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Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma a
b
c
d
Florence Roufosse , Laurence de Leval , Han van Krieken & Marcel van Deuren a
Department of Internal Medicine, Hôpital Erasme, Brussels and Institute for Medical Immunology, Gosselies, Université Libre de Bruxelles, Belgium b
Service de Pathologie Clinique, Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland c
Department of Pathology
d
Click for updates
Department of General Internal Medicine and N4i Center for Immune-deficiency and Autoinflammation, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Published online: 24 Jun 2015.
To cite this article: Florence Roufosse, Laurence de Leval, Han van Krieken & Marcel van Deuren (2015) Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma, Leukemia & Lymphoma, 56:6, 1891-1894, DOI: 10.3109/10428194.2014.976823 To link to this article: http://dx.doi.org/10.3109/10428194.2014.976823
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, June 2015; 56(6): 1891–1894 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.976823
LETTER TO THE EDITOR
Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma Florence Roufosse1, Laurence de Leval2, Han van Krieken3 & Marcel van Deuren4 1Department of Internal Medicine, Hôpital Erasme, Brussels and Institute for Medical Immunology, Gosselies, Université Libre
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de Bruxelles, Belgium, 2Service de Pathologie Clinique, Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland and 3Department of Pathology and 4Department of General Internal Medicine and N4i Center for Immune-deficiency and Auto-inflammation, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Lymphocytic variant hypereosinophilic syndrome (L-HES) is a benign T-cell lymphoproliferative disorder, wherein clonal T-cells often display a CD3 ⫺ CD4⫹ phenotype and produce large amounts of interleukin (IL)-5, resulting in marked hypereosinophilia [1]. Patients most commonly present with cutaneous manifestations. The association of episodic angioedema, fever and elevated immunoglobulin M (IgM) levels with hypereosinophilia characterizes Gleich syndrome, which has a reputedly favorable outcome in terms of eosinophil-mediated end-organ damage [2]. However, this clinically defined entity represents one mode of expression of L-HES, which is known to be associated with an increased risk of developing peripheral T-cell lymphoma, generally many years after detection of hypereosinophilia [1]. Herein, we report the first case of angioimmunoblastic T-cell lymphoma (AITL) developing in a patient with treatment-refractory, CD3 ⫺ CD4⫹ T-cell-associated Gleich syndrome. A 49-year old female Caucasian patient with a past medical history of anorexia nervosa, depression and breast implants first presented in 2006 with intense fatigue. Blood testing revealed marked polyclonal hypergammaglobulinemia and eosinophilia, and comprehensive etiological investigations ruled out parasitosis, drug allergy, cancer, immunodeficiency and vasculitis. Several months later, she developed recurrent episodes of fever (⬎ 39°C) and angioedema with 5–9 kg weight gain (baseline weight 44 kg), associated with myalgia and stiffness around the pelvic girdle, night sweats and pruritis. Routine biology showed a normal total white blood cell count (7.3 ⫻ 109/L, 38% neutrophils, 27% lymphocytes) with persistent hypereosinophilia (28%, absolute count 2–3.6 ⫻ 109/L) and polyclonal hypergammaglobulinemia (IgG 55.4 g/L, IgM 14.4 g/L). Serum IgE level was moderately increased (457 U/mL), vitamin B12 and tryptase were normal. Bone marrow aspirate showed increased eosinophils and a normal plasma cell count; cytogenetic testing was normal, including fluorescence in situ hybridization (FISH) for CHIC2. A fluorodeoxyglucose positron emission tomography
