Case Report Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
Received: March 5, 2013 Accepted after revision: June 17, 2013 Published online: October 22, 2013
Angioimmunoblastic T Cell Lymphoma: An Unusual Presentation of Posttransplant Lymphoproliferative Disorder in a Pediatric Patient Teresa S. Kraus a Clare J. Twist b Brent T. Tan c
a
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Okla., Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Palo Alto, Calif., and c Department of Pathology, Stanford University, Stanford, Calif., USA
b
Key Words Posttransplant lymphoproliferative disorder · Angioimmunoblastic T cell lymphoma · Pediatric patients
Abstract Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy. © 2013 S. Karger AG, Basel
Introduction
Posttransplant lymphoproliferative disorders (PTLD) are a group of abnormal, usually Epstein-Barr virus (EBV)-associated, lymphoid proliferations occurring in immunosuppressed recipients of solid organ or hematopoietic stem cell transplants. The 2008 World Health Organization (WHO) classification separates PTLD into © 2013 S. Karger AG, Basel 0001–5792/14/1312–0095$39.50/0 E-Mail [email protected] www.karger.com/aha
early lesions (plasmacytic and infectious mononucleosislike lesions), polymorphic, monomorphic and classic Hodgkin types [1]. The majority of PTLD cases are B cell proliferations with the minority being T cell proliferations, while NK cell proliferations are rare [2]. Monomorphic PTLD fulfills the diagnostic criteria for B or NK/T cell lymphoma in an immunocompetent patient, and is further subclassified according to the WHO classification system for lymphomas [1, 3, 4]. Most cases of monomorphic PTLD are B cell lesions, the majority of which are EBV-positive [4, 5]. Monomorphic T cell PTLD is less common, comprising no more than 15% of PTLD cases in Western countries. T cell PTLD tends to occur later after transplant, and is EBV-negative in 60–80% of cases [4–6]. Reported subtypes of monomorphic T cell PTLD include peripheral T cell lymphoma NOS (nototherwise-specified), hepatosplenic T cell lymphoma, T lymphoblastic leukemia/lymphoma, anaplastic large cell lymphoma, adult T cell leukemia/lymphoma and large granular lymphocytic leukemia [4–7]. Monomorphic T cell PTLD appears to be particularly uncommon in the pediatric population, with few cases reported in the literature [5, 7–9]. In this report, we present an unusual case of angioimmunoblastic T cell lymphoma (AITL) in an 8-year-old boy after a heart transplant. Teresa S. Kraus, MD Department of Pathology University of Oklahoma Health Sciences Center 940 Stanton L. Young Blvd, BSMB 451, Oklahoma City, OK, 73104 (USA) E-Mail Teresa-Kraus @ ouhsc.edu
Clinical History An 8-year-old boy presented to our institution with a new onset of left-cranial third-nerve palsy, manifested by ptosis and diplopia. His medical history was significant for a heart transplant at the age of 2 years, primary ciliary dyskinesia, and hypersensitivity pneumonitis diagnosed approximately 4 months prior to presentation. His immunosuppressive regimen included mycophenolate mofetil, tacrolimus and prednisone. The patient had had a history of chronic lymphadenopathy and waxing/waning skin lesions for at least 1 year prior to this presentation, which had improved following steroid treatment for his hypersensitivity pneumonitis, but had recently worsened as the steroids were tapered. Upon examination, the patient had limited left eye movements with a dilated left pupil, and no other neurologic deficits. There was diffuse lymphadenopathy, with nodes of 3–4 cm in the axilla, without organomegaly. An excoriated papular rash was present, which was reportedly chronic but had recently worsened. A brain MRI showed contrast enhancement and thickening of the third cranial nerve, raising a radiologic differential diagnosis of infectious/inflammatory neuritis, sarcoidosis or a neoplastic process such as PTLD. Imaging by FDG-PET/CT demonstrated extensive hypermetabolic lymphadenopathy involving the cervical, bilateral axillary, mediastinal, hilar, retroperitoneal and iliac regions. Laboratory studies revealed a serum IgG level of 8,940 mg/dl (normal: 608–1,229 mg/dl), and no monoclonal bands were detected by serum protein electrophoresis. The CBC showed a hemoglobin concentration of 11.3 g/dl, a platelet count of 150 × 109/l and a WBC count of 13.8 × 109/l. A direct antiglobulin test (DAT) was positive. On review of the peripheral smear, approximately 50% of leukocytes were plasmacytoid cells. The eosinophil count was also increased at 13%. The CSF WBC count was 20/μl (normal: 0–10/μl), with 88% heterogeneous lymphocytes showing plasmacytoid and immunoblastic morphology. EBV polymerase chain reaction (PCR) was negative in the CSF and peripheral blood. Flow cytometric immunophenotyping was performed on the peripheral blood and CSF specimens, and bone marrow and axillary lymph node biopsies were subsequently performed.
Methods Four-color flow cytometric analysis was performed using a FACSCanto II flow cytometer using commercially available antibodies and FACSDiva analysis software (BD Biosciences, San Jose, Calif., USA). The percentage of events reactive with each monoclonal antibody was determined by comparison to isotype controls. Immunohistochemical stains were performed on 4-μm, formalin-fixed, paraffin-embedded (FFPE) sections with appropriate controls using automated stainers (Ventana XT autostainer, Ventana Medical Systems, Tucson, Ariz., USA and Leica Bond-Max autostainer, Leica Microsystems Inc., Buffalo Grove, Ill., USA). In situ hybridization for EBV-encoded small RNA, kappa and lambda was performed on FFPE sections using a Ventana Benchmark instrument running a standardized program of deparaffinization, hybridization with probe cocktails and detection with ISH iVIEW nitroblue tetrazolium (Ventana). PCR for immunoglobulin heavy chain, kappa light chain and T cell receptor beta and gamma gene rearrangements was performed on the bone marrow aspirate and
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Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
FFPE lymph node tissue using BIOMED-2 primers (InVivoScribe, San Diego, Calif., USA). The PCR products were resolved by capillary electrophoresis and the data were analyzed using GeneScan software (Applied Biosystems, Foster City, Calif., USA).
