Posttransplant lymphoproliferative disorder (PTLD) is a unifying term for a spectrum of lymphoid expansion entities brought about by immunosuppression and is strongly associated with Epstein-Barr virus (EBV). Otolaryngological findings tend to present early in the clinical course; therefore, disease awareness among otolaryngologists is of utmost importance. This review synthesizes the body of literature pertaining to PTLD involving the head and neck, summarizes contemporary management, and highlights areas for future research.
Data Sources
PubMed/Medline.
Review Methods
Primary literature search of the Medline database was performed for all titles published in the past 10 years pertaining to PTLD. The database search included PTLD combined with a collection of otolaryngological MeSH terms. Full manuscripts were reviewed based on relevance of their title and abstract. Selection into this review was according to clinical and scientific relevance.
Conclusion
Adenotonsillar focus is common in children in whom adenotonsillectomy may be diagnostic and prevents potentially morbid airway obstruction. Sinonasal PTLD may mimic fungal infection. Laryngotracheal involvement predominately presents in children with symptoms of airway obstruction. PTLD limited to the esophagus is rare. Oral PTLD is rare and phenotypically varied. Cutaneous presentation of PTLD is infrequent, yet one-third of cases affects the head and neck. PTLD may present as cervical lymphadenopathy.
Implications for Practice
PTLD consideration is vital when evaluating posttransplant patients. Children and EBV-seronegative patients should receive otolaryngological follow-up after transplant. PTLD treatment is multidisciplinary and typically led by lymphoma specialists. Formal partnerships between otolaryngologists and transplant centers may improve patient care and research quality.
BrennerMJTungTHJensenJNMackinnonSE. The spectrum of complications of immunosuppression: is the time right for hand transplantation?J Bone Joint Surg Am. 2002;84:1861-1870.
2.
CollettDMumfordLBannerNRNeubergerJWatsonC. Comparison of the incidence of malignancy in recipients of different types of organ: a UK Registry audit. Am J Transplant. 2010;10:1889-1896.
3.
SampaioMSChoYWQaziYBunnapradistSHutchinsonIVShahT. Posttransplant malignancies in solid organ adult recipients: an analysis of the US National Transplant Database. Transplantation. 2012;94:990-998.
4.
SwerdllowSHCampoEHarrisNL, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed.Lyon, France: IARC, 2008.
5.
VégsőGHajduMSebestyénA. Lymphoproliferative disorders after solid organ transplantation—classification, incidence, risk factors, early detection and treatment options. Pathol Oncol Res. 2011;17:443-454.
6.
QuinlanSCPfeifferRMMortonLMEngelsEA. Risk factors for early-onset and late-onset post-transplant lymphoproliferative disorder in kidney recipients in the United States. Am J Hematol. 2011;86:206-209.
7.
DierickxDTousseynTGheysensO. How I treat posttransplant lymphoproliferative disorders. Blood. 2015;126:2274-2283.
8.
YoshizumiTShirabeKIkegamiTet al. Impact of human T cell leukemia virus type 1 in living donor liver transplantation. Am J Transplant. 2012;12:1479-1485.
9.
TaokaKNannyaYYamamotoGet al. Progressive transition of Epstein-Barr virus associated lymphoproliferative disease subtypes with the development of lung cancer. Am J Hematol. 2009;84:600-603.
10.
ChinnockRWebberSADipchandAIBrownRNGeorgeJF. A 16-year multi-institutional study of the role of age and EBV status on PTLD incidence among pediatric heart transplant recipients. Am J Transplant. 2012;12:3061-3068.
11.
XiongGZhangBHuangMYet al. Epstein-Barr virus (EBV) infection in Chinese children: a retrospective study of age-specific prevalence. PloS One. 2014;9:e99857.
12.
DowdJBPalermoTBriteJMcDadeTWAielloA. Seroprevalence of Epstein-Barr virus infection in US children ages 6-19, 2003-2010. PLoS One. 2013;8:e64921.
13.
ShapiroNLGuan-Zhong TangCBhattacharyyaN. Association between Epstein-Barr virus seroconversion and immunohistochemical changes in tonsils of pediatric solid organ transplant recipients. Laryngoscope. 2011;121:1718-1725.