scan with whole-body computed tomography (FDG-PET CT) showed several small hypermetabolic lymph nodes (LNs) in the pelvis and enhancement of pertrochanteric muscles. Diagnosis of Gleich syndrome was proposed, and T-cell analyses revealed a small population of clonal CD3 ⫺ CD4⫹ T-cells in peripheral blood and bone marrow (Table I). The CD3 ⫺ CD4⫹ cells displayed increased helper T-cell type 2 (Th2) cytokine expression by flow cytometry (17.8% IL-5⫹, 18% IL-4 ⫹ and 14% IL-13 ⫹ cells), establishing the diagnosis of L-HES, further corroborated by a markedly increased serum thymus and activation-regulated chemokine (TARC) level (390 000 pg/mL, normal range 109–696). Serum IL-5 levels were normal at baseline (⬍ 2 pg/mL), but reached 521 pg/mL during a flare. Treatment with prednisone was initiated (0.5 mg/kg/ day), with prompt normalization of eosinophils, although angioedema and CD3 ⫺ CD4⫹ cells persisted. Severe psychiatric side effects mandated interruption of maintenance corticosteroid therapy, and prednisone (maximal dose 30 mg daily) was given intermittently, only during flares, without clear-cut clinical benefit. From 2007 to 2011, the disease worsened progressively: eosinophilia increased (15 ⫻ 109/L), and the frequency and severity of flares increased. Various agents (cyclosporine, tacrolimus, interferon-alpha/gamma, imatinib, IL-1 receptor antagonist, cyclophosphamide) were administered unsuccessfully, and the proportion of blood CD3 ⫺ CD4⫹ cells progressively increased. In 2011, she was re-evaluated extensively before initiation of treatment with mepolizumab, a monoclonal anti-IL-5 antibody shown to be an equally effective corticosteroid-sparing agent in patients with L-HES and idiopathic HES [3]. Although the number of small hypermetabolic LNs had increased, bone marrow and LN biopsies showed no evidence of lymphoma [Table I, Figure 1(A)], and monthly intravenous infusions of 750 mg mepolizumab were initiated in December on a compassionate-use basis (NCT00244686), while prednisone treatment was maintained at 5 mg daily. Eosinophil levels declined rapidly, and a clear-cut regression of angioedema
Correspondence: Florence Roufosse, Hôpital Erasme, Department of Internal Medicine, 808 Route de Lennik, 1070 Brussels, Belgium. Tel: 00-32-2-555-3806. Fax: 00-32-2-555-3211. E-mail: [email protected] Received 19 September 2014; revised 5 October 2014; accepted 9 October 2014
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Table I. Sequential investigations in a patient with lymphocytic variant hypereosinophilic syndrome who developed angioimmunoblastic T-cell lymphoma. 2006–2007 (diagnosis) Ly phenotyping*, % (⫻ 109/L) CD3 ⫺ CD4⫹ TCR vβ/γ gene rearrangement
March 2011 (before anti-IL-5)
Summer 2012 (progression to AITL)
PB: 2% (0.03), BM: 1.5%
PB: 7–9% (0.15–0.19), BM: not done
PB: 19% (0.52), BM: nl T- and B-cell distribution
PB: 7.8% (0.06), BM: not done
PB: Sorted CD3 ⫺ CD4⫹ cells polyclonal Not done
BM: sorted CD3 ⫺ CD4⫹ cells clonal
PB, BM: not done, LN: polyclonal
PB: same clone as in 2008‡, LN: same clone as in 2008
46,XX
46,XX
Thoraco-abdominal CT scan
Axillary and para-aortic LNs (infracentimetric)
Numerous small pelvic LNs (unchanged)
FDG-PET CT†
Small pelvic LNs; myositis (hips)
Unchanged inguinal and iliac LNs; myositis (hips)
BM histology
Abundant eosinophils
Abundant eosinophils
LN histology
Not done
Not done
EBV documentation
Not done
Not done
Thickening of subcutaneous and intra-abdominal fat; small unchanged cervical, axillary, para-aortic and pelvic LNs Increased number of small LNs (cervical, axillary, mediastinal, retroperitoneal, pelvic); myositis (hips); spleen Abundant eosinophils, normal maturation Axillary: preserved architecture, abundant eosinophils, no atypical ly; granulomatous reaction toward leakage of breast implant material Axillary LN: scattered small EBER-positive cells (reactivation)
46,XX,t(1;5)(p36.1;p13) [4]/46,XX,t(1;5) (p36.1;p13),del(10)(q2?5) [7]/46,XX[19] Unchanged cervical, axillary and mediastinal lymph nodes; small condensation in left lung, inferior lobe
Karyotype
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November 2008
Numerous new intensely FDG-avid enlarged lymph nodes above and below diaphragm; solitary lesion in left lung, inferior lobe Absence of atypical lymphoid cells Cervical: angioimmunoblastic T-cell lymphoma, most atypical cells CD3 ⫹ CD4⫺ CD10 ⫹ CD45RO⫹ CD7 ⫺ PD-1 ⫹ ICOS⫹ BCL-6⫹ Cervical LN: numerous large EBER-positive B cells
BM, bone marrow; CT, computed tomography; EBER, Epstein–Barr virus encoded small RNAs; EBV, Epstein–Barr virus; FDG-PET, fluorodeoxyglucose positron emission tomography; LN, lymph node; Ly, lymphocyte; nl, normal; PB, peripheral blood; TCR, T-cell receptor. *Lymphocyte phenotypes were assessed by flow cytometry in blood and bone marrow, except for the bone marrow biopsy in March 2011, where qualitative results of immunohistochemistry are given. †Hypermetabolic sites are described. ‡Confirmed by sequencing.