Results
Flow cytometric immunophenotyping revealed an abnormal T cell population expressing dim CD3, CD4, CD2 and CD5 with loss of CD7, present in both the cerebrospinal fluid (CSF; 34% of cells; fig. 1a, b) and peripheral blood (4% of cells; fig. 1c–e). A more comprehensive antibody panel was performed on the peripheral blood specimen, revealing brighter CD5 on the abnormal T cells compared to background T cells (fig. 1e) and coexpression of CD10 (data not shown). The abnormal T cells were detected in a background of plasmacytoid cells that expressed CD45, CD19 and bright CD38, and lacked surface light chains (12% in CSF and 19% in peripheral blood) (data not shown). This plasmacytoid population was also present in both the bone marrow and lymph node specimens and was shown to express polytypic cytoplasmic light chains (see below). The bone marrow showed trilineage hematopoiesis with erythroid hyperplasia, eosinophilia and numerous plasmacytoid cells (10%). The plasmacytoid cells were shown to be polytypic by in situ hybridization for kappa and lambda, and flow cytometric immunophenotyping detected a plasmacytoid population (6% of cells) expressing CD19 and bright CD38 and lacking surface light chains, but expressing polytypic cytoplasmic light chains. Examination of the HE-stained sections of the bone marrow core biopsy did not reveal a demonstrable lymphoid infiltrate; however, flow cytometric immunophenotyping revealed a small abnormal T cell population (1% of cells) expressing dim CD3 and CD4 with loss of CD7 similar to that detected in the peripheral blood and CSF (fig. 1f, g). Gene rearrangement studies by PCR showed multiple peaks in the TCR beta (fig. 2b, d) and TCR gamma genes (data not shown) that were interpreted as oligoclonal as well as a clonal IG kappa gene rearrangement (not shown). The axillary lymph node had a partially effaced architecture with scattered preserved germinal centers, and a mixed interfollicular infiltrate of small- to medium-sized lymphocytes, eosinophils, plasma cells and numerous arborizing vessels (fig. 3a, b). There were also scattered large atypical lymphoid cells with prominent nucleoli (fig. 3b). Kraus/Twist/Tan
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Fig. 1. a, b Flow cytometric immunophenotyping performed on the CSF revealed an abnormal population of T cells with a CD3(dim)+, CD4+, CD7– immunophenotype. c–e Flow cytometric immunophenotyping on the peripheral blood using a more extensive antibody panel detected a similar abnormal T cell population, with coexpression of CD10 (data not shown). The abnormal T cell population was also detected in the bone marrow (f, g) and axillary lymph node (h–j; note CD10 coexpression shown in j). a–j The population of interest is circled.
Fig. 2. Electropherograms for PCR for TCRβ rearrangements. The
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Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
x-axis indicates DNA length in nucleotides. The y-axis indicates relative fluorescence units. The InVivoScribe TCRβ assay was performed on the lymph node (a, c) and bone marrow (b, d). The primers and corresponding expected product sizes are shown above the x-axis. The arrows indicate clonal peaks that are identical in size in the lymph node and bone marrow.
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Fig. 3. a, b Axillary lymph node biopsy revealed partial effacement of the nodal architecture by a paracortical infiltrate of small lymphocytes, scattered large atypical lymphoid cells, plasma cells, eosinophils and histiocytes. HE. ×20, ×40. Proliferation of high endothelial venules in an arborizing pattern is seen. c Immunohistochemical staining for CD3 highlighted numerous small- to medium-sized T cells. ×40. d, e The T cell infiltrate showed coexpression of PD-1 and CD10. ×20. f A CD21 stain demonstrated an expansion of follicular dendritic cell meshworks beyond B cell follicles. ×10. g CD20-stained scattered large atypical B cells. ×40. h In situ hybridization for EBV was negative. ×20.
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Immunohistochemical stains showed the infiltrate to contain numerous small- to medium-sized CD3+ T cells with coexpression of PD-1 and CD10 (fig. 3c–e). CXCL13 was positive in a subset of these cells. CD21 highlighted an expansion of follicular dendritic cell meshworks beyond the follicles (fig. 3f). CD20 stained the B lymphocytes in the follicles as well as scattered large atypical B cells in the interfollicular region (fig. 3g). CD138 and 98
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CD79a highlighted scattered plasma cells and plasmacytoid cells. Both the large B cells and plasmacytoid cells were polyclonal, based on kappa and lambda protein stains and in situ hybridization for kappa and lambda. In situ hybridization for EBV and an immunohistochemical stain for HHV-8 were negative (fig. 3h). Flow cytometric immunophenotyping again showed an abnormal population of T cells (17% of cells) expressing dim CD3, Kraus/Twist/Tan
CD4 and CD10, with a loss of CD7 (fig. 1h–j). This population was identical to that detected in the peripheral blood, CSF and bone marrow (fig. 1a–g). In addition, a background of plasmacytoid cells expressing CD19 and bright CD38, and lacking surface light chains was also detected (4% of cells). Molecular studies were positive for TCR beta (fig. 2a, c) and TCR gamma gene rearrangements (data not shown), and many of the clonal peaks in the lymph node (fig. 2a, c) were also present in the bone marrow specimen (fig. 2b, d). A clonal IG kappa peak identical to the one detected in the marrow was also detected in the lymph node (not shown). The overall clinical, morphologic, immunophenotypic and molecular findings were consistent with a diagnosis of monomorphic T cell PTLD (angioimmunoblastic T cell lymphoma). The patient initiated treatment with cyclophosphamide, etoposide, vincristine and prednisone with intrathecal methotrexate, cytarabine and hydrocortisone. A CSF specimen prior to the initiation of chemotherapy revealed a WBC count of 51/μl with atypical lymphocytes and plasmacytoid cells present. A subsequent CSF evaluation on day 15 of systemic therapy (and following a single dose of intrathecal chemotherapy) was within normal limits. The patient’s cranial nerve palsy resolved soon after the initiation of systemic chemotherapy. Reimaging by FDG-PET/CT following three cycles of chemotherapy showed significant improvement in both the size and metabolic activity of the involved lymph nodes. Following six cycles of chemotherapy, the patient’s exam has essentially normalized, with resolution of his skin rash and palpable lymphadenopathy. He has tolerated the therapy well without any significant complications.
