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Post-transplant Lymphoproliferative Disorder of Naso-orbital Region in Adult Renal Transplant Recipients: A Case Report and Literature Review
Post-transplant Lymphoproliferative Disorder of Naso-orbital Region in Adult Renal Transplant Recipients: A Case Report and Literature Review Panachai Nimitpanyaa, Pawarich Limpanavongsaena, Suwasin Udomkarnjananunb, Kamonwan Jutivorakoolc, and Jakapat Vanichananc,* a Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; bDivision of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and c Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
ABSTRACT Post-transplant lymphoproliferative disorder (PTLD) is an uncommon but fatal complication following both solid organ and hematologic stem cell transplantations. Epstein-Barr virus (EBV) has been considered a main etiologic agent causing PTLD, especially in the first year after transplantation. Extranodal manifestations are frequently found in PTLD; however, naso-orbital involvement in adults is rare. We report a case of EBV-associated PTLD of the naso-orbital region in a 72-year-old patient that occurred 10 years after kidney transplant. Six additional adults with naso-orbital PTLD were identified after completing this literature review, including 2 cases with eyelid swelling, 3 cases with proptosis, and 1 case with facial numbness. The majority of cases occurred after 1 year of transplantation and were associated with EBV. This report emphasizes recognizing PTLD as differential diagnosis in transplant recipients who present with naso-orbital symptoms.
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OST-TRANSPLANT lymphoproliferative disorder (PTLD) is well-recognized as lymphoma that occurs following solid organ or hematopoietic stem cell transplantation [1]. Primary infection or reactivation of EpsteinBarr virus (EBV) plays an important role in the pathogenesis of PTLD, especially in the first year after transplantation. The majority of PTLD cases have lymph node involvement, and clinical manifestations can vary from asymptomatic to severe, resembling aggressive non-Hodgkin lymphoma [2]. Extranodal involvement of PTLD, including the gastrointestinal system, allograft, or central nervous system, is frequently documented [3,4]. However, extranodal manifestations of the head and neck, such as naso-orbital involvement among solid organ transplant recipients, are rarely reported in adults [5]. Here, we report a case of EBV-associated PTLD involving the naso-orbital region in an adult kidney transplant recipient who presented with bilateral proptosis and gaze palsy, mimicking invasive fungal infection. Characteristics and outcomes of naso-orbital involvement of PTLD in adults are also demonstrated in another 6 cases identified after extensive literature review. ª 2020 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e5 (2020)
CASE REPORT A 72-year-old man with a history of end-stage renal disease due to hypertension underwent a cadaveric kidney transplant 10 years prior to hospitalization. His post-transplant course had been uneventful without significant infection or allograft rejection. Maintenance immunosuppressive agents included cyclosporine A 125 mg/d, mycophenolate mofetil (MMF) 1000 mg/d, and prednisolone 2.5 mg every other day. He was transferred from a local hospital to our institute with progressive painful swelling of both eyes for 3 weeks. He denied a history of fever, nasal congestion, or visual disturbance. Physical examination revealed proptosis with chemosis of both eyes and bulging of soft palate. Visual acuity and fundoscopic examination were normal, but eye movement was limited in all directions. Cervical lymph node was not palpable. Complete blood count showed a white blood count of 9280 cells/mL, including an absolute lymphocyte count of 3062 cells/mL. His creatinine level
*Address correspondence to Jakapat Vanichanan, Division of Infectious Disease, Department of Medicine, Faculty of Medicine, Chulalongkorn University, 1841 Rama IV Rd, Pathum Wan District, Bangkok, 10330, Thailand. Tel: þ66 81-654-4587; Fax: þ66 2-649-4000 (Ext. 80507). E-mail: [email protected] 0041-1345/20 https://doi.org/10.1016/j.transproceed.2020.01.047
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NIMITPANYA, LIMPANAVONGSAEN, UDOMKARNJANANUN ET AL