was observed. The absolute counts of CD3 ⫺ CD4⫹ T cells in peripheral blood decreased significantly. Surprisingly, serum IgG, IgE and TARC levels also decreased, suggesting that IL-5 -targeted eosinophil-depleting therapy may indirectly affect cells known to functionally depend on and/or interact with eosinophils (e.g. plasma cells or resident cells [4,5]). In June 2012, when she presented for her sixth mepolizumab infusion, a single enlarged cervical LN was found at physical examination; there were no associated systemic signs or symptoms. The LN (3 ⫻ 2 ⫻ 2 cm) was excised, and pathological examination [Figure 1(B)] revealed complete architectural effacement by diffuse lymphoproliferation in association with an abundant histiocytic infiltrate, scattered plasma cells and occasional eosinophils. The lymphoid infiltrate extended into the surrounding tissues, and comprised a population of atypical medium-sized cells as well as scattered large cells. The atypical lymphoid cells stained positively for T-cell antigens CD2, CD3 and CD5 but negatively for CD4 and CD7 (Table I). Scattered cells were positive for CXCL13, and large lymphoid cells were positive for CD20, CD79a and CD30. Epstein–Barr virus (EBV) encoded small RNA (EBER)-staining showed the presence of EBER in the latter. Pathological diagnosis was unequivocally AITL. Polymerase chain reaction (PCR) studies evidenced an identical monoclonal TCRG gene rearrangement in both the LN and blood, and this was the same clone as already present in the
bone marrow in 2008 (Table I). Within weeks, she developed generalized lymphadenopathy and itching, and treatment with R-CHOP was initiated (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisolone), to target both T-cell lymphoma cells and the blastic EBER-positive CD20 ⫹ B lymphoid component. Disease progressed despite eight courses of R-CHOP, her general status further worsened due to infectious complications and she died in palliative care. This case history is remarkable in that, although T-cell lymphoma has already been documented in patients with L-HES [1,6], AITL has not yet been reported in this setting, and we provide well-documented sequential investigations indicating a possible link between the clonal CD3 CD4 ⫹ T-cells that characterized disease for 6 years, and the lymphoid malignancy. AITL is a rare hematological neoplasm derived from follicular helper T-cells (TFH) [7], which may be accompanied by hypereosinophilia in 32–50% of cases, and occasionally presents with circulating CD3 ⫺ CD4⫹ T-cells [8]. Thorough sequential work-up of our patient from 2006 to 2011 argues strongly against occult pre-existing AITL as the underlying cause of prolonged hypereosinophilia, but rather suggests that AITL developed secondarily in a patient with longstanding L-HES. Indeed, the first biopsy of a hypermetabolic LN, performed a year before AITL developed showed no hyperplastic follicles or any other evidence for AITL. It has
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L-HES progressing to AITL
Figure 1. Sequential lymph node biopsies in a patient with lymphocytic variant hypereosinophilic syndrome who developed angioimmunoblastic T-cell lymphoma. A small hypermetabolic axillary lymph node was excised in 2011, before initiation of mepolizumab treatment (A). Hematoxylin and eosin staining shows an inflammatory infiltrate mostly composed of small lymphocytes and plasma cells, in close proximity to small fragments of silicone (arrow-heads) related to breast implants in place since 1990. In 2012, she developed angioimmunoblastic T-cell lymphoma (BA–BD). Biopsy of an enlarged lymph node showed an atypical lymphoid infiltrate composed of medium-sized cells plus scattered blasts and plasma cells in association with abundant epithelioid histiocytes (BA, hematoxylin and eosin). The atypical lymphoid cells were positive for CD10 (BB), ICOS (BC) and PD1 (BD) (BB–BD, immunoperoxidase).