Discussion
T cell PTLD is distinctly uncommon in pediatric patients. In a 19-center study of 1,184 pediatric heart-transplant patients, Webber et al. [9] reported 1 case of T cell PTLD out of a total of 56 PTLD cases. In literature reviews published in 2004 and 2006, Lundell et al. [5] and Yang et al. [7] identified 14 and 17 reported cases of pediatric T cell PTLD, respectively, including peripheral T cell lymphoma, NOS, hepatosplenic gamma-delta T cell lymphoma, anaplastic large cell lymphoma and T lymphoblastic leukemia/lymphoma. AITL, previously known as angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) arising in the setting of a posttransplant lymphoproliferative disAngioimmunoblastic T Cell Lymphoma
order is extremely rare. To our knowledge, only 2 previous cases of transplant-associated AILD/AITL have been reported in the literature. Zutter et al. [10] reported a case of AILD in a 22-year-old patient after a bone marrow transplant for acute lymphoblastic leukemia. Miyazaki et al. [11] reported a case of AITL occurring in a 62-year-old female 4 months after an autologous stem cell transplant for follicular lymphoma. AITL was initially believed to be a nonneoplastic though potentially fatal lymphoproliferative disorder, possibly arising from an abnormal immune response [12]. It is now recognized as a peripheral T cell lymphoma with follicular helper T cell differentiation. Affected patients often present with a variety of systemic symptoms including generalized lymphadenopathy, hepatosplenomegaly and skin rash [1]. Eosinophilia, polyclonal hypergammaglobulinemia and hemolytic anemia (often DATpositive) are also common [12]. The symptomatology of AITL may vary; in this case, the patient had lymphadenopathy, skin rash, hypergammaglobulinemia and a positive DAT. Three histologic patterns of AITL have been described: pattern I (as seen in our case) in which residual hyperplastic B cell follicles are present, pattern II in which occasional regressed follicles are identified and pattern III where the nodal architecture is completely effaced and follicles are absent [13]. AITL is characterized by a proliferation of high endothelial venules, expanded follicular dendritic cell meshworks outside of the follicles and a polymorphous paracortical infiltrate composed of lymphocytes, eosinophils, plasma cells and histiocytes [1] (fig. 3a, b, f). The malignant cells, which in some cases represent only a small fraction of the infiltrate [14], are typically small- to medium-sized lymphocytes with variably pale cytoplasm, and have a follicular helper T cell phenotype, with expression of CD4, CD10, PD-1 and CXCL-13 (fig. 1, 3c–e). Increased numbers of large B cells are often present (fig. 3g) and in some cases, these form confluent sheets that meet the diagnostic criteria for diffuse large B cell lymphoma [1, 12]. The large B cells in AITL are EBV-positive in many but not all cases [15, 16]. Molecular studies reveal clonal TCR gene rearrangements in 75–90% of cases. Immunoglobulin gene rearrangements are also present in 25–30% of AITL, including cases where there is no morphologic evidence of large B cell lymphoma [1, 15]. Circulating CD10+ lymphoma cells, which may have dim or absent surface CD3 expression, can be detected by flow cytometry in patients with AITL [17, 18]. In this case, an abnormal CD10+, CD3(dim), CD5(bright) and Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
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CD7– T cell population was present in the peripheral blood as well as at other sites (fig. 1). A CD3(dim), CD7+ T cell population was also present at multiple sites (fig. 1b, d, i). Assessment of clonality in these T cell subsets by flow cytometric analysis of the TCR-Vβ repertoire would have been of interest to determine whether the CD3(dim), CD7+ population and CD3(dim), CD7– population were subsets of the same T cell clone; however, this assay was not available in our laboratory. The peripheral blood in patients with AITL may also show rouleaux, eosinophilia and polyclonal plasmacytosis, which may mimic plasma cell leukemia in extreme cases [19]. Bone marrow involvement is not uncommon, and reactive changes such as erythroid hyperplasia, polyclonal plasmacytosis, eosinophilia and hemophagocytosis are often present, even in the absence of marrow infiltration by lymphoma [12, 20]. AITL is a disease of the middle-aged and elderly, presenting at a median age of 60–65 years [14]. Very few pediatric cases of AILD/AITL have been described in the literature. In 1976, Howarth and Bird [21] reported a case of AILD with progression to ‘immunoblastic sarcoma’ in a 7-year-old boy. Fiorillo et al. [22] described clinical, laboratory and lymph node biopsy findings consistent with AILD in an 8-year-old boy, which spontaneously regressed over a 6-month period and did not recur during a 16-month follow-up period. de Terlizzi et al. [23] reported a case of a 14-month-old boy who presented with fever, lymphadenopathy, hepatosplenomegaly and a positive DAT. A lymph node biopsy was consistent with AILD, and the patient was initially treated with prednisone. Recurrences were treated with prednisone and later with prednisone and vincristine. The patient then presented with recurrent disease and positive serology for hepatitis B, and succumbed to hepatic failure 100 months after initial diagnosis. In a series of 27 patients with AITL by Lee et al. [24], 1 was a 17-year-old female and the remaining 26 were adults. In a study of nonanaplastic peripheral T cell lymphoma in pediatric patients, Kobayashi et al. [25] reported 1 case of AITL, occurring in a 14-year-old male, out of a total of 1,711 pediatric patients presenting with non-Hodgkin lymphoma over an 18-year period. Horneff et al. [26] reported a case of a 13-year-old girl presenting with rash, fever, lymphadenopathy and splenomegaly, who was diagnosed with AILD based on lymph node biopsy. Neurologic manifestations, as seen in our patient, have occasionally been reported in patients with AITL/AILD. In a study of 77 patients, Lachenal et al. [27] reported neurologic symptoms, including confusion, loss of hearing or 100
Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
vision, motor and sensory polyneuritis and aphasia, in 8 patients (10%). In 2 of these patients, tumor cells were identified in the CSF and lymphocytic meningoencephalitis was present in 1 patient. Peripheral neuropathy was suggested to represent an immune-mediated phenomenon in the affected patients. Ferrer et al. [28] and Sonobe et al. [29] each described patients with AILD/AILT and peripheral neuropathy wherein nerve biopsies showed histologic features suggestive of lymphomatous infiltration. Occasional cases of AILD/AITL arising in the setting of immunosuppressive/immunomodulatory therapy have been described in adults, mostly in patients being treated for autoimmune diseases. The implicated drugs include cyclophosphamide [30], arsenic [31], sulfasalazine [32], steroids and antimalarials [33]. Lymphoproliferative disorders mimicking AITL have been described in patients undergoing methotrexate therapy for rheumatoid arthritis [34]. The morphologic features of AITL can overlap with reactive conditions, including changes secondary to immunomodulatory therapy. Therefore, ancillary studies such as T cell clonality, immunostaining and/or flow cytometry to detect aberrancies such as CD10, along with evaluation of the clinical and laboratory features, are important when considering a diagnosis of AITL. In our case, a drug reaction was considered in the differential diagnosis; however, the clinical, histologic and immunophenotypic findings (including CD10 expression), detection of the presence of a T cell clone by PCR and the presence of the abnormal T cell population at multiple sites supported the diagnosis of AITL. In summary, we present an unusual manifestation of monomorphic T cell PTLD, i.e. AITL in a pediatric patient. Given the array of clinical and laboratory abnormalities that may be seen in AITL, this entity should be included in the differential diagnosis of rash, plasmacytosis and/or autoimmune manifestations in transplant recipients, particularly because it is often misdiagnosed as a reactive condition. The prognostic implications and optimal treatment of AITL-type T cell PTLD are not yet clear; however, increased awareness of this entity may lead to advances in clinical management in the future.
Disclosure Statement The authors declare no competing financial interests and did not receive any financial support.