Fig 1. Axial and coronal T1-weighted (A and D), T2-weighted (B and E), and gadolinium-enhanced T1WI of the orbits (C and F). MRI showed enlargement of bilateral lacrimal glands (arrow), with isointense on T1WI and heterogeneous isohyperintense on T2WI. Heterogeneous enhancement could be seen on gadolinium-enhanced T1WI. T1WI, T1-weighted image; T2WI, T2-weighted image. was at his baseline (1.36 mg/dL), and liver function test was unremarkable. Since his symptoms were concerning for invasive fungal infection, liposomal amphotericin B and posaconazole were initiated. Serum EBV viral load was undetectable at the time of presentation. Magnetic resonance image (MRI) of the sinus and orbital area revealed symmetrical bilateral lacrimal glands enlargement with heterogeneous enhancement after gadolinium injection, resulting in proptosis of both eyes (Fig 1). Diffusion MRI showed low apparent diffusion coefficient, which was suggestive of highgrade malignancy or lymphoproliferative disorder. Multiple nodular enhancements at posterior auricular lymph nodes and the right parotid gland were also noted. There was no abnormality of structure including orbits, paranasal sinuses, and cavernous sinus. Nasal endoscopy demonstrated generalized inflammation of mucosa and necrotic tissue with crusting at right nasal septum. Endoscopic sinonasal biopsies of inferior turbinate, septum, and right lacrimal gland were performed. Pathologic studies of lacrimal gland and right nasal turbinate revealed extensive coagulative necrosis with atypical medium-sized round cell. Further immunohistochemistry stain was positive for CD20 and EBV-encoded small RNAs (EBERs) by in situ hybridization (Fig 2). The results were compatible with EBV-associated PTLD of lacrimal gland and nasal turbinate. The patient’s immunosuppressive regimen was adjusted including discontinuation of MMF, decreasing dose of prednisolone, and switching cyclosporine A to sirolimus. Further treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and corticosteroid (R-CHOP regimen) was scheduled in daycare
infusion clinic. Unfortunately, he did not return for a follow-up visit and died from an unknown cause.
REVIEW OF LITERATURE
After extensive literature review, a total of 7 adults with PTLD of the naso-orbital area, including our case, were identified, as demonstrated in Table 1 [6-10]. The median age of patients at presentation was 53 years old. The onset after transplantation varies from 4 to more than 10 years. All of them were solid organ transplant patients, including 3 kidney, 3 lung, and 1 heart transplant recipients. Lacrimal gland and paranasal sinus were the most common involved organs (43%) followed by orbital apex (29%). Among 6 cases with available EBER result, the majority (83%) had positive results. A total of 5 patients received either systemic or local therapy, and 4 patients had remission of PTLD. DISCUSSION
PTLD is the second most common malignancy in transplant recipients after nonmelanoma skin cancer [1,11]. The spectrum of PTLD ranges from self-limited benign diseases to aggressively disseminated lymphoid malignancy, which follow both solid organ transplant and hematopoietic stem cell transplantation [12]. According to the World Health
PTLD OF NASO-ORBITAL REGION
Organization (WHO) criteria, PTLD can be subclassified into 6 types including plasmacytic PTLD, infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma PTLD [13]. Overall, the prevalence of PTLD varies from 1% to 20% depending on EBV serology status, level of immunosuppression, type of transplanted organ, and genetic factors [14]. Cumulative 5-year incidence of PTLD among kidney transplant recipients appeared to be around 0.6%, which was the lowest among all types transplanted organs [15]. The majority of PTLD cases have lymph node involvement. However, extranodal involvement of PTLD including gastrointestinal tract, transplanted allografts, or central nervous system appears to be more frequent compared to lymphoma in nontransplant individual [8,16]. PTLD of the head and neck is more common and can be found in up to 25% of the pediatric population, whereas reports in adult recipients are relatively scarce [17,18]. Those patients usually manifest as mononucleosis-like syndrome characterized by fever with pharyngitis, tonsillar enlargement, and cervical lymphadenopathy [16,18]. Waldeyer ring and cervical lymph nodes are the most common sites of involvement in both adult and pediatric populations [5,17,19]. Naso-orbital PTLD has been rarely reported, especially in adults. Only 7 cases were identified, including our case, after extensive literature review. The incidence appeared to be lower compared to extranodal lymphoma of the head and neck in nontransplant patients, which ranged from 1.9 to 11.4 cases per year, and naso-orbital involvement accounted for less than 2% of all cases [20,21]. Lacrimal gland, orbital apex, and paranasal sinuses were commonly involved. Clinical presentation among those patients ranged from eyes swelling to proptosis, gaze paralysis, and cranial nerve
3