been shown by others that histological changes do occur during the AITL disease course, but T-cell abnormalities remain stable from early limited nodal involvement to more typical AITL patterns [9]. In addition, the rapid progression observed within weeks after the appearance of the transformed cervical LN in 2012 is consistent with the aggressive
disease course of AITL, contrasting with the prolonged stability of LN size and distribution prior to AITL diagnosis. An obvious question is whether the transformed cells derive from the CD3 ⫺ CD4⫹ T-cell clone driving L-HES, as previously reported in a patient with L-HES who developed peripheral T-cell lymphoma unspecified (PTCL-U),
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and whose malignant cells conserved the CD3 ⫺ CD4⫹ phenotype and were shown to share many gene-expression alterations with the pre-malignant cells [10]. The TCR gene rearrangement pattern on the AITL-biopsy material was identical to that observed in purified benign CD3 ⫺ CD4⫹ cells 4 years earlier, suggesting that these cells may indeed have become the malignant clone. Alternatively, untransformed “by-stander” L-HES-associated CD3 ⫺ CD4⫹ cells may have homed to AITL tissue in response to local TARC production by accessory cells [11], accounting for the T-cell receptor (TCR) gene rearrangement findings on the LN biopsy and the decreased CD3 ⫺ CD4⫹ cell counts observed in peripheral blood as lymphoma developed. This hypothesis is supported by the fact that, in contrast to malignant cells characterizing AITL, CD3 ⫺ CD4⫹ cells appear not to derive from TFH cells; peripheral blood CD3 ⫺ CD4⫹ cells from our patient showed negative staining for TFH markers (ICOS, CXCR5, IL-21) by flow cytometry (not shown), and mRNA for these markers was not shown to be overexpressed by CD3 ⫺ CD4⫹ cells from three patients with L-HES in our previous study [10]. Finally, it is conceivable that the consecutive occurrence of L-HES, then AITL, in our patient reflects an as-of-yet unexplained predisposition to clonal T-cell lymphoproliferative disease, as suggested by another report wherein distinct TCR gene rearrangement patterns were observed over time in a patient who first presented with HES, and then developed CD30 ⫹ anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma [12]. The second unresolved issue pertains to the factors that may have contributed to disease progression. Although the most likely scenario is step-wise accumulation of cytogenetic perturbations in a patient with initially benign clonal T-cell lymphoproliferative disease, the potential role of therapeutic eosinophil depletion and/or EBV-driven transformation deserves attention. The fact that this patient progressed rapidly when hypereosinophilia was finally controlled by mepolizumab raises the possibility that eosinophils were regulating growth of the T-cell clone, thereby contributing to tumor surveillance. A recent in vitro study has indeed shown that eosinophils inhibit proliferation and cytokine production by CD3 ⫺ CD4⫹ T-cells isolated from patients with L-HES [13], and two patients with HES developed T-cell lymphoma during an open-label trial with anti-IL-5 treatment, both of which had elevated serum TARC levels although they were not classified as L-HES [14]. However, T-cell lymphoma is a known complication of L-HES regardless of treatment [1]. Furthermore, in vivo, there is no evidence to date that an absence of eosinophils is associated with an increased incidence of tumors [15]. This holds true both for humans with unexplained eosinophilopenia and for genetically engineered eosinophil-deficient mice. As for the role of EBV, EBER is commonly found in AITL-associated B-cells as in this case, but may also less commonly be located in malignant AITL T-cells. A recent study has revealed EBER in untransformed skin and marrow-infiltrating T-cells in one patient among 16 with L-HES [16]. A role for EBV in B-cell lymphoma complicating the AITL disease course has been proposed [9], but the impact on T-cell biology remains largely unexplored.
In conclusion, this is the first case report describing the development of AITL in a patient with a 6-year history of L-HES associated with CD3 ⫺ CD4⫹ T-cells. The clinical presentation was typical of Gleich syndrome, indicating that lymphoma may complicate the disease course of this reputedly benign clinical variant. Although T-cell malignancy is known to occur in L-HES, regardless of treatment, the fact that transformation occurred when eosinophil counts were finally controlled by IL-5-targeted therapy raises the possibility that eosinophils may contribute to T-cell tumor surveillance. Clearly, the functional and/or cytogenetic perturbations ultimately resulting in development of AITL in the setting of L-HES deserve further study.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Roufosse F, Cogan E, Goldman M. Lymphocytic variant hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007; 27:389–413. [2] Gleich GJ, Schroeter AL, Marcoux JP, et al. Episodic angioedema associated with eosinophilia. N Engl J Med 1984;310:1621–1626. [3] Roufosse F, de Lavareille A , Schandene L, et al. Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome. J Allergy Clin Immunol 2010;126:828–835 e3. [4] Chu VT, Frohlich A , Steinhauser G, et al. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol 2011;12:151–159. [5] Jacobsen EA , Ochkur SI, Pero RS, et al. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells. J Exp Med 2008;205:699–710. [6] Ravoet M, Sibille C, Roufosse F, et al. 6q- is an early and persistent chromosomal aberration in CD3-CD4 ⫹ T-cell clones associated with the lymphocytic variant of hypereosinophilic syndrome. Haematologica 2005;90:753–765. [7] de Leval L, Rickman DS, Thielen C, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 2007;109:4952–4963. [8] Roufosse F, Garaud S, de Leval L. Lymphoproliferative disorders associated with hypereosinophilia. Semin Hematol 2012; 49:138–148. [9] Attygalle AD, Kyriakou C, Dupuis J, et al. 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. [10] Ravoet M, Sibille C, Gu C, et al. Molecular profiling of CD3-CD4 ⫹ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways. Blood 2009; 114:2969–2983. [11] Thielen C, Radermacher V, Trimeche M, et al. TARC and IL-5 expression correlates with tissue eosinophilia in peripheral T-cell lymphomas. Leuk Res 2008;32:1431–1438. [12] McKelvie P, Oon S, Romas E, et al. A case of systemic anaplastic lymphoma kinase-negative anaplastic large cell lymphoma associated with hypereosinophilia, granulomatous myositis and vasculitis. Leuk Lymphoma 2012;53:2279–2282. [13] Harfi I, Schandene L, Dremier S, et al. Eosinophils affect functions of in vitro-activated human CD3-CD4 ⫹ T cells. J Transl Med 2013;11:112. [14] Roufosse FE, Kahn JE, Gleich GJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol 2013;131:461–467 e1-5. [15] Gleich GJ, Klion AD, Lee JJ, et al. The consequences of not having eosinophils. Allergy 2013;68:829–835. [16] Klion AD, Mejia R, Cowen EW, et al. Chronic active Epstein-Barr virus infection:a novel cause of lymphocytic variant hypereosinophilic syndrome. Blood 2013;121:2364–2366.
Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma a
b
c
d
Florence Roufosse , Laurence de Leval , Han van Krieken & Marcel van Deuren a
Department of Internal Medicine, Hôpital Erasme, Brussels and Institute for Medical Immunology, Gosselies, Université Libre de Bruxelles, Belgium b
Service de Pathologie Clinique, Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland c
Department of Pathology
d
Click for updates
Department of General Internal Medicine and N4i Center for Immune-deficiency and Autoinflammation, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Published online: 24 Jun 2015.
To cite this article: Florence Roufosse, Laurence de Leval, Han van Krieken & Marcel van Deuren (2015) Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma, Leukemia & Lymphoma, 56:6, 1891-1894, DOI: 10.3109/10428194.2014.976823 To link to this article: http://dx.doi.org/10.3109/10428194.2014.976823
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, June 2015; 56(6): 1891–1894 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.976823
LETTER TO THE EDITOR
Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma Florence Roufosse1, Laurence de Leval2, Han van Krieken3 & Marcel van Deuren4 1Department of Internal Medicine, Hôpital Erasme, Brussels and Institute for Medical Immunology, Gosselies, Université Libre
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de Bruxelles, Belgium, 2Service de Pathologie Clinique, Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland and 3Department of Pathology and 4Department of General Internal Medicine and N4i Center for Immune-deficiency and Auto-inflammation, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Lymphocytic variant hypereosinophilic syndrome (L-HES) is a benign T-cell lymphoproliferative disorder, wherein clonal T-cells often display a CD3 ⫺ CD4⫹ phenotype and produce large amounts of interleukin (IL)-5, resulting in marked hypereosinophilia [1]. Patients most commonly present with cutaneous manifestations. The association of episodic angioedema, fever and elevated immunoglobulin M (IgM) levels with hypereosinophilia characterizes Gleich syndrome, which has a reputedly favorable outcome in terms of eosinophil-mediated end-organ damage [2]. However, this clinically defined entity represents one mode of expression of L-HES, which is known to be associated with an increased risk of developing peripheral T-cell lymphoma, generally many years after detection of hypereosinophilia [1]. Herein, we report the first case of angioimmunoblastic T-cell lymphoma (AITL) developing in a patient with treatment-refractory, CD3 ⫺ CD4⫹ T-cell-associated Gleich syndrome. A 49-year old female Caucasian patient with a past medical history of anorexia nervosa, depression and breast implants first presented in 2006 with intense fatigue. Blood testing revealed marked polyclonal hypergammaglobulinemia and eosinophilia, and comprehensive etiological investigations ruled out parasitosis, drug allergy, cancer, immunodeficiency and vasculitis. Several months later, she developed recurrent episodes of fever (⬎ 39°C) and angioedema with 5–9 kg weight gain (baseline weight 44 kg), associated with myalgia and stiffness around the pelvic girdle, night sweats and pruritis. Routine biology showed a normal total white blood cell count (7.3 ⫻ 109/L, 38% neutrophils, 27% lymphocytes) with persistent hypereosinophilia (28%, absolute count 2–3.6 ⫻ 109/L) and polyclonal hypergammaglobulinemia (IgG 55.4 g/L, IgM 14.4 g/L). Serum IgE level was moderately increased (457 U/mL), vitamin B12 and tryptase were normal. Bone marrow aspirate showed increased eosinophils and a normal plasma cell count; cytogenetic testing was normal, including fluorescence in situ hybridization (FISH) for CHIC2. A fluorodeoxyglucose positron emission tomography