Kraus/Twist/Tan
References 1 Swerdlow SH, International Agency for Research on Cancer, World Health Organization: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, International Agency for Research on Cancer, 2008. 2 Blaes AH, Morrison VA: Post-transplant lymphoproliferative disorders following solid-organ transplantation. Expert Rev Hematol 2010;3:35–44. 3 Tsao L, Hsi ED: The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med 2007; 131:1209–1218. 4 Morovic A, Jaffe ES, Raffeld M, Schrager JA: Metachronous EBV-associated B-cell and Tcell posttransplant lymphoproliferative disorders in a heart transplant recipient. Am J Surg Pathol 2009;33:149–154. 5 Lundell R, Elenitoba-Johnson KS, Lim MS: Tcell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient. Am J Surg Pathol 2004;28:967– 973. 6 Draoua HY, Tsao L, Mancini DM, Addonizio LJ, Bhagat G, Alobeid B: T-cell post-transplantation lymphoproliferative disorders after cardiac transplantation: a single institutional experience. Br J Haematol 2004; 127: 429–432. 7 Yang F, Li Y, Braylan R, Hunger SP, Yang LJ: Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation. Pediatr Blood Cancer 2008; 50: 415– 418. 8 Williams KM, Higman MA, Chen AR, Schwartz CL, Wharam M, Colombani P, Arceci RJ: Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma. Pediatr Blood Cancer 2008;50:667–670. 9 Webber SA, Naftel DC, Fricker FJ, Olesnevich P, Blume ED, Addonizio L, Kirklin JK, Canter CE: Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study. Lancet 2006;367:233–239. 10 Zutter MM, Martin PJ, Sale GE, Shulman HM, Fisher L, Thomas ED, Durnam DM: Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 1988;72: 520–529. 11 Miyazaki K, Masuya M, Yamaguchi M, Isaka S, Nakase K, Kobayashi T, Nakamura S, Shiku H: Angioimmunoblastic T-cell lymphoma occurring four months after autologous peripheral blood stem cell transplantation with high-dose chemotherapy for follicular lymphoma. Rinsho Ketsueki 2005;46:1065–1070. 12 de Leval L, Gisselbrecht C, Gaulard P: Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol 2010;148:673–689.
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13 Attygalle A, Al-Jehani R, Diss TC, Munson P, Liu H, Du MQ, Isaacson PG, Dogan A: Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 2002; 99: 627–633. 14 Iannitto E, Ferreri AJ, Minardi V, Tripodo C, Kreipe HH: Angioimmunoblastic T-cell lymphoma. Crit Rev Oncol Hematol 2008; 68: 264–271. 15 Attygalle AD, Kyriakou C, Dupuis J, Grogg KL, Diss TC, Wotherspoon AC, Chuang SS, Cabecadas J, Isaacson PG, Du MQ, Gaulard P, Dogan A: Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression. Am J Surg Pathol 2007;31:1077–1088. 16 Warnke RA, Jones D, Hsi ED: Morphologic and immunophenotypic variants of nodal Tcell lymphomas and T-cell lymphoma mimics. Am J Clin Pathol 2007;127:511–527. 17 Baseggio L, Berger F, Morel D, Delfau-Larue MH, Goedert G, Salles G, Magaud JP, Felman P: Identification of circulating CD10 positive T cells in angioimmunoblastic T-cell lymphoma. Leukemia 2006;20:296–303. 18 Diaz-Alderete A, Menarguez J, Alvarez-Doval A, Sabin P, Escudero A, Fernandez-Cruz E, Gil J: Lymphocyte immunophenotype of circulating angioimmunoblastic T-cell lymphoma cells. Br J Haematol 2006;134:347–348. 19 Ahsanuddin AN, Brynes RK, Li S: Peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia in patients with angioimmunoblastic T-cell lymphoma: report of 3 cases and review of the literature. Int J Clin Exp Pathol 2011;4:416–420. 20 Grogg KL, Morice WG, Macon WR: Spectrum of bone marrow findings in patients with angioimmunoblastic T-cell lymphoma. Br J Haematol 2007;137:416–422. 21 Howarth CB, Bird CC: Immunoblastic sarcoma arising in child with immunoblastic lymphadenopathy. Lancet 1976;2:747–748. 22 Fiorillo A, Pettinato G, Raia V, Migliorati R, Angrisani P, Buffolano W: Angioimmunoblastic lymphadenopathy with dysproteinemia: report of the first case in childhood evolving toward spontaneous remission. Cancer 1981;48:1611–1614. 23 de Terlizzi M, Toma MG, Santostasi T, Colella R, Ceci A, De Benedictis G: Angioimmunoblastic lymphadenopathy with dysproteinemia: report of a case in infancy with review of literature. Pediatr Hematol Oncol 1989;6:37–44.
24 Lee Y, Lee KW, Kim JH, Bang SM, Lee JS, Park BB, Kim WS, Suh C, Kang JH, Ryoo BY, Lee JH, Shin DB: Epstein-Barr virus-positivity in tumor has no correlation with the clinical outcomes of patients with angioimmunoblastic T-cell lymphoma. Korean J Intern Med 2008; 23:30–36. 25 Kobayashi R, Yamato K, Tanaka F, Takashima Y, Inada H, Kikuchi A, Kumagai MA, Sunami S, Nakagawa A, Fukano R, Fujita N, Mitsui T, Tsurusawa M, Mori T: Retrospective analysis of non-anaplastic peripheral Tcell lymphoma in pediatric patients in Japan. Pediatr Blood Cancer 2010;54:212–215. 26 Horneff G, Althaus C, Engelbrecht V, Wahn V: CNS complications in a girl with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Neuropediatrics 1996; 27: 219–222. 27 Lachenal F, Berger F, Ghesquieres H, Biron P, Hot A, Callet-Bauchu E, Chassagne C, Coiffier B, Durieu I, Rousset H, Salles G: Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients. Medicine (Baltimore) 2007;86:282–292. 28 Ferrer I, Vidaller A, Fernandez de Sevilla A, Martinez-Matos JA, Montero J, Romagosa V: Peripheral neuropathy associated with angioimmunoblastic lymphadenopathy. Clin Neurol Neurosurg 1988;90:159–162. 29 Sonobe M, Yasuda H, Okabe H, Terada M, Maeda K, Kawabata T, Kikkawa R: Neuropathy associated with angioimmunoblastic lymphadenopathy-like T-cell lymphoma. Intern Med 1998;37:631–634. 30 Yamamoto H, Miwa H, Kato Y, Nakamura S, Hara K, Nitta M: Angioimmunoblastic T cell lymphoma with an unusual proliferation of Epstein-Barr virus-associated large B cells arising in a patient with progressive systemic sclerosis. Acta Haematol 2005;114:108–112. 31 Offit K, Macris NT: Arsenic-associated angioimmunoblastic lymphadenopathy. Lancet 1985;1:220. 32 Pay S, Dinc A, Simsek I, Can C, Erdem H: Sulfasalazine-induced angioimmunoblastic lymphadenopathy developing in a patient with juvenile chronic arthritis. Rheumatol Int 2000;20:25–27. 33 Ozoran K, Turgay M, Kinikli G, Duman M, Tolunay O, Tokgoz G: Angioimmunoblastic lymphadenopathy with disproteinemia arising in a patient with rheumatoid arthritis. Scand J Rheumatol 1995;24:58–60. 34 Hatanaka K, Nakamura N, Kojima M, Ando K, Irie S, Bunno M, Nakamine H, Uekusa T: Methotrexate-associated lymphoproliferative disorders mimicking angioimmunoblastic Tcell lymphoma. Pathol Res Pract 2010; 206: 9–13.