palsies, which resembled invasive fungal infection. Nevertheless, imaging studies such as computerized tomography or MRI can be used for distinguishing PTLD from invasive fungal infection. Absence of destruction to adjacent structures including bone, brain, and sinuses lessens the suspicion of invasive fungal sinusitis in those patients with nasoorbital PTLD [22]. Onset of PTLD expresses in bimodal distribution. Most of the cases occur within the first year after transplantation. The incidence then decreases and becomes stable 3 to 5 years after transplant [23,24]. EBV plays an important role in the pathogenesis of PTLD cases, especially those occurring within the first year of organ transplant. However, EBV-negative PTLD has been increasingly reported, especially in late onset (> 5 years after transplant) PTLD. Interesting, according to our review, the majority of nasoorbital PTLD occurred after 5 years, and almost all cases were EBV-associated since EBV is able to infect both lymphocytes and epithelial cells and has a strong association to lymphoma of the head and neck as well as nasopharyngeal carcinoma [25]. This unique feature is probably due to an abundance of EBV-infected cells of the nasopharyngeal area as the primary site of infection. Currently, whole blood and plasma quantitative EBV viral load (VL) have been used for the diagnosis of PTLD in some transplant centers. In our case, EBV VL was undetectable, despite definite diagnosis of PTLD in the patient. The utility of this assay remains questionable owing to the lack of standardization, poor diagnostic performance, and heterogeneity of the disease spectrum [26,27]. However, preemptive monitoring EBV VL in high-risk patients (especially Dþ/R- recipients) may be beneficial [28]. According to recommendation from the guidelines, reduction of immunosuppression is the most important
Fig 2. Histology of both right lacrimal gland (A) and turbinate (B) showed extensive coagulative necrosis with atypical medium-sized mature round cell (hematoxylin and eosin x60). In situ hybridization (C) showed positive staining for Epstein-Barr virus with EBER mRNA probe. Immunohistochemistry (D) was positive for CD20. EBER, Epstein-Barr viruseencoded small ribonucleic acid; mRNA, mitochondrial ribonucleic acid.
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Table 1. Summary of Case Reports of PTLD With Naso-orbital Involvement in Adult Immunosuppressive Agents
71/M
Lung, unknown
Azathioprine, tacrolimus, and prednisolone
53/M
Lung, 7 years
Tacrolimus, MMF, and prednisolone
61/M
Heart, 42 months
Azathioprine
Progressive, asymmetric, bilateral proptosis with difficulty urination/3 months
53/M
Lung, 8 years
Tacrolimus, MMF, and prednisolone
49/M
Kidney, 10 years
Cyclosporine
Diplopia, left eye proptosis, left CN III, IV, V1, V2, VI palsy/2 days Bilateral upper lid swelling/2 weeks
45/F
Kidney, >10 years
Cyclosporine and prednisolone
72/M
Kidney, 10 years
MMF, cyclosporine, and prednisolone
Presentation/Onset
Involved Area
Left facial numbness with left Left posterior ethmoidal and V2 CN palsy/2 weeks sphenoid sinuses, left clivus and vidian canal, bilateral foramen rotundum Diplopia in all fields of gaze Left orbit extending to orbital and proptosis of the left apex, cavernous sinus globe/2 days
Right upper lid swelling and unable to wear contact lens/2 years Progressive bilateral proptosis with gaze palsy/ 3 weeks
EBER
Treatment
Negative
Radiotherapy, dosage reduction of tacrolimus, discontinue azathioprine,
Positive
Rituximab, orbital irradiation
Bilateral orbit extending to orbital apex, prostate gland
Unknown
Posterior ethmoidal and sphenoid sinuses
Positive
Bilateral lacrimal glands, cervical lymph nodes
Positive
Rituximab, orbital irradiation and change immunosuppression to cyclosporine and prednisone Rituximab, dosage reduction of tacrolimus, discontinue MMF Rituximab, discontinue cyclosporine
Right Lacrimal gland
Positive
Bilateral lacrimal glands, inferior turbinate, nasal septum, parotid glands and cervical lymph nodes
Positive
Mass excision and reduction of immunosuppression Dosage reduction of cyclosporine, substitute MMF with sirolimus
Outcome
Reference
Unknown
[6]
Remission, but no improvement of visual acuity and motility Death from PTLD
[7]
Complete clinical response except VI nerve palsy Remission, required hemodialysis after graft rejection Remission
[8]
Loss of follow-up and expired before RCHOP treatment
[7]
[9]
[10]
Present case
Abbreviations: CN, cranial nerve; EBER, Epstein-Barr viruseencoded small ribonucleic acid; F, female; M, male; MMF, mycophenolate mofetil; PTLD, posttransplant lymphoproliferative disorder; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; Tx, transplant.