scan with whole-body computed tomography (FDG-PET CT) showed several small hypermetabolic lymph nodes (LNs) in the pelvis and enhancement of pertrochanteric muscles. Diagnosis of Gleich syndrome was proposed, and T-cell analyses revealed a small population of clonal CD3 ⫺ CD4⫹ T-cells in peripheral blood and bone marrow (Table I). The CD3 ⫺ CD4⫹ cells displayed increased helper T-cell type 2 (Th2) cytokine expression by flow cytometry (17.8% IL-5⫹, 18% IL-4 ⫹ and 14% IL-13 ⫹ cells), establishing the diagnosis of L-HES, further corroborated by a markedly increased serum thymus and activation-regulated chemokine (TARC) level (390 000 pg/mL, normal range 109–696). Serum IL-5 levels were normal at baseline (⬍ 2 pg/mL), but reached 521 pg/mL during a flare. Treatment with prednisone was initiated (0.5 mg/kg/ day), with prompt normalization of eosinophils, although angioedema and CD3 ⫺ CD4⫹ cells persisted. Severe psychiatric side effects mandated interruption of maintenance corticosteroid therapy, and prednisone (maximal dose 30 mg daily) was given intermittently, only during flares, without clear-cut clinical benefit. From 2007 to 2011, the disease worsened progressively: eosinophilia increased (15 ⫻ 109/L), and the frequency and severity of flares increased. Various agents (cyclosporine, tacrolimus, interferon-alpha/gamma, imatinib, IL-1 receptor antagonist, cyclophosphamide) were administered unsuccessfully, and the proportion of blood CD3 ⫺ CD4⫹ cells progressively increased. In 2011, she was re-evaluated extensively before initiation of treatment with mepolizumab, a monoclonal anti-IL-5 antibody shown to be an equally effective corticosteroid-sparing agent in patients with L-HES and idiopathic HES [3]. Although the number of small hypermetabolic LNs had increased, bone marrow and LN biopsies showed no evidence of lymphoma [Table I, Figure 1(A)], and monthly intravenous infusions of 750 mg mepolizumab were initiated in December on a compassionate-use basis (NCT00244686), while prednisone treatment was maintained at 5 mg daily. Eosinophil levels declined rapidly, and a clear-cut regression of angioedema
Correspondence: Florence Roufosse, Hôpital Erasme, Department of Internal Medicine, 808 Route de Lennik, 1070 Brussels, Belgium. Tel: 00-32-2-555-3806. Fax: 00-32-2-555-3211. E-mail: [email protected] Received 19 September 2014; revised 5 October 2014; accepted 9 October 2014
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Table I. Sequential investigations in a patient with lymphocytic variant hypereosinophilic syndrome who developed angioimmunoblastic T-cell lymphoma. 2006–2007 (diagnosis) Ly phenotyping*, % (⫻ 109/L) CD3 ⫺ CD4⫹ TCR vβ/γ gene rearrangement
March 2011 (before anti-IL-5)
Summer 2012 (progression to AITL)
PB: 2% (0.03), BM: 1.5%
PB: 7–9% (0.15–0.19), BM: not done
PB: 19% (0.52), BM: nl T- and B-cell distribution
PB: 7.8% (0.06), BM: not done
PB: Sorted CD3 ⫺ CD4⫹ cells polyclonal Not done
BM: sorted CD3 ⫺ CD4⫹ cells clonal
PB, BM: not done, LN: polyclonal
PB: same clone as in 2008‡, LN: same clone as in 2008
46,XX
46,XX
Thoraco-abdominal CT scan
Axillary and para-aortic LNs (infracentimetric)
Numerous small pelvic LNs (unchanged)
FDG-PET CT†
Small pelvic LNs; myositis (hips)
Unchanged inguinal and iliac LNs; myositis (hips)
BM histology
Abundant eosinophils
Abundant eosinophils
LN histology
Not done
Not done
EBV documentation
Not done
Not done
Thickening of subcutaneous and intra-abdominal fat; small unchanged cervical, axillary, para-aortic and pelvic LNs Increased number of small LNs (cervical, axillary, mediastinal, retroperitoneal, pelvic); myositis (hips); spleen Abundant eosinophils, normal maturation Axillary: preserved architecture, abundant eosinophils, no atypical ly; granulomatous reaction toward leakage of breast implant material Axillary LN: scattered small EBER-positive cells (reactivation)
46,XX,t(1;5)(p36.1;p13) [4]/46,XX,t(1;5) (p36.1;p13),del(10)(q2?5) [7]/46,XX[19] Unchanged cervical, axillary and mediastinal lymph nodes; small condensation in left lung, inferior lobe
Karyotype
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November 2008
Numerous new intensely FDG-avid enlarged lymph nodes above and below diaphragm; solitary lesion in left lung, inferior lobe Absence of atypical lymphoid cells Cervical: angioimmunoblastic T-cell lymphoma, most atypical cells CD3 ⫹ CD4⫺ CD10 ⫹ CD45RO⫹ CD7 ⫺ PD-1 ⫹ ICOS⫹ BCL-6⫹ Cervical LN: numerous large EBER-positive B cells
BM, bone marrow; CT, computed tomography; EBER, Epstein–Barr virus encoded small RNAs; EBV, Epstein–Barr virus; FDG-PET, fluorodeoxyglucose positron emission tomography; LN, lymph node; Ly, lymphocyte; nl, normal; PB, peripheral blood; TCR, T-cell receptor. *Lymphocyte phenotypes were assessed by flow cytometry in blood and bone marrow, except for the bone marrow biopsy in March 2011, where qualitative results of immunohistochemistry are given. †Hypermetabolic sites are described. ‡Confirmed by sequencing.