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Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: March 5, 2013 Accepted after revision: June 17, 2013 Published online: October 22, 2013
Angioimmunoblastic T Cell Lymphoma: An Unusual Presentation of Posttransplant Lymphoproliferative Disorder in a Pediatric Patient Teresa S. Kraus a Clare J. Twist b Brent T. Tan c
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Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Okla., Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Palo Alto, Calif., and c Department of Pathology, Stanford University, Stanford, Calif., USA
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Key Words Posttransplant lymphoproliferative disorder · Angioimmunoblastic T cell lymphoma · Pediatric patients
Abstract Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy. © 2013 S. Karger AG, Basel
Introduction
Posttransplant lymphoproliferative disorders (PTLD) are a group of abnormal, usually Epstein-Barr virus (EBV)-associated, lymphoid proliferations occurring in immunosuppressed recipients of solid organ or hematopoietic stem cell transplants. The 2008 World Health Organization (WHO) classification separates PTLD into © 2013 S. Karger AG, Basel 0001–5792/14/1312–0095$39.50/0 E-Mail [email protected] www.karger.com/aha
early lesions (plasmacytic and infectious mononucleosislike lesions), polymorphic, monomorphic and classic Hodgkin types [1]. The majority of PTLD cases are B cell proliferations with the minority being T cell proliferations, while NK cell proliferations are rare [2]. Monomorphic PTLD fulfills the diagnostic criteria for B or NK/T cell lymphoma in an immunocompetent patient, and is further subclassified according to the WHO classification system for lymphomas [1, 3, 4]. Most cases of monomorphic PTLD are B cell lesions, the majority of which are EBV-positive [4, 5]. Monomorphic T cell PTLD is less common, comprising no more than 15% of PTLD cases in Western countries. T cell PTLD tends to occur later after transplant, and is EBV-negative in 60–80% of cases [4–6]. Reported subtypes of monomorphic T cell PTLD include peripheral T cell lymphoma NOS (nototherwise-specified), hepatosplenic T cell lymphoma, T lymphoblastic leukemia/lymphoma, anaplastic large cell lymphoma, adult T cell leukemia/lymphoma and large granular lymphocytic leukemia [4–7]. Monomorphic T cell PTLD appears to be particularly uncommon in the pediatric population, with few cases reported in the literature [5, 7–9]. In this report, we present an unusual case of angioimmunoblastic T cell lymphoma (AITL) in an 8-year-old boy after a heart transplant. Teresa S. Kraus, MD Department of Pathology University of Oklahoma Health Sciences Center 940 Stanton L. Young Blvd, BSMB 451, Oklahoma City, OK, 73104 (USA) E-Mail Teresa-Kraus @ ouhsc.edu
Clinical History An 8-year-old boy presented to our institution with a new onset of left-cranial third-nerve palsy, manifested by ptosis and diplopia. His medical history was significant for a heart transplant at the age of 2 years, primary ciliary dyskinesia, and hypersensitivity pneumonitis diagnosed approximately 4 months prior to presentation. His immunosuppressive regimen included mycophenolate mofetil, tacrolimus and prednisone. The patient had had a history of chronic lymphadenopathy and waxing/waning skin lesions for at least 1 year prior to this presentation, which had improved following steroid treatment for his hypersensitivity pneumonitis, but had recently worsened as the steroids were tapered. Upon examination, the patient had limited left eye movements with a dilated left pupil, and no other neurologic deficits. There was diffuse lymphadenopathy, with nodes of 3–4 cm in the axilla, without organomegaly. An excoriated papular rash was present, which was reportedly chronic but had recently worsened. A brain MRI showed contrast enhancement and thickening of the third cranial nerve, raising a radiologic differential diagnosis of infectious/inflammatory neuritis, sarcoidosis or a neoplastic process such as PTLD. Imaging by FDG-PET/CT demonstrated extensive hypermetabolic lymphadenopathy involving the cervical, bilateral axillary, mediastinal, hilar, retroperitoneal and iliac regions. Laboratory studies revealed a serum IgG level of 8,940 mg/dl (normal: 608–1,229 mg/dl), and no monoclonal bands were detected by serum protein electrophoresis. The CBC showed a hemoglobin concentration of 11.3 g/dl, a platelet count of 150 × 109/l and a WBC count of 13.8 × 109/l. A direct antiglobulin test (DAT) was positive. On review of the peripheral smear, approximately 50% of leukocytes were plasmacytoid cells. The eosinophil count was also increased at 13%. The CSF WBC count was 20/μl (normal: 0–10/μl), with 88% heterogeneous lymphocytes showing plasmacytoid and immunoblastic morphology. EBV polymerase chain reaction (PCR) was negative in the CSF and peripheral blood. Flow cytometric immunophenotyping was performed on the peripheral blood and CSF specimens, and bone marrow and axillary lymph node biopsies were subsequently performed.
Methods Four-color flow cytometric analysis was performed using a FACSCanto II flow cytometer using commercially available antibodies and FACSDiva analysis software (BD Biosciences, San Jose, Calif., USA). The percentage of events reactive with each monoclonal antibody was determined by comparison to isotype controls. Immunohistochemical stains were performed on 4-μm, formalin-fixed, paraffin-embedded (FFPE) sections with appropriate controls using automated stainers (Ventana XT autostainer, Ventana Medical Systems, Tucson, Ariz., USA and Leica Bond-Max autostainer, Leica Microsystems Inc., Buffalo Grove, Ill., USA). In situ hybridization for EBV-encoded small RNA, kappa and lambda was performed on FFPE sections using a Ventana Benchmark instrument running a standardized program of deparaffinization, hybridization with probe cocktails and detection with ISH iVIEW nitroblue tetrazolium (Ventana). PCR for immunoglobulin heavy chain, kappa light chain and T cell receptor beta and gamma gene rearrangements was performed on the bone marrow aspirate and
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FFPE lymph node tissue using BIOMED-2 primers (InVivoScribe, San Diego, Calif., USA). The PCR products were resolved by capillary electrophoresis and the data were analyzed using GeneScan software (Applied Biosystems, Foster City, Calif., USA).