NIMITPANYA, LIMPANAVONGSAEN, UDOMKARNJANANUN ET AL
Case
Tx Organ, Duration From Tx
PTLD OF NASO-ORBITAL REGION
management modality. Other treatment strategies including rituximab, chemotherapy, radiation, and surgical resection are also considered options in selective patients [29]. All except 1 patient from our review had reduction of immunosuppression, and of those 4 patients received rituximab, 1 patient underwent radiation, and none received chemotherapy. One patient underwent only surgical removal of the right lacrimal gland because of highly localized disease. The majority of cases (4 out of 7) had favorable outcomes after treatment. CONCLUSION
PTLD of the naso-orbital region is rarely reported and may have manifestations similar to invasive fungal infections. Imaging studies can help distinguish between those 2 conditions. Tissue diagnosis is crucially required, while diagnostic value of EBV VL is uncertain. Prompt recognition and early appropriate management are important and can significantly affect the outcomes of patients. ACKNOWLEDGMENTS The authors sincerely acknowledge the contribution of Dr Thamathorn Assanasen (Department of Pathology, Faculty of Medicine, Chulalongkorn University) and Dr Netsiri Dumrongpisutikul (Department of Radiology, Faculty of Medicine, Chulalongkorn University) for providing images during the process of manuscript preparation.
REFERENCES [1] Engels EA, Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891e901. [2] Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Engl J Med 2018;378:549e62. [3] Kinch A, Baecklund E, Backlin C, Ekman T, Molin D, Tufveson G, et 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 Oncol 2014;53:669e79. [4] Aull MJ, Buell JF, Trofe J, First MR, Alloway RR, Hanaway MJ, et al. Experience with 274 cardiac transplant recipients with posttransplant lymphoproliferative disorder: a report from the Israel Penn International Transplant Tumor Registry. Transplantation 2004;78:1676e82. [5] Loevner LA, Karpati RL, Kumar P, Yousem DM, Hsu W, Montone KT. Posttransplantation lymphoproliferative disorder of the head and neck: imaging features in seven adults. Radiology 2000;216:363e9. [6] Hatten KM, Loevner LA, Palmer JN, Adappa ND. Isolated sinonasal posttransplantation lymphoproliferative disorder: a clinical and radiographic invasive fungal sinusitis look-a-like. ORL J Otorhinolaryngol Relat Spec 2012;74:339e42. [7] Douglas RS, Goldstein SM, Katowitz JA, Gausas RE, Ibarra MS, Tsai D, et al. Orbital presentation of posttransplantation lymphoproliferative disorder: a small case series. Ophthalmology 2002;109:2351e5. [8] Gordon AR, Loevner LA, Sonners AI, Bolger WE, Wasik MA. Posttransplantation lymphoproliferative disorder of the paranasal sinuses mimicking invasive fungal sinusitis: case report. AJNR Am J Neuroradiol 2002;23:855e7.