was observed. The absolute counts of CD3 ⫺ CD4⫹ T cells in peripheral blood decreased significantly. Surprisingly, serum IgG, IgE and TARC levels also decreased, suggesting that IL-5 -targeted eosinophil-depleting therapy may indirectly affect cells known to functionally depend on and/or interact with eosinophils (e.g. plasma cells or resident cells [4,5]). In June 2012, when she presented for her sixth mepolizumab infusion, a single enlarged cervical LN was found at physical examination; there were no associated systemic signs or symptoms. The LN (3 ⫻ 2 ⫻ 2 cm) was excised, and pathological examination [Figure 1(B)] revealed complete architectural effacement by diffuse lymphoproliferation in association with an abundant histiocytic infiltrate, scattered plasma cells and occasional eosinophils. The lymphoid infiltrate extended into the surrounding tissues, and comprised a population of atypical medium-sized cells as well as scattered large cells. The atypical lymphoid cells stained positively for T-cell antigens CD2, CD3 and CD5 but negatively for CD4 and CD7 (Table I). Scattered cells were positive for CXCL13, and large lymphoid cells were positive for CD20, CD79a and CD30. Epstein–Barr virus (EBV) encoded small RNA (EBER)-staining showed the presence of EBER in the latter. Pathological diagnosis was unequivocally AITL. Polymerase chain reaction (PCR) studies evidenced an identical monoclonal TCRG gene rearrangement in both the LN and blood, and this was the same clone as already present in the
bone marrow in 2008 (Table I). Within weeks, she developed generalized lymphadenopathy and itching, and treatment with R-CHOP was initiated (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisolone), to target both T-cell lymphoma cells and the blastic EBER-positive CD20 ⫹ B lymphoid component. Disease progressed despite eight courses of R-CHOP, her general status further worsened due to infectious complications and she died in palliative care. This case history is remarkable in that, although T-cell lymphoma has already been documented in patients with L-HES [1,6], AITL has not yet been reported in this setting, and we provide well-documented sequential investigations indicating a possible link between the clonal CD3 CD4 ⫹ T-cells that characterized disease for 6 years, and the lymphoid malignancy. AITL is a rare hematological neoplasm derived from follicular helper T-cells (TFH) [7], which may be accompanied by hypereosinophilia in 32–50% of cases, and occasionally presents with circulating CD3 ⫺ CD4⫹ T-cells [8]. Thorough sequential work-up of our patient from 2006 to 2011 argues strongly against occult pre-existing AITL as the underlying cause of prolonged hypereosinophilia, but rather suggests that AITL developed secondarily in a patient with longstanding L-HES. Indeed, the first biopsy of a hypermetabolic LN, performed a year before AITL developed showed no hyperplastic follicles or any other evidence for AITL. It has
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L-HES progressing to AITL
Figure 1. Sequential lymph node biopsies in a patient with lymphocytic variant hypereosinophilic syndrome who developed angioimmunoblastic T-cell lymphoma. A small hypermetabolic axillary lymph node was excised in 2011, before initiation of mepolizumab treatment (A). Hematoxylin and eosin staining shows an inflammatory infiltrate mostly composed of small lymphocytes and plasma cells, in close proximity to small fragments of silicone (arrow-heads) related to breast implants in place since 1990. In 2012, she developed angioimmunoblastic T-cell lymphoma (BA–BD). Biopsy of an enlarged lymph node showed an atypical lymphoid infiltrate composed of medium-sized cells plus scattered blasts and plasma cells in association with abundant epithelioid histiocytes (BA, hematoxylin and eosin). The atypical lymphoid cells were positive for CD10 (BB), ICOS (BC) and PD1 (BD) (BB–BD, immunoperoxidase).