14.
OdumadeOAHogquistKABalfourHH. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011;24:193-209.
15.
HöckerBFickenscherHDelecluseHJet al. Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. Clin Infect Dis. 2013;56:84-92.
16.
PiselliPSerrainoDSegoloniGPet al. Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009. Eur J Cancer. 2013;49:336-344.
17.
MortonMCoupesBRitchieJet al. Post-transplant lymphoproliferative disorder in adult renal transplant recipients: survival and prognosis. Leuk Lymphoma. 2016;57:299-305.
18.
NaRGrulichAEMeagherNSMcCaughanGWKeoghAMVajdicCM. Comparison of de novo cancer incidence in Australian liver, heart and lung transplant recipients. Am J Transplant. 2013;13:174-183.
19.
SanaeiAKAliakbarianMKazemiKet al. De novo malignancy after liver transplant. Exp Clin Transplant. 2015;13:163-166.
20.
SmithJMSkeansMAHorslenSPet al. OPTN/SRTR 2013 annual data report: intestine. Am J Transplant. 2015;15(suppl 2):1-6.
21.
LuskinMRHeilDSTanKSet al. The impact of EBV status on characteristics and outcomes of posttransplantation lymphoproliferative disorder. Am J Transplant. 2015;15:2665-2673.
22.
Finalet FerreiroJMorscioJDierckxDet al. EBV-positive and EBV-negative posttransplant diffuse large B cell lymphomas have distinct genomic and transcriptomic features. Am J Transplant. 2016;16:414-425.
23.
HagueKCatalanoPStrauchenJRothschildMFyfeB. Posttransplant lymphoproliferative disease presenting as sudden respiratory arrest in a three-year-old child. Ann Otol Rhinol Laryngol. 1997;106:244-247.
24.
ShapiroNLStrockerAMBhattacharyyaN. Risk factors for adenotonsillar hypertrophy in children following solid organ transplantation. Int J Pediatr Otorhinolaryngol. 2003;67:151-155.
25.
ChiangSVuMCNguyenMStrockerAHorvathSShapiroN. Adenotonsillar enlargement in pediatric organ transplant recipients: a cross-sectional analysis. Otolaryngol Head Neck Surg. 2002;127:109-114.
26.
ShapiroNLStrockerAM. Adenotonsillar hypertrophy and Epstein-Barr virus in pediatric organ transplant recipients. Laryngoscope. 2001;111:997-1001.
27.
MowrySEStrockerAMChanJet al. Immunohistochemical analysis and Epstein-Barr virus in the tonsils of transplant recipients and healthy controls. Arch Otolaryngol Head Neck Surg. 2008;134:936-939.
28.
Sturm-O’BrienAKHicksMJGiannoniCMSulekMFriedmanEM. Tonsillectomy in post-transplant lymphoproliferative disease in children. Laryngoscope. 2010;120:608-611.
29.
RoySViveroRJSmithLP. Adenotonsillar pathology in post-transplant patients. Int J Pediatr Otorhinolaryngol. 2008;72:865-868.
30.
WilliamsonRAHuangRYShapiroNL. Adenotonsillar histopathology after organ transplantation. Otolaryngol Head Neck Surg. 2001;125:231-240.
31.
BroughtonSMcClayJEMurrayAet al. The effectiveness of tonsillectomy in diagnosing lymphoproliferative disease in pediatric patients after liver transplantation. Arch Otolaryngol Head Neck Surg. 2000;126:1444-1447.
32.
KhedmatHTaheriS. Post-transplantation lymphoproliferative disorders localizing in the adenotonsillar region: report from the PTLD.Int survey. Ann Transplant. 2010;16:109-116.
33.
AkbasATiedeCLemoundJMaecker-KolhoffBKreipeHHusseinK. Post-transplant lymphoproliferative disorders with naso- and oropharyngeal manifestation. Transpl Int. 2015;28:1299-1307.
34.
SpinatoLBrihayePDe GansemanAMarquetTMansbachAL. Necrotic adenoids in post-transplant lymphoproliferative disorders. B-ENT. 2010;7:61-64.