5 [9] Cheung D, Prabhakaran V, Brown L, Stitson RN, Sampath R. Bilateral lacrimal gland enlargement due to posttransplant lymphoproliferative disorder. Eye (Lond) 2006;20:972e4. [10] Gold K. Contact lens intolerance and lid swelling offer clues to this patient’s condition. Rev Ophthalmol 2008. [11] Chapman JR, Webster AC, Wong G. Cancer in the transplant recipient. Cold Spring Harb Perspect Med 2013;3. [12] Torlakovic EE, Bailey D. Post-transplant lymphoproliferative disorders. Diagn Histopathol 2012;18:281e9. [13] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: International Agency for Research on Cancer; 2017. [14] Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep 2013;8:173e83. [15] American Society of Transplantation, American Society of Transplant Surgeons. Organ procurement and transplantation network and scientific registry of transplant recipients 2010 data report. Am J Transplant 2012;12(Suppl 1):1e156. [16] Everly MJ, Bloom RD, Tsai DE, Trofe J. Posttransplant lymphoproliferative disorder. Ann Pharmacother 2007;41:1850e8. [17] Lattyak BV, Rosenthal P, Mudge C, Roberts JP, Renze JF, Osorio RW, et al. Posttransplant lymphoproliferative disorder presenting in the head and neck. Laryngoscope 1998;108:1195e8. [18] Pickhardt PJ, Siegel MJ, Hayashi RJ, Kelly M. Posttransplantation lymphoproliferative disorder in children: clinical, histopathologic, and imaging features. Radiology 2000;217:16e25. [19] Akbas A, Tiede C, Lemound J, Maecker-Kolhoff B, Kreipe H, Hussein K. Post-transplant lymphoproliferative disorders with naso- and oropharyngeal manifestation. Transpl Int 2015;28: 1299e307. [20] Picard A, Cardinne C, Denoux Y, Wagner I, Chabolle F, Bach CA. Extranodal lymphoma of the head and neck: a 67-case series. Eur Ann Otorhinolaryngol Head Neck Dis 2015;132:71e5. [21] Peng KA, Kita AE, Suh JD, Bhuta SM, Wang MB. Sinonasal lymphoma: case series and review of the literature. Int Forum Allergy Rhinol 2014;4:670e4. [22] Aribandi M, McCoy VA, Bazan C 3rd. Imaging features of invasive and noninvasive fungal sinusitis: a review. Radiographics 2007;27:1283e96. [23] Francis A, Johnson DW, Teixeira-Pinto A, Craig JC, Wong G. Incidence and predictors of post-transplant lymphoproliferative disease after kidney transplantation during adulthood and childhood: a registry study. Nephrol Dial Transplant 2018;33:881e9. [24] Camacho JC, Moreno CC, Harri PA, Aguirre DA, Torres WE, Mittal PK. Posttransplantation lymphoproliferative disease: proposed imaging classification. Radiographics 2014;34: 2025e38. [25] Prabhu SR, Wilson DF. Evidence of Epstein-Barr virus association with head and neck cancers: a review. J Can Dent Assoc 2016;82:g2. [26] Fellner MD, Durand KA, Solernou V, Bosaleh A, Balbarrey Z, Garcia de Davila MT, et al. Epstein-Barr virus load in transplant patients: early detection of post-transplant lymphoproliferative disorders. Rev Argent Microbiol 2016;48:110e8. [27] Semenova T, Lupo J, Alain S, Perrin-Confort G, Grossi L, Dimier J, et al. Multicenter evaluation of whole-blood Epstein-Barr viral load standardization using the WHO international standard. J Clin Microbiol 2016;54:1746e50. [28] Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, Fontana F, et al. Clinical utility of Epstein-Barr virus viral load monitoring and risk factors for posttransplant lymphoproliferative disorders after kidney transplantation: a single-center, 10-year observational cohort study. Transplant Direct 2017;3:e182. [29] Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS guidelines. Br J Haematol 2010;149:693e705.
ABSTRACT Post-transplant lymphoproliferative disorder (PTLD) is an uncommon but fatal complication following both solid organ and hematologic stem cell transplantations. Epstein-Barr virus (EBV) has been considered a main etiologic agent causing PTLD, especially in the first year after transplantation. Extranodal manifestations are frequently found in PTLD; however, naso-orbital involvement in adults is rare. We report a case of EBV-associated PTLD of the naso-orbital region in a 72-year-old patient that occurred 10 years after kidney transplant. Six additional adults with naso-orbital PTLD were identified after completing this literature review, including 2 cases with eyelid swelling, 3 cases with proptosis, and 1 case with facial numbness. The majority of cases occurred after 1 year of transplantation and were associated with EBV. This report emphasizes recognizing PTLD as differential diagnosis in transplant recipients who present with naso-orbital symptoms.