Results
Flow cytometric immunophenotyping revealed an abnormal T cell population expressing dim CD3, CD4, CD2 and CD5 with loss of CD7, present in both the cerebrospinal fluid (CSF; 34% of cells; fig. 1a, b) and peripheral blood (4% of cells; fig. 1c–e). A more comprehensive antibody panel was performed on the peripheral blood specimen, revealing brighter CD5 on the abnormal T cells compared to background T cells (fig. 1e) and coexpression of CD10 (data not shown). The abnormal T cells were detected in a background of plasmacytoid cells that expressed CD45, CD19 and bright CD38, and lacked surface light chains (12% in CSF and 19% in peripheral blood) (data not shown). This plasmacytoid population was also present in both the bone marrow and lymph node specimens and was shown to express polytypic cytoplasmic light chains (see below). The bone marrow showed trilineage hematopoiesis with erythroid hyperplasia, eosinophilia and numerous plasmacytoid cells (10%). The plasmacytoid cells were shown to be polytypic by in situ hybridization for kappa and lambda, and flow cytometric immunophenotyping detected a plasmacytoid population (6% of cells) expressing CD19 and bright CD38 and lacking surface light chains, but expressing polytypic cytoplasmic light chains. Examination of the HE-stained sections of the bone marrow core biopsy did not reveal a demonstrable lymphoid infiltrate; however, flow cytometric immunophenotyping revealed a small abnormal T cell population (1% of cells) expressing dim CD3 and CD4 with loss of CD7 similar to that detected in the peripheral blood and CSF (fig. 1f, g). Gene rearrangement studies by PCR showed multiple peaks in the TCR beta (fig. 2b, d) and TCR gamma genes (data not shown) that were interpreted as oligoclonal as well as a clonal IG kappa gene rearrangement (not shown). The axillary lymph node had a partially effaced architecture with scattered preserved germinal centers, and a mixed interfollicular infiltrate of small- to medium-sized lymphocytes, eosinophils, plasma cells and numerous arborizing vessels (fig. 3a, b). There were also scattered large atypical lymphoid cells with prominent nucleoli (fig. 3b). Kraus/Twist/Tan
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Fig. 1. a, b Flow cytometric immunophenotyping performed on the CSF revealed an abnormal population of T cells with a CD3(dim)+, CD4+, CD7– immunophenotype. c–e Flow cytometric immunophenotyping on the peripheral blood using a more extensive antibody panel detected a similar abnormal T cell population, with coexpression of CD10 (data not shown). The abnormal T cell population was also detected in the bone marrow (f, g) and axillary lymph node (h–j; note CD10 coexpression shown in j). a–j The population of interest is circled.
Fig. 2. Electropherograms for PCR for TCRβ rearrangements. The
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Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
x-axis indicates DNA length in nucleotides. The y-axis indicates relative fluorescence units. The InVivoScribe TCRβ assay was performed on the lymph node (a, c) and bone marrow (b, d). The primers and corresponding expected product sizes are shown above the x-axis. The arrows indicate clonal peaks that are identical in size in the lymph node and bone marrow.
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Fig. 3. a, b Axillary lymph node biopsy revealed partial effacement of the nodal architecture by a paracortical infiltrate of small lymphocytes, scattered large atypical lymphoid cells, plasma cells, eosinophils and histiocytes. HE. ×20, ×40. Proliferation of high endothelial venules in an arborizing pattern is seen. c Immunohistochemical staining for CD3 highlighted numerous small- to medium-sized T cells. ×40. d, e The T cell infiltrate showed coexpression of PD-1 and CD10. ×20. f A CD21 stain demonstrated an expansion of follicular dendritic cell meshworks beyond B cell follicles. ×10. g CD20-stained scattered large atypical B cells. ×40. h In situ hybridization for EBV was negative. ×20.
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Immunohistochemical stains showed the infiltrate to contain numerous small- to medium-sized CD3+ T cells with coexpression of PD-1 and CD10 (fig. 3c–e). CXCL13 was positive in a subset of these cells. CD21 highlighted an expansion of follicular dendritic cell meshworks beyond the follicles (fig. 3f). CD20 stained the B lymphocytes in the follicles as well as scattered large atypical B cells in the interfollicular region (fig. 3g). CD138 and 98
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CD79a highlighted scattered plasma cells and plasmacytoid cells. Both the large B cells and plasmacytoid cells were polyclonal, based on kappa and lambda protein stains and in situ hybridization for kappa and lambda. In situ hybridization for EBV and an immunohistochemical stain for HHV-8 were negative (fig. 3h). Flow cytometric immunophenotyping again showed an abnormal population of T cells (17% of cells) expressing dim CD3, Kraus/Twist/Tan
CD4 and CD10, with a loss of CD7 (fig. 1h–j). This population was identical to that detected in the peripheral blood, CSF and bone marrow (fig. 1a–g). In addition, a background of plasmacytoid cells expressing CD19 and bright CD38, and lacking surface light chains was also detected (4% of cells). Molecular studies were positive for TCR beta (fig. 2a, c) and TCR gamma gene rearrangements (data not shown), and many of the clonal peaks in the lymph node (fig. 2a, c) were also present in the bone marrow specimen (fig. 2b, d). A clonal IG kappa peak identical to the one detected in the marrow was also detected in the lymph node (not shown). The overall clinical, morphologic, immunophenotypic and molecular findings were consistent with a diagnosis of monomorphic T cell PTLD (angioimmunoblastic T cell lymphoma). The patient initiated treatment with cyclophosphamide, etoposide, vincristine and prednisone with intrathecal methotrexate, cytarabine and hydrocortisone. A CSF specimen prior to the initiation of chemotherapy revealed a WBC count of 51/μl with atypical lymphocytes and plasmacytoid cells present. A subsequent CSF evaluation on day 15 of systemic therapy (and following a single dose of intrathecal chemotherapy) was within normal limits. The patient’s cranial nerve palsy resolved soon after the initiation of systemic chemotherapy. Reimaging by FDG-PET/CT following three cycles of chemotherapy showed significant improvement in both the size and metabolic activity of the involved lymph nodes. Following six cycles of chemotherapy, the patient’s exam has essentially normalized, with resolution of his skin rash and palpable lymphadenopathy. He has tolerated the therapy well without any significant complications.