35.
MuchaKForoncewiczBNiemczykKet al. Tonsil enlargement after liver transplantation in adults—reason enough for tonsillectomy? Two cases of tonsillar posttransplantation lymphoproliferative disease. Liver Transpl. 2007;13:918-923.
36.
HattenKMLoevnerLAPalmerJNAdappaND. Isolated sinonasal posttransplantation lymphoproliferative disorder: a clinical and radiographic invasive fungal sinusitis look-a-like. ORL. 2013;74:339-342.
37.
GordonARLoevnerLASonnersAIBolgerWEWasikMA. Posttransplantation lymphoproliferative disorder of the paranasal sinuses mimicking invasive fungal sinusitis: case report. AJNR Am J Neuroradiol. 2002;23:855-857.
38.
TurnerJHSoudryENayakJVHwangPH. Survival outcomes in acute invasive fungal sinusitis: a systematic review and quantitative synthesis of published evidence. Laryngoscope. 2013;123:1112-1118.
39.
ParikhSLVenkatramanGDelGaudioJM. Invasive fungal sinusitis: a 15-year review from a single institution. Am J Rhinol. 2004;18:75-81.
40.
GroppoEREl-SayedIHAikenAHGlastonburyCM. Computed tomography and magnetic resonance imaging characteristics of acute invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg. 2011;137:1005-1010.
41.
MomoseAMizunoHKajiharaSet al. EBV-associated nasal-type NK/T-cell lymphoma of the nasal cavity/paranasal sinus in a renal allograft recipient. Nephrol Dial Transplant. 2006;21:1413-1416.
42.
HerrmannBWSweetSCMolterDW. Sinonasal posttransplant lymphoproliferative disorder in pediatric lung transplant patients. Otolaryngol Head Neck Surg. 2005;133:38-41.
43.
LoweryEMGrimSMahoneyELoveRBClarkNLaydenJE. Increased incidence of PTLD in adult lung transplant recipients with cystic fibrosis: analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant. 2013;32:S145.
YapDYChanGCMokMMChanTM. Epistaxis in a kidney transplant recipient: an uncommon presentation of post-transplant lymphoproliferative disease. Nephrology. 2013;18:531.
46.
SculeratiNArriagaM. Otolaryngologic management of posttransplant lymphoproliferative disease in children. Ann Otol Rhinol Laryngol. 1990;99:445-450.
47.
LeeHHLeeDSParkJHet al. A case of laryngeal posttransplantation lymphoproliferative disease. Transplant Proc. 2004;36:2305-2306.
48.
NishimuraKOmoriKHagaHFujimotoYItoJ. Successful laser ablation of diffuse laryngeal swelling in posttransplant lymphoproliferative disorder: the Japanese first case. Int J Pediatr Otorhinolaryngol. 2005;69:869-873.
49.
BanksCAMeierJDStallworthCRWhiteDR. Recurrent posttransplant lymphoproliferative disorder involving the larynx and trachea: case report and review of the literature. Ann Otol Rhinol Laryngol. 2012;121:291-295.
50.
RosbeKWPerez-AtaydeARRobersonDWKennaM. Quiz case 1. Arch Otolaryngol Head Neck Surg. 2000;126:1153.
51.
KranzBVesterUBeckerJet al. Unusual manifestation of posttransplant lymphoproliferative disorder in the esophagus. Transplant Proc. 2006;38:693-696.
52.
HaverkosBMOzaVMJohnsonAWalkerJShana’ahA. Rare presentation of post-transplant lymphoproliferative disorder isolated to gastroesophageal junction. World J Gastrointest Oncol. 2013;5:230.
53.
KindelSJJoyBFPahlEWaldEL. Eosinophilic esophagitis in children following cardiac transplantation: association with post-transplant lymphoproliferative disorder and other transplant outcomes. Pediatr Transplant. 2014;18:491-496.
54.
AllenUDAvitzurY. Eosinophilic esophagitis after organ transplantation and post-transplant lymphoproliferative disorder: more questions than answers. Pediatr Transplant. 2014;18:665-667.
