post - transplant lymphoproliferative disease ( ptld ) is a serious , often fatal complication after solid organ transplantation . the incidence of ptld is greatest among heart ( 213% ) , lung ( 12% ) , and heart / lung ( 59% ) transplant recipients , but occurs less frequently in liver ( 2% ) , renal ( 13% ) , and bone marrow ( 12% ) transplant recipients . the patient s age , transplanted organ , epstein - barr virus ( ebv ) status of the donor and recipient before transplantation and the dosage of immunosuppressive drugs are considered risk factors . these differences in the incidence of ptld may be partly attributed to the higher doses of immunosuppressive drugs necessary following heart and lung transplantation . other possible contributing factors may be bronchus - associated lymphoid tissue ( balt ) and nodal tissue harboring ebv in the donor transplant . ebv infection , either preexisting in the recipient or acquired from the donor , is strongly implicated in the pathogenesis of ptld . immunosuppression may permit uncontrolled proliferation of ebv - stimulated b cells by inhibition of suppressor t cells , from polyclonal to monomorphic and monoclonal proliferations . monoclonal proliferations can subsequently accrue mutations of oncogenes or tumor suppressor genes , and lead to gain a fully malignant behavior and loss of responsiveness to immune regulation . moreover , mutation of c - myc , n - ras and p53 genes has recently been implicated in the terminal progression of ptld . the peak incidence of ptld occurs 3 to 4 months after transplantation , but may develop as early as 6 days later . patients with early onset ptld , within the first year , have a better prognosis than those with one developed late onset . in lung transplant recipients , ptld may develop in the allograft lung , lymph nodes or other malt sites , which frequently involves extranodal locations , including the lung . a lung involved by ptld may present as nodular or diffuse reticulonodular infiltrates , as solitary or multiple lung masses , or as hilar and mediastinal lymphadenopathy , and pulmonary nodules often have foci of necrosis . histologically , ptld can range from polymorphic b cell hyperplasia to monomorphic b - cell proliferation that is indistinguishable from diffuse large cell or immunoblastic lymphomas . these lymphomas are generally high grade with diffuse large cell , immunoblastic , or small noncleaved cell burkitt or burkitt - like morphologies . herein , our experience of two recently encountered cases of ptld following a lung transplantation , which demonstrated an aggressive clinical behavior , is reported , with a review of the literature . a 42-year - old man was admitted with a fever and chills for 3 days . his past medical history included dyspnea on exertion , which had developed from childhood , and was diagnosed as having a large patent ductus arteriosus with eisenmenger syndrome at the age of 20 . six months prior to this presentation , the patient had undergone heart - lung transplantation due to progressive dyspnea , chest pain and peripheral cyanosis . his preoperative examination revealed cytomegalovirus ( cmv ) igm antibody negative , cmv igg antibody positive , herpes simplex virus ( hsv ) igm antibody negative , hsv igg antibody positive , varicella zoster virus ( vzv ) igm antibody negative and vzv igg antibody positive . the tests for ebv early antigen ( ea)-igm was positive , ea - igg negative and epstein - barr nuclear antigen ( eana ) igg positive . the donor was a 25-year - old male whose preoperative examination revealed cmv igm antibody negative and cmv igg antibody positive . the test for ebv ea - igm was negative and ea - igg positive . during the immediate postoperative period , two months after the transplantation , he developed spiking fever with right lower lung field haziness and an accompanying pleural effusion , which was treated under the impression of bacterial pneumonia . one month later , he suffered a sudden fever and chill , and was admitted for further evaluation . on physical examination his chest examination revealed coarse breathing sounds in both lung fields and a grade i / iv systolic murmur in the aortic and tricuspid areas . laboratory tests showed a white cell count of 11,090/l , hemoglobin 9.2 g / dl , platelet 315,000/l , wintrobe erythrocyte sedimentation rate ( esr ) 5 mm / hr ( reference range ; 010 mm / hr ) , serum protein 5.1 g / dl , albumin 2.4 g / dl , aspartate aminotransferase ( ast ) / alanine aminotransferase ( alt ) 22/21 iu / l ( reference range ; < 37/<43 iu / l , respectively ) , creatinine 0.8 mg / dl , cmv igm antibody positive , cmv igg antibody positive , urine cmv - pcr negative , hsv antibody igm negative , hsv antibody igg positive , vzv antibody igm negative and vzv antibody igg positive . the tests for ebv revealed ea - igm antibody positive , ea - igg antibody negative , ebna igg antibody positive and ebv - pcr negative . a plain chest radiograph and computerized tomography revealed multiple , variably sized nodular lesions at the apical segments of both upper