Discussion
T cell PTLD is distinctly uncommon in pediatric patients. In a 19-center study of 1,184 pediatric heart-transplant patients, Webber et al. [9] reported 1 case of T cell PTLD out of a total of 56 PTLD cases. In literature reviews published in 2004 and 2006, Lundell et al. [5] and Yang et al. [7] identified 14 and 17 reported cases of pediatric T cell PTLD, respectively, including peripheral T cell lymphoma, NOS, hepatosplenic gamma-delta T cell lymphoma, anaplastic large cell lymphoma and T lymphoblastic leukemia/lymphoma. AITL, previously known as angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) arising in the setting of a posttransplant lymphoproliferative disAngioimmunoblastic T Cell Lymphoma
order is extremely rare. To our knowledge, only 2 previous cases of transplant-associated AILD/AITL have been reported in the literature. Zutter et al. [10] reported a case of AILD in a 22-year-old patient after a bone marrow transplant for acute lymphoblastic leukemia. Miyazaki et al. [11] reported a case of AITL occurring in a 62-year-old female 4 months after an autologous stem cell transplant for follicular lymphoma. AITL was initially believed to be a nonneoplastic though potentially fatal lymphoproliferative disorder, possibly arising from an abnormal immune response [12]. It is now recognized as a peripheral T cell lymphoma with follicular helper T cell differentiation. Affected patients often present with a variety of systemic symptoms including generalized lymphadenopathy, hepatosplenomegaly and skin rash [1]. Eosinophilia, polyclonal hypergammaglobulinemia and hemolytic anemia (often DATpositive) are also common [12]. The symptomatology of AITL may vary; in this case, the patient had lymphadenopathy, skin rash, hypergammaglobulinemia and a positive DAT. Three histologic patterns of AITL have been described: pattern I (as seen in our case) in which residual hyperplastic B cell follicles are present, pattern II in which occasional regressed follicles are identified and pattern III where the nodal architecture is completely effaced and follicles are absent [13]. AITL is characterized by a proliferation of high endothelial venules, expanded follicular dendritic cell meshworks outside of the follicles and a polymorphous paracortical infiltrate composed of lymphocytes, eosinophils, plasma cells and histiocytes [1] (fig. 3a, b, f). The malignant cells, which in some cases represent only a small fraction of the infiltrate [14], are typically small- to medium-sized lymphocytes with variably pale cytoplasm, and have a follicular helper T cell phenotype, with expression of CD4, CD10, PD-1 and CXCL-13 (fig. 1, 3c–e). Increased numbers of large B cells are often present (fig. 3g) and in some cases, these form confluent sheets that meet the diagnostic criteria for diffuse large B cell lymphoma [1, 12]. The large B cells in AITL are EBV-positive in many but not all cases [15, 16]. Molecular studies reveal clonal TCR gene rearrangements in 75–90% of cases. Immunoglobulin gene rearrangements are also present in 25–30% of AITL, including cases where there is no morphologic evidence of large B cell lymphoma [1, 15]. Circulating CD10+ lymphoma cells, which may have dim or absent surface CD3 expression, can be detected by flow cytometry in patients with AITL [17, 18]. In this case, an abnormal CD10+, CD3(dim), CD5(bright) and Acta Haematol 2014;131:95–101 DOI: 10.1159/000353783
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CD7– T cell population was present in the peripheral blood as well as at other sites (fig. 1). A CD3(dim), CD7+ T cell population was also present at multiple sites (fig. 1b, d, i). Assessment of clonality in these T cell subsets by flow cytometric analysis of the TCR-Vβ repertoire would have been of interest to determine whether the CD3(dim), CD7+ population and CD3(dim), CD7– population were subsets of the same T cell clone; however, this assay was not available in our laboratory. The peripheral blood in patients with AITL may also show rouleaux, eosinophilia and polyclonal plasmacytosis, which may mimic plasma cell leukemia in extreme cases [19]. Bone marrow involvement is not uncommon, and reactive changes such as erythroid hyperplasia, polyclonal plasmacytosis, eosinophilia and hemophagocytosis are often present, even in the absence of marrow infiltration by lymphoma [12, 20]. AITL is a disease of the middle-aged and elderly, presenting at a median age of 60–65 years [14]. Very few pediatric cases of AILD/AITL have been described in the literature. In 1976, Howarth and Bird [21] reported a case of AILD with progression to ‘immunoblastic sarcoma’ in a 7-year-old boy. Fiorillo et al. [22] described clinical, laboratory and lymph node biopsy findings consistent with AILD in an 8-year-old boy, which spontaneously regressed over a 6-month period and did not recur during a 16-month follow-up period. de Terlizzi et al. [23] reported a case of a 14-month-old boy who presented with fever, lymphadenopathy, hepatosplenomegaly and a positive DAT. A lymph node biopsy was consistent with AILD, and the patient was initially treated with prednisone. Recurrences were treated with prednisone and later with prednisone and vincristine. The patient then presented with recurrent disease and positive serology for hepatitis B, and succumbed to hepatic failure 100 months after initial diagnosis. In a series of 27 patients with AITL by Lee et al. [24], 1 was a 17-year-old female and the remaining 26 were adults. In a study of nonanaplastic peripheral T cell lymphoma in pediatric patients, Kobayashi et al. [25] reported 1 case of AITL, occurring in a 14-year-old male, out of a total of 1,711 pediatric patients presenting with non-Hodgkin lymphoma over an 18-year period. Horneff et al. [26] reported a case of a 13-year-old girl presenting with rash, fever, lymphadenopathy and splenomegaly, who was diagnosed with AILD based on lymph node biopsy. Neurologic manifestations, as seen in our patient, have occasionally been reported in patients with AITL/AILD. In a study of 77 patients, Lachenal et al. [27] reported neurologic symptoms, including confusion, loss of hearing or 100
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vision, motor and sensory polyneuritis and aphasia, in 8 patients (10%). In 2 of these patients, tumor cells were identified in the CSF and lymphocytic meningoencephalitis was present in 1 patient. Peripheral neuropathy was suggested to represent an immune-mediated phenomenon in the affected patients. Ferrer et al. [28] and Sonobe et al. [29] each described patients with AILD/AILT and peripheral neuropathy wherein nerve biopsies showed histologic features suggestive of lymphomatous infiltration. Occasional cases of AILD/AITL arising in the setting of immunosuppressive/immunomodulatory therapy have been described in adults, mostly in patients being treated for autoimmune diseases. The implicated drugs include cyclophosphamide [30], arsenic [31], sulfasalazine [32], steroids and antimalarials [33]. Lymphoproliferative disorders mimicking AITL have been described in patients undergoing methotrexate therapy for rheumatoid arthritis [34]. The morphologic features of AITL can overlap with reactive conditions, including changes secondary to immunomodulatory therapy. Therefore, ancillary studies such as T cell clonality, immunostaining and/or flow cytometry to detect aberrancies such as CD10, along with evaluation of the clinical and laboratory features, are important when considering a diagnosis of AITL. In our case, a drug reaction was considered in the differential diagnosis; however, the clinical, histologic and immunophenotypic findings (including CD10 expression), detection of the presence of a T cell clone by PCR and the presence of the abnormal T cell population at multiple sites supported the diagnosis of AITL. In summary, we present an unusual manifestation of monomorphic T cell PTLD, i.e. AITL in a pediatric patient. Given the array of clinical and laboratory abnormalities that may be seen in AITL, this entity should be included in the differential diagnosis of rash, plasmacytosis and/or autoimmune manifestations in transplant recipients, particularly because it is often misdiagnosed as a reactive condition. The prognostic implications and optimal treatment of AITL-type T cell PTLD are not yet clear; however, increased awareness of this entity may lead to advances in clinical management in the future.
Disclosure Statement The authors declare no competing financial interests and did not receive any financial support.
