surgical resection Radiation Interferon-alpha Pediat Transplant 2001; 5:198

Reduction of Immunosuppression Most will resolve with this Best response among those with early disease where immunosuppression is a major contributing factor Depends on severity of disease Could reduce Prednisone to maintenance doses ( mg) and stop other agents Could reduce Cyclosporine or Tacrolimus by 50% and discontinue Azathioprine or MMF Risk is allograft rejection Transplantation 1999; 68:1517

Other methods of treatment Only case reports at this time Largely dependent on severity of disease and treatment center

Thanks!