P
OST-TRANSPLANT lymphoproliferative disorder (PTLD) is well-recognized as lymphoma that occurs following solid organ or hematopoietic stem cell transplantation [1]. Primary infection or reactivation of EpsteinBarr virus (EBV) plays an important role in the pathogenesis of PTLD, especially in the first year after transplantation. The majority of PTLD cases have lymph node involvement, and clinical manifestations can vary from asymptomatic to severe, resembling aggressive non-Hodgkin lymphoma [2]. Extranodal involvement of PTLD, including the gastrointestinal system, allograft, or central nervous system, is frequently documented [3,4]. However, extranodal manifestations of the head and neck, such as naso-orbital involvement among solid organ transplant recipients, are rarely reported in adults [5]. Here, we report a case of EBV-associated PTLD involving the naso-orbital region in an adult kidney transplant recipient who presented with bilateral proptosis and gaze palsy, mimicking invasive fungal infection. Characteristics and outcomes of naso-orbital involvement of PTLD in adults are also demonstrated in another 6 cases identified after extensive literature review. ª 2020 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e5 (2020)
CASE REPORT A 72-year-old man with a history of end-stage renal disease due to hypertension underwent a cadaveric kidney transplant 10 years prior to hospitalization. His post-transplant course had been uneventful without significant infection or allograft rejection. Maintenance immunosuppressive agents included cyclosporine A 125 mg/d, mycophenolate mofetil (MMF) 1000 mg/d, and prednisolone 2.5 mg every other day. He was transferred from a local hospital to our institute with progressive painful swelling of both eyes for 3 weeks. He denied a history of fever, nasal congestion, or visual disturbance. Physical examination revealed proptosis with chemosis of both eyes and bulging of soft palate. Visual acuity and fundoscopic examination were normal, but eye movement was limited in all directions. Cervical lymph node was not palpable. Complete blood count showed a white blood count of 9280 cells/mL, including an absolute lymphocyte count of 3062 cells/mL. His creatinine level
*Address correspondence to Jakapat Vanichanan, Division of Infectious Disease, Department of Medicine, Faculty of Medicine, Chulalongkorn University, 1841 Rama IV Rd, Pathum Wan District, Bangkok, 10330, Thailand. Tel: þ66 81-654-4587; Fax: þ66 2-649-4000 (Ext. 80507). E-mail: [email protected] 0041-1345/20 https://doi.org/10.1016/j.transproceed.2020.01.047
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NIMITPANYA, LIMPANAVONGSAEN, UDOMKARNJANANUN ET AL
Fig 1. Axial and coronal T1-weighted (A and D), T2-weighted (B and E), and gadolinium-enhanced T1WI of the orbits (C and F). MRI showed enlargement of bilateral lacrimal glands (arrow), with isointense on T1WI and heterogeneous isohyperintense on T2WI. Heterogeneous enhancement could be seen on gadolinium-enhanced T1WI. T1WI, T1-weighted image; T2WI, T2-weighted image. was at his baseline (1.36 mg/dL), and liver function test was unremarkable. Since his symptoms were concerning for invasive fungal infection, liposomal amphotericin B and posaconazole were initiated. Serum EBV viral load was undetectable at the time of presentation. Magnetic resonance image (MRI) of the sinus and orbital area revealed symmetrical bilateral lacrimal glands enlargement with heterogeneous enhancement after gadolinium injection, resulting in proptosis of both eyes (Fig 1). Diffusion MRI showed low apparent diffusion coefficient, which was suggestive of highgrade malignancy or lymphoproliferative disorder. Multiple nodular enhancements at posterior auricular lymph nodes and the right parotid gland were also noted. There was no abnormality of structure including orbits, paranasal sinuses, and cavernous sinus. Nasal endoscopy demonstrated generalized inflammation of mucosa and necrotic tissue with crusting at right nasal septum. Endoscopic sinonasal biopsies of inferior turbinate, septum, and right lacrimal gland were performed. Pathologic studies of lacrimal gland and right nasal turbinate revealed extensive coagulative necrosis with atypical medium-sized round cell. Further immunohistochemistry stain was positive for CD20 and EBV-encoded small RNAs (EBERs) by in situ hybridization (Fig 2). The results were compatible with EBV-associated PTLD of lacrimal gland and nasal turbinate. The patient’s immunosuppressive regimen was adjusted including discontinuation of MMF, decreasing dose of prednisolone, and switching cyclosporine A to sirolimus. Further treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and corticosteroid (R-CHOP regimen) was scheduled in daycare
infusion clinic. Unfortunately, he did not return for a follow-up visit and died from an unknown cause.