Kraus/Twist/Tan
References 1 Swerdlow SH, International Agency for Research on Cancer, World Health Organization: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, International Agency for Research on Cancer, 2008. 2 Blaes AH, Morrison VA: Post-transplant lymphoproliferative disorders following solid-organ transplantation. Expert Rev Hematol 2010;3:35–44. 3 Tsao L, Hsi ED: The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med 2007; 131:1209–1218. 4 Morovic A, Jaffe ES, Raffeld M, Schrager JA: Metachronous EBV-associated B-cell and Tcell posttransplant lymphoproliferative disorders in a heart transplant recipient. Am J Surg Pathol 2009;33:149–154. 5 Lundell R, Elenitoba-Johnson KS, Lim MS: Tcell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient. Am J Surg Pathol 2004;28:967– 973. 6 Draoua HY, Tsao L, Mancini DM, Addonizio LJ, Bhagat G, Alobeid B: T-cell post-transplantation lymphoproliferative disorders after cardiac transplantation: a single institutional experience. Br J Haematol 2004; 127: 429–432. 7 Yang F, Li Y, Braylan R, Hunger SP, Yang LJ: Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation. Pediatr Blood Cancer 2008; 50: 415– 418. 8 Williams KM, Higman MA, Chen AR, Schwartz CL, Wharam M, Colombani P, Arceci RJ: Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma. Pediatr Blood Cancer 2008;50:667–670. 9 Webber SA, Naftel DC, Fricker FJ, Olesnevich P, Blume ED, Addonizio L, Kirklin JK, Canter CE: Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study. Lancet 2006;367:233–239. 10 Zutter MM, Martin PJ, Sale GE, Shulman HM, Fisher L, Thomas ED, Durnam DM: Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 1988;72: 520–529. 11 Miyazaki K, Masuya M, Yamaguchi M, Isaka S, Nakase K, Kobayashi T, Nakamura S, Shiku H: Angioimmunoblastic T-cell lymphoma occurring four months after autologous peripheral blood stem cell transplantation with high-dose chemotherapy for follicular lymphoma. Rinsho Ketsueki 2005;46:1065–1070. 12 de Leval L, Gisselbrecht C, Gaulard P: Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol 2010;148:673–689.
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13 Attygalle A, Al-Jehani R, Diss TC, Munson P, Liu H, Du MQ, Isaacson PG, Dogan A: Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 2002; 99: 627–633. 14 Iannitto E, Ferreri AJ, Minardi V, Tripodo C, Kreipe HH: Angioimmunoblastic T-cell lymphoma. Crit Rev Oncol Hematol 2008; 68: 264–271. 15 Attygalle AD, Kyriakou C, Dupuis J, Grogg KL, Diss TC, Wotherspoon AC, Chuang SS, Cabecadas J, Isaacson PG, Du MQ, Gaulard P, Dogan A: Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression. Am J Surg Pathol 2007;31:1077–1088. 16 Warnke RA, Jones D, Hsi ED: Morphologic and immunophenotypic variants of nodal Tcell lymphomas and T-cell lymphoma mimics. Am J Clin Pathol 2007;127:511–527. 17 Baseggio L, Berger F, Morel D, Delfau-Larue MH, Goedert G, Salles G, Magaud JP, Felman P: Identification of circulating CD10 positive T cells in angioimmunoblastic T-cell lymphoma. Leukemia 2006;20:296–303. 18 Diaz-Alderete A, Menarguez J, Alvarez-Doval A, Sabin P, Escudero A, Fernandez-Cruz E, Gil J: Lymphocyte immunophenotype of circulating angioimmunoblastic T-cell lymphoma cells. Br J Haematol 2006;134:347–348. 19 Ahsanuddin AN, Brynes RK, Li S: Peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia in patients with angioimmunoblastic T-cell lymphoma: report of 3 cases and review of the literature. Int J Clin Exp Pathol 2011;4:416–420. 20 Grogg KL, Morice WG, Macon WR: Spectrum of bone marrow findings in patients with angioimmunoblastic T-cell lymphoma. Br J Haematol 2007;137:416–422. 21 Howarth CB, Bird CC: Immunoblastic sarcoma arising in child with immunoblastic lymphadenopathy. Lancet 1976;2:747–748. 22 Fiorillo A, Pettinato G, Raia V, Migliorati R, Angrisani P, Buffolano W: Angioimmunoblastic lymphadenopathy with dysproteinemia: report of the first case in childhood evolving toward spontaneous remission. Cancer 1981;48:1611–1614. 23 de Terlizzi M, Toma MG, Santostasi T, Colella R, Ceci A, De Benedictis G: Angioimmunoblastic lymphadenopathy with dysproteinemia: report of a case in infancy with review of literature. Pediatr Hematol Oncol 1989;6:37–44.
24 Lee Y, Lee KW, Kim JH, Bang SM, Lee JS, Park BB, Kim WS, Suh C, Kang JH, Ryoo BY, Lee JH, Shin DB: Epstein-Barr virus-positivity in tumor has no correlation with the clinical outcomes of patients with angioimmunoblastic T-cell lymphoma. Korean J Intern Med 2008; 23:30–36. 25 Kobayashi R, Yamato K, Tanaka F, Takashima Y, Inada H, Kikuchi A, Kumagai MA, Sunami S, Nakagawa A, Fukano R, Fujita N, Mitsui T, Tsurusawa M, Mori T: Retrospective analysis of non-anaplastic peripheral Tcell lymphoma in pediatric patients in Japan. Pediatr Blood Cancer 2010;54:212–215. 26 Horneff G, Althaus C, Engelbrecht V, Wahn V: CNS complications in a girl with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Neuropediatrics 1996; 27: 219–222. 27 Lachenal F, Berger F, Ghesquieres H, Biron P, Hot A, Callet-Bauchu E, Chassagne C, Coiffier B, Durieu I, Rousset H, Salles G: Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients. Medicine (Baltimore) 2007;86:282–292. 28 Ferrer I, Vidaller A, Fernandez de Sevilla A, Martinez-Matos JA, Montero J, Romagosa V: Peripheral neuropathy associated with angioimmunoblastic lymphadenopathy. Clin Neurol Neurosurg 1988;90:159–162. 29 Sonobe M, Yasuda H, Okabe H, Terada M, Maeda K, Kawabata T, Kikkawa R: Neuropathy associated with angioimmunoblastic lymphadenopathy-like T-cell lymphoma. Intern Med 1998;37:631–634. 30 Yamamoto H, Miwa H, Kato Y, Nakamura S, Hara K, Nitta M: Angioimmunoblastic T cell lymphoma with an unusual proliferation of Epstein-Barr virus-associated large B cells arising in a patient with progressive systemic sclerosis. Acta Haematol 2005;114:108–112. 31 Offit K, Macris NT: Arsenic-associated angioimmunoblastic lymphadenopathy. Lancet 1985;1:220. 32 Pay S, Dinc A, Simsek I, Can C, Erdem H: Sulfasalazine-induced angioimmunoblastic lymphadenopathy developing in a patient with juvenile chronic arthritis. Rheumatol Int 2000;20:25–27. 33 Ozoran K, Turgay M, Kinikli G, Duman M, Tolunay O, Tokgoz G: Angioimmunoblastic lymphadenopathy with disproteinemia arising in a patient with rheumatoid arthritis. Scand J Rheumatol 1995;24:58–60. 34 Hatanaka K, Nakamura N, Kojima M, Ando K, Irie S, Bunno M, Nakamine H, Uekusa T: Methotrexate-associated lymphoproliferative disorders mimicking angioimmunoblastic Tcell lymphoma. Pathol Res Pract 2010; 206: 9–13.
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Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