lungs , anterior segment of the left lung , posterobasal segment of the left lower lobe , hilar portion of the right middle lobe and superior segment of the right lower lobe . irregular thickening of the alveolar septa and the perivascular connective tissue , due to diffuse infiltration of atypical lymphoid cells , were observed . the ebv - dna reaction was positive by in situ hybridization , but light chain restriction could not be confirmed ( figure 1d ) . thirty days after admission , the patient began to complain of visual disturbance , and was treated with intravitreal ganciclovir and foscarnet under the diagnosis of cmv retinitis . the chest lesion continued to progress , with multiple infectious foci , and multiorgan failure developed . a 33-year - old woman was admitted for evaluation of multiple air space nodules in the left lung field . seven years before this presentation , she began to suffer from progressive dyspnea and dry cough . four years before presentation , she was transferred to a general hospital and diagnosed as having severe emphysema ( fvc 1.34 l ( 35.0% ) , fev1 0.61l / sec ( 20.0% ) , dlco 53% of expected value ) . she was a healthy hepatitis b virus ( hbv ) carrier and her  1-antitrypsine levels were 189 , 381 and 225.3 mg / dl , by three separate tests . two years before presentation , she underwent left lung transplantation and had been administered cyclosporine a , azathioprine and corticosteroid for immunosuppression , and lamivudine for hbv management . preoperative serologic tests revealed cmv igm antibody negative , cmv igg antibody positive , hsv igm antibody negative , hsv igg antibody positive , vzv igm antibody negative and vzv igg antibody positive . there was no information regarding the donor . during 18 months of follow - up after the transplantation however , a routine follow up plain chest radiograph showed multiple air space nodules in the transplanted lung . on physical examination , she had a chronic ill - looking appearance and a moon face , although the lung sounds were clear in both lung fields without rales . laboratory tests revealed a white cell count of 5,440/l , hemoglobin 11.7 g / dl , platelet 232,000/l , c - reactive protein ( crp ) quantitation 25.9 ( reference range ; 08 mg / l ) , wintrobe esr 58 mm / hr , serum protein 5.6 g / dl , albumin 3.2 g / dl , ast / alt 19/12 iu / l , bun 33 mg / dl and creatinine 0.9 mg / dl . the ea - igm and igg antibodies were positive , and the ebna - igg antibody was positive , which is a typical reactivity pattern for ebv reactivation , e.g. ebv - associated lymphoproliferative diseases or epithelial carcinomas , such as nasopharyngeal carcinoma . chest high resolution computed tomogram revealed multiple air spaced nodules at the left upper lobe and collapse of the lingular segment . these nodules had speculated margins with accompanying peripheral ground glass opacity , suggesting inflammatory changes ( figure 2a2c ) . a comparison of inspiratory and expiratory phase images showed neither mosaic perfusion nor small airway disease . a percutaneous transthoracic needle biopsy was performed on a nodule in the left upper lobe . these nodules consisted of lymphocytes , which by immunohistochemical study revealed positive reactions to l-26 and negative reactions to uchl-1 , kappa , lambda , cytokeratin and ki-1 in the tumor cells . a malignant lymphoma , of high - grade large b - cell type , was confirmed ( figure 2d ) . she was given a chemotherapeutic regimen comprising of cytoxan 1200 mg , vincristine 2 mg and prednisone 100 mg for 5 days , and one - week later epirubicin 90 mg was administered before being discharged . two weeks later the patient developed sudden dyspnea and died of pulmonary edema and a pneumothorax . a 42-year - old man was admitted with a fever and chills for 3 days . his past medical history included dyspnea on exertion , which had developed from childhood , and was diagnosed as having a large patent ductus arteriosus with eisenmenger syndrome at the age of 20 . six months prior to this presentation , the patient had undergone heart - lung transplantation due to progressive dyspnea , chest pain and peripheral cyanosis . his preoperative examination revealed cytomegalovirus ( cmv ) igm antibody negative , cmv igg antibody positive , herpes simplex virus ( hsv ) igm antibody negative , hsv igg antibody positive , varicella zoster virus ( vzv ) igm antibody negative and vzv igg antibody positive . the tests for ebv early antigen ( ea)-igm was positive , ea - igg negative and epstein - barr nuclear antigen ( eana ) igg positive . the donor was a 25-year - old male whose preoperative examination revealed cmv igm antibody negative and cmv igg antibody positive . the test for ebv ea - igm was negative and ea - igg positive . during the immediate postoperative period , two months after the transplantation , he developed spiking fever with right lower lung field haziness and an accompanying pleural effusion , which was treated under the impression of bacterial pneumonia . one month later , he suffered a sudden fever and chill , and was admitted for further evaluation . on physical examination his chest examination revealed coarse breathing sounds in both lung fields and a grade i / iv systolic murmur in the aortic and tricuspid areas . laboratory tests showed a white cell count of 11,090/l , hemoglobin 9.2 g / dl , platelet 315,000/l , wintrobe erythrocyte sedimentation rate ( esr ) 5 mm / hr ( reference range ; 010 mm / hr ) , serum protein 5.1 g / dl , albumin 2.4 g / dl , aspartate aminotransferase ( ast ) / alanine aminotransferase ( alt ) 22/21 iu / l ( reference range ; < 37/<43 iu / l , respectively ) , creatinine 0.8 mg / dl , cmv igm antibody positive , cmv igg antibody positive , urine cmv - pcr negative , hsv antibody igm negative , hsv antibody igg positive , vzv antibody igm negative and vzv antibody igg positive . the tests for ebv revealed ea - igm antibody positive , ea - igg antibody negative , ebna igg antibody positive and ebv - pcr negative . a plain chest radiograph and computerized tomography revealed multiple , variably sized nodular lesions at the apical segments of both upper lungs , anterior segment of the left lung , posterobasal segment of the left lower lobe , hilar portion of the right middle lobe and superior segment of the right lower lobe . irregular thickening of the alveolar septa and the perivascular connective tissue , due to diffuse infiltration of atypical lymphoid cells , were observed . the ebv - dna reaction was positive by in situ hybridization , but light chain restriction could not be confirmed ( figure 1d ) . thirty days after admission , the patient began to complain of visual disturbance , and was treated with intravitreal ganciclovir and foscarnet under the diagnosis of cmv retinitis . the chest lesion continued to progress , with multiple infectious foci , and multiorgan failure developed . a 33-year - old woman was admitted for evaluation of multiple air space nodules in the left lung field . seven years before this presentation , she began to suffer from progressive dyspnea and dry cough . four years before presentation , she was transferred to a general hospital and diagnosed as having severe emphysema ( fvc 1.34 l ( 35.0% ) , fev1 0.61l / sec ( 20.0% ) , dlco 53% of expected value ) . she was a healthy hepatitis b virus ( hbv ) carrier and her  1-antitrypsine levels were 189 , 381 and 225.3 mg / dl , by three separate tests . two years before presentation , she underwent left lung transplantation and had been administered cyclosporine a , azathioprine and corticosteroid for immunosuppression , and lamivudine for hbv management . preoperative serologic tests revealed cmv igm antibody negative , cmv igg antibody positive , hsv igm antibody negative , hsv igg antibody positive , vzv igm antibody negative and vzv igg antibody positive . there was no information regarding the donor . during 18 months of follow - up after the transplantation however , a routine follow up plain chest radiograph showed multiple air space nodules in the transplanted lung . on physical examination , her body temperature , pulse and respiration rates were 36.2c , 74/min and 20/min . she had a chronic ill - looking appearance and a moon face , although the lung sounds were clear in both lung fields without rales . laboratory tests revealed a white cell count of 5,440/l , hemoglobin 11.7 g / dl , platelet 232,000/l , c - reactive protein ( crp ) quantitation 25.9 ( reference range ; 08 mg / l ) , wintrobe esr 58 mm / hr , serum protein 5.6 g / dl , albumin 3.2 g / dl , ast / alt 19/12 iu / l , bun 33 mg / dl and creatinine 0.9 mg / dl . the ea - igm and igg antibodies were positive , and the ebna - igg antibody was positive , which is a typical reactivity pattern for ebv reactivation , e.g. ebv - associated lymphoproliferative diseases or epithelial carcinomas , such as nasopharyngeal carcinoma . chest high resolution computed tomogram revealed multiple air spaced nodules at the left upper lobe and collapse of the lingular segment . these nodules had speculated margins with accompanying peripheral ground glass opacity , suggesting inflammatory changes ( figure 2a2c ) . a comparison of inspiratory and expiratory phase images showed neither mosaic perfusion nor small airway disease . a percutaneous transthoracic needle biopsy was performed on a nodule in the left upper lobe . these nodules consisted of lymphocytes , which by immunohistochemical study revealed positive reactions to l-26 and negative reactions to uchl-1 , kappa , lambda , cytokeratin and ki-1 in the tumor cells . a malignant lymphoma , of high - grade large b - cell type , was confirmed ( figure 2d ) . she was given a chemotherapeutic regimen comprising of cytoxan 1200 mg , vincristine 2 mg and prednisone 100 mg for 5 days , and one - week later epirubicin 90 mg was administered before being discharged . two weeks later the patient developed sudden dyspnea and died of pulmonary edema and a pneumothorax . the incidence of ptld after lung transplantation is 2-fold higher than that seen after any other type of organ transplantation . primary ebv infection has been