REVIEW OF LITERATURE
After extensive literature review, a total of 7 adults with PTLD of the naso-orbital area, including our case, were identified, as demonstrated in Table 1 [6-10]. The median age of patients at presentation was 53 years old. The onset after transplantation varies from 4 to more than 10 years. All of them were solid organ transplant patients, including 3 kidney, 3 lung, and 1 heart transplant recipients. Lacrimal gland and paranasal sinus were the most common involved organs (43%) followed by orbital apex (29%). Among 6 cases with available EBER result, the majority (83%) had positive results. A total of 5 patients received either systemic or local therapy, and 4 patients had remission of PTLD. DISCUSSION
PTLD is the second most common malignancy in transplant recipients after nonmelanoma skin cancer [1,11]. The spectrum of PTLD ranges from self-limited benign diseases to aggressively disseminated lymphoid malignancy, which follow both solid organ transplant and hematopoietic stem cell transplantation [12]. According to the World Health
PTLD OF NASO-ORBITAL REGION
Organization (WHO) criteria, PTLD can be subclassified into 6 types including plasmacytic PTLD, infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma PTLD [13]. Overall, the prevalence of PTLD varies from 1% to 20% depending on EBV serology status, level of immunosuppression, type of transplanted organ, and genetic factors [14]. Cumulative 5-year incidence of PTLD among kidney transplant recipients appeared to be around 0.6%, which was the lowest among all types transplanted organs [15]. The majority of PTLD cases have lymph node involvement. However, extranodal involvement of PTLD including gastrointestinal tract, transplanted allografts, or central nervous system appears to be more frequent compared to lymphoma in nontransplant individual [8,16]. PTLD of the head and neck is more common and can be found in up to 25% of the pediatric population, whereas reports in adult recipients are relatively scarce [17,18]. Those patients usually manifest as mononucleosis-like syndrome characterized by fever with pharyngitis, tonsillar enlargement, and cervical lymphadenopathy [16,18]. Waldeyer ring and cervical lymph nodes are the most common sites of involvement in both adult and pediatric populations [5,17,19]. Naso-orbital PTLD has been rarely reported, especially in adults. Only 7 cases were identified, including our case, after extensive literature review. The incidence appeared to be lower compared to extranodal lymphoma of the head and neck in nontransplant patients, which ranged from 1.9 to 11.4 cases per year, and naso-orbital involvement accounted for less than 2% of all cases [20,21]. Lacrimal gland, orbital apex, and paranasal sinuses were commonly involved. Clinical presentation among those patients ranged from eyes swelling to proptosis, gaze paralysis, and cranial nerve
3
palsies, which resembled invasive fungal infection. Nevertheless, imaging studies such as computerized tomography or MRI can be used for distinguishing PTLD from invasive fungal infection. Absence of destruction to adjacent structures including bone, brain, and sinuses lessens the suspicion of invasive fungal sinusitis in those patients with nasoorbital PTLD [22]. Onset of PTLD expresses in bimodal distribution. Most of the cases occur within the first year after transplantation. The incidence then decreases and becomes stable 3 to 5 years after transplant [23,24]. EBV plays an important role in the pathogenesis of PTLD cases, especially those occurring within the first year of organ transplant. However, EBV-negative PTLD has been increasingly reported, especially in late onset (> 5 years after transplant) PTLD. Interesting, according to our review, the majority of nasoorbital PTLD occurred after 5 years, and almost all cases were EBV-associated since EBV is able to infect both lymphocytes and epithelial cells and has a strong association to lymphoma of the head and neck as well as nasopharyngeal carcinoma [25]. This unique feature is probably due to an abundance of EBV-infected cells of the nasopharyngeal area as the primary site of infection. Currently, whole blood and plasma quantitative EBV viral load (VL) have been used for the diagnosis of PTLD in some transplant centers. In our case, EBV VL was undetectable, despite definite diagnosis of PTLD in the patient. The utility of this assay remains questionable owing to the lack of standardization, poor diagnostic performance, and heterogeneity of the disease spectrum [26,27]. However, preemptive monitoring EBV VL in high-risk patients (especially Dþ/R- recipients) may be beneficial [28]. According to recommendation from the guidelines, reduction of immunosuppression is the most important
Fig 2. Histology of both right lacrimal gland (A) and turbinate (B) showed extensive coagulative necrosis with atypical medium-sized mature round cell (hematoxylin and eosin x60). In situ hybridization (C) showed positive staining for Epstein-Barr virus with EBER mRNA probe. Immunohistochemistry (D) was positive for CD20. EBER, Epstein-Barr viruseencoded small ribonucleic acid; mRNA, mitochondrial ribonucleic acid.