LeónJEJúniorATVassalloJSoaresFAAlmeidaOPLopesMA. EBV-associated polymorphic posttransplant lymphoproliferative disorder presenting as gingival ulcers. Int J Surg Pathol. 2011;19:241-246.
57.
Krasuska-SławińskaEMinko-ChojnowskaIPawłowskaJDembowska-BagińskaBPronickiMOlczak-KowalczykD. Post-transplant lymphoproliferative disorder (PTLD) manifesting in the oral cavity of a 13-year-old liver transplant recipient (LTx). Ann Transplant. 2014;20:478-482.
58.
Cole-HawkinsHFyfeEPriceCPringM. Posttransplant lymphoproliferative disorder presenting as a nonhealing extraction socket: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:e12-e18.
59.
HartMThakralBYoheSet al. EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder. Am J Surg Pathol. 2014;38:1522-1529.
60.
DojcinovSDVenkataramanGRaffeldMPittalugaSJaffeES. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34:405-417.
61.
SeçkinDBareteSEuvrardSet al. Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series. Am J Transplant. 2013;13:2146-2153.
62.
HanasonoMMParrettBMBreitbartAS. Posttransplant lymphoproliferative disorder presenting as a cutaneous forehead mass. Otolaryngol Head Neck Surg. 2004;130:372-374.
63.
WaltonRCOnciuMMIrshadFAWilsonTD. Conjunctival posttransplantation lymphoproliferative disorder. Am J Ophthalmol. 2007;143:1050-1051.
64.
IuLPYeungJCLoongFChiangAK. Successful treatment of intraocular post-transplant lymphoproliferative disorder with intravenous rituximab. Pediatr Blood Cancer. 2015;62:169-172.
65.
ParkerABowlesKBradleyJAet al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients—BCSH and BTS guidelines. Br J Haematol. 2010;149:693-705.
66.
HumarAMichaelsM. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006;6:262-274.
67.
WagnerHJWesselMJabsWet al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation. 2001;72:1012.
68.
MortonMCoupesBRobertsSAet al. Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients. Transplantation. 2013;95:470-478.
69.
SidellDVenickRSShapiroNL. Epstein-Barr DNA serology and positron-emission tomography imaging of the head and neck in pediatric transplant recipients. Laryngoscope. 2014;124:1236-1241.
70.
McCormackLHanyTIHübnerMet al. How useful is PET/CT imaging in the management of post-transplant lymphoproliferative disease after liver transplantation?Am J Transplant. 2006;6:1731-1736.
71.
ValiRPunnettABajnoLMoineddinRShammasA. The value of 18F-FDG PET in pediatric patients with post-transplant lymphoproliferative disorder at initial diagnosis. Pediatr Transplant. 2015;19:932-939.
72.
DierickxDTousseynTRequiléAet al. The accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder. Haematologica. 2013;98:771-775.
73.
Stuhlmann-LaeiszCOschliesIKlapperW. Detection of EBV in reactive and neoplastic lymphoproliferations in adults—when and how?J Hematop. 2014;7:165-170.
74.
TrappeROertelSLeblondVet al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012;13:196-206.
75.
VickersMAWilkieGMRobinsonNet al. Establishment and operation of a Good Manufacturing Practice–compliant allogeneic Epstein-Barr virus (EBV)–specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. Br J Haematol. 2014;167:402-410.
76.
HaqueTWilkieGMJonesMMet al. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007;110:1123-1131.
77.
RooneyCMSmithCANgCYet al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus–induced lymphoma in allogeneic transplant recipients. Blood. 1998;92:1549-1555.
78.
DierickxDTousseynTMorscioJFieuwsSVerhoefG. Validation of prognostic scores in post-transplantation lymphoproliferative disorders. J Clin Oncol. 2013;31:3443-3444.
79.
CaillardSPorcherRProvotFet al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score. J Clin Oncol. 2013;31:1302-1309.
80.
A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.
81.
TrappeRUChoquetSDierickxDet al. International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 Trial. Am J Transplant. 2015;15:1091-1100.
82.
KinchABaecklundEBacklinCet al. A population-based study of 135 lymphomas after solid organ transplantation: the role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival. Acta Oncologica. 2014;53:669-679.