implicated as the major risk factor for ptld , particularly for ebv - naive patients who seroconverted after the lung transplantation . a 20-fold increase in the risk of developing ptld was reported to occur in ebv - seronegative vs ebv - seropositive lung recipients after transplantation . in our cases , serologic ebv testing of the recipients showed that ea - igm was positive and ea - igg negative , suggesting a recent ebv infection prior to the transplantation . in the local community , ebv spreads by contact with oral secretion , but has been transmitted by blood transfusion and bone marrow transplantation in a hospital setting through the ebv receptor ( cd21 ) , which present on the surface of b cells and epithelial cells . the most likely source of ebv infection through solid organ transplantation is transmission through an organ from an ebv - positive to an ebv - seronegative recipient . the exact mechanism by which the donor virus is transmitted from the transplanted organ to the recipient is unknown , although in solid organ transplant recipients , virus - infected cells in ptld of recipient origin have been identified . thus , the donor virus may either be transmitted in a cell - free state or released by donor cells in the recipient . a sufficient number of ebv - carrying b cells may remain in the blood within the allograft and pass into the circulation of the recipient ; the virus would then enter the lytic cycle and infect the recipient b - cell population . alternatively , heart and lung tissue may contain foci of ebv - infected cells , which may act as sites of virus replication . ebv infection in a naive recipient , occurring in the setting of altered host immunity , leads to uncontrolled proliferation and transformation of recipient b cells infected with ebv . these possible patterns of events require identification of high - risk causes and the development of effective therapeutic modalities . a recent study found that continuous , specific anti - viral prophylaxis in high - risk ebv - seronegative recipients significantly reduced the incidence of ptld after lung transplantation in the absence of induction therapy . lymphoid proliferations that are morphologically indistinguishable from a malignant lymphoma occur with greater frequency in organ transplant recipients than in the general population ; but are unlikely to progress to malignant lymphomas in immunocompetent patients , but often regress if the immunosuppression is sufficiently reduced . polymorphic b - cell hyperplasia is associated with a mixture of small lymphocytes , plasma cells and immmunoblasts , without significant cytologic atypia . monomorphic ptld has sheets of large transformed monoclonal cells or immunoblasts . despite their overt malignant appearance , neither the histological appearance nor clonality can accurately predict the response to modulation of immunosuppression . over the past decades , numerous attempts have been made to classify these lesions using morphology , immunohistochemistry and monoclonality , but none of these tools alone or in combination was found to accurately predict the biological behavior . the first case was confirmed as polymorphic , and was treated by conservative means by adjusting the immunosuppressant and anti - viral agent used to treat the accompanying cmv infection , whereas the second case was suspected as monomorphic ptld , and treated aggressively using a chemo - therapeutic regimen , but did not respond to treatment . because ptld treatments are most effective in the early stage , prior to the occurrence of progression of monomorphic or monoclonal proliferations , not only the early detection of ptld , but also the identification of the clonality of ptld , are of importance in planning the means of treatment .
post - transplant lymphoproliferative disease ( ptld ) is a serious , often fatal complication after solid organ transplantation . 
 the incidence of ptld is greater among heart ( 213% ) , lung ( 12% ) and heart / lung ( 59% ) transplant recipients than among liver ( 2% ) , renal ( 13% ) and bone marrow ( 12% ) transplants recipients . 
 the difference in the incidence of ptld may be partly attributed to the higher dose of immunosuppressant therapy used for heart and lung transplantation . 
 the epstein - barr virus ( ebv ) infection status of the donor and recipient before a transplant , and high dose of immunosuppressive drugs are considered major risk factors . 
 recently , 2 cases of ptld in a single lung and a heart - lung transplantation recipient were encountered . 
 both patients presented with multiple pulmonary nodules in the transplanted lung , which developed 6 months and 2 years after the transplantation , respectively . following a transthoracic lung biopsy for diagnostic confirmation , 
 one patient underwent chemotherapy for ptld and the other conservative care for an accompanying viral infection . 
 both patients showed rapid clinical deterioration , without response to treatment , and then rapidly succumbed . 
 herein , our experiences are reported , with a review of the literature .