4
Table 1. Summary of Case Reports of PTLD With Naso-orbital Involvement in Adult Immunosuppressive Agents
71/M
Lung, unknown
Azathioprine, tacrolimus, and prednisolone
53/M
Lung, 7 years
Tacrolimus, MMF, and prednisolone
61/M
Heart, 42 months
Azathioprine
Progressive, asymmetric, bilateral proptosis with difficulty urination/3 months
53/M
Lung, 8 years
Tacrolimus, MMF, and prednisolone
49/M
Kidney, 10 years
Cyclosporine
Diplopia, left eye proptosis, left CN III, IV, V1, V2, VI palsy/2 days Bilateral upper lid swelling/2 weeks
45/F
Kidney, >10 years
Cyclosporine and prednisolone
72/M
Kidney, 10 years
MMF, cyclosporine, and prednisolone
Presentation/Onset
Involved Area
Left facial numbness with left Left posterior ethmoidal and V2 CN palsy/2 weeks sphenoid sinuses, left clivus and vidian canal, bilateral foramen rotundum Diplopia in all fields of gaze Left orbit extending to orbital and proptosis of the left apex, cavernous sinus globe/2 days
Right upper lid swelling and unable to wear contact lens/2 years Progressive bilateral proptosis with gaze palsy/ 3 weeks
EBER
Treatment
Negative
Radiotherapy, dosage reduction of tacrolimus, discontinue azathioprine,
Positive
Rituximab, orbital irradiation
Bilateral orbit extending to orbital apex, prostate gland
Unknown
Posterior ethmoidal and sphenoid sinuses
Positive
Bilateral lacrimal glands, cervical lymph nodes
Positive
Rituximab, orbital irradiation and change immunosuppression to cyclosporine and prednisone Rituximab, dosage reduction of tacrolimus, discontinue MMF Rituximab, discontinue cyclosporine
Right Lacrimal gland
Positive
Bilateral lacrimal glands, inferior turbinate, nasal septum, parotid glands and cervical lymph nodes
Positive
Mass excision and reduction of immunosuppression Dosage reduction of cyclosporine, substitute MMF with sirolimus
Outcome
Reference
Unknown
[6]
Remission, but no improvement of visual acuity and motility Death from PTLD
[7]
Complete clinical response except VI nerve palsy Remission, required hemodialysis after graft rejection Remission
[8]
Loss of follow-up and expired before RCHOP treatment
[7]
[9]
[10]
Present case
Abbreviations: CN, cranial nerve; EBER, Epstein-Barr viruseencoded small ribonucleic acid; F, female; M, male; MMF, mycophenolate mofetil; PTLD, posttransplant lymphoproliferative disorder; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; Tx, transplant.
NIMITPANYA, LIMPANAVONGSAEN, UDOMKARNJANANUN ET AL
Case
Tx Organ, Duration From Tx
PTLD OF NASO-ORBITAL REGION
management modality. Other treatment strategies including rituximab, chemotherapy, radiation, and surgical resection are also considered options in selective patients [29]. All except 1 patient from our review had reduction of immunosuppression, and of those 4 patients received rituximab, 1 patient underwent radiation, and none received chemotherapy. One patient underwent only surgical removal of the right lacrimal gland because of highly localized disease. The majority of cases (4 out of 7) had favorable outcomes after treatment. CONCLUSION
PTLD of the naso-orbital region is rarely reported and may have manifestations similar to invasive fungal infections. Imaging studies can help distinguish between those 2 conditions. Tissue diagnosis is crucially required, while diagnostic value of EBV VL is uncertain. Prompt recognition and early appropriate management are important and can significantly affect the outcomes of patients. ACKNOWLEDGMENTS The authors sincerely acknowledge the contribution of Dr Thamathorn Assanasen (Department of Pathology, Faculty of Medicine, Chulalongkorn University) and Dr Netsiri Dumrongpisutikul (Department of Radiology, Faculty of Medicine, Chulalongkorn University) for providing images during the process of manuscript preparation.
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