been shown by others that histological changes do occur during the AITL disease course, but T-cell abnormalities remain stable from early limited nodal involvement to more typical AITL patterns [9]. In addition, the rapid progression observed within weeks after the appearance of the transformed cervical LN in 2012 is consistent with the aggressive
disease course of AITL, contrasting with the prolonged stability of LN size and distribution prior to AITL diagnosis. An obvious question is whether the transformed cells derive from the CD3 ⫺ CD4⫹ T-cell clone driving L-HES, as previously reported in a patient with L-HES who developed peripheral T-cell lymphoma unspecified (PTCL-U),
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and whose malignant cells conserved the CD3 ⫺ CD4⫹ phenotype and were shown to share many gene-expression alterations with the pre-malignant cells [10]. The TCR gene rearrangement pattern on the AITL-biopsy material was identical to that observed in purified benign CD3 ⫺ CD4⫹ cells 4 years earlier, suggesting that these cells may indeed have become the malignant clone. Alternatively, untransformed “by-stander” L-HES-associated CD3 ⫺ CD4⫹ cells may have homed to AITL tissue in response to local TARC production by accessory cells [11], accounting for the T-cell receptor (TCR) gene rearrangement findings on the LN biopsy and the decreased CD3 ⫺ CD4⫹ cell counts observed in peripheral blood as lymphoma developed. This hypothesis is supported by the fact that, in contrast to malignant cells characterizing AITL, CD3 ⫺ CD4⫹ cells appear not to derive from TFH cells; peripheral blood CD3 ⫺ CD4⫹ cells from our patient showed negative staining for TFH markers (ICOS, CXCR5, IL-21) by flow cytometry (not shown), and mRNA for these markers was not shown to be overexpressed by CD3 ⫺ CD4⫹ cells from three patients with L-HES in our previous study [10]. Finally, it is conceivable that the consecutive occurrence of L-HES, then AITL, in our patient reflects an as-of-yet unexplained predisposition to clonal T-cell lymphoproliferative disease, as suggested by another report wherein distinct TCR gene rearrangement patterns were observed over time in a patient who first presented with HES, and then developed CD30 ⫹ anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma [12]. The second unresolved issue pertains to the factors that may have contributed to disease progression. Although the most likely scenario is step-wise accumulation of cytogenetic perturbations in a patient with initially benign clonal T-cell lymphoproliferative disease, the potential role of therapeutic eosinophil depletion and/or EBV-driven transformation deserves attention. The fact that this patient progressed rapidly when hypereosinophilia was finally controlled by mepolizumab raises the possibility that eosinophils were regulating growth of the T-cell clone, thereby contributing to tumor surveillance. A recent in vitro study has indeed shown that eosinophils inhibit proliferation and cytokine production by CD3 ⫺ CD4⫹ T-cells isolated from patients with L-HES [13], and two patients with HES developed T-cell lymphoma during an open-label trial with anti-IL-5 treatment, both of which had elevated serum TARC levels although they were not classified as L-HES [14]. However, T-cell lymphoma is a known complication of L-HES regardless of treatment [1]. Furthermore, in vivo, there is no evidence to date that an absence of eosinophils is associated with an increased incidence of tumors [15]. This holds true both for humans with unexplained eosinophilopenia and for genetically engineered eosinophil-deficient mice. As for the role of EBV, EBER is commonly found in AITL-associated B-cells as in this case, but may also less commonly be located in malignant AITL T-cells. A recent study has revealed EBER in untransformed skin and marrow-infiltrating T-cells in one patient among 16 with L-HES [16]. A role for EBV in B-cell lymphoma complicating the AITL disease course has been proposed [9], but the impact on T-cell biology remains largely unexplored.
In conclusion, this is the first case report describing the development of AITL in a patient with a 6-year history of L-HES associated with CD3 ⫺ CD4⫹ T-cells. The clinical presentation was typical of Gleich syndrome, indicating that lymphoma may complicate the disease course of this reputedly benign clinical variant. Although T-cell malignancy is known to occur in L-HES, regardless of treatment, the fact that transformation occurred when eosinophil counts were finally controlled by IL-5-targeted therapy raises the possibility that eosinophils may contribute to T-cell tumor surveillance. Clearly, the functional and/or cytogenetic perturbations ultimately resulting in development of AITL in the setting of L-HES deserve further study.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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