- Email: [email protected]
Peripheral T-cell lymphoma developing after diagnosis of lymphocytic variant hypereosinophilic syndrome: misdiagnosed lymphoma or natural disease progression?
Accepted Manuscript Peripheral T-cell lymphoma developing after diagnosis of lymphocytic variant hypereosinophilic syndrome: misdiagnosed lymphoma or natural disease progression? F. Roufosse PII:
S2212-4403(14)00641-5
DOI:
10.1016/j.oooo.2014.04.018
Reference:
OOOO 958
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 22 April 2014 Accepted Date: 23 April 2014
Please cite this article as: Roufosse F, Peripheral T-cell lymphoma developing after diagnosis of lymphocytic variant hypereosinophilic syndrome: misdiagnosed lymphoma or natural disease progression?, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/ j.oooo.2014.04.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Peripheral T-cell lymphoma developing after diagnosis of lymphocytic variant hypereosinophilic syndrome: misdiagnosed lymphoma or natural disease progression?
RI PT
Roufosse F.
Department of Internal Medicine, Hôpital Erasme, Brussels, and Institute for Medical
SC
Immunology, Gosselies; Université Libre de Bruxelles, Brussels, Belgium.
M AN U
Corresponding author: Dr. Florence Roufosse
Erasme Hospital, Department of Internal Medicine 808 Route de Lennik
Phone : 00 32 2 555 3806
Fax : 00 32 2 555 3211
EP
Email : [email protected]
TE D
B-1070 Brussels, Belgium
AC C
The author has no conflict of interest to declare.
Word count: 1500 References: 23 Figures: 1
1
ACCEPTED MANUSCRIPT Dear Editor,
We would like to comment on the recent case report submitted by d’Elbée et al 1, and seize this opportunity to underline the diagnostic complexity of distinguishing
RI PT
lymphocytic variant hypereosinophilic syndrome (L-HES) from T-cell lymphoma.
The authors report the case of a patient with hypereosinophilia and a phenotypically
SC
aberrant (CD3-CD4+CD30+) clonal T cell population, presenting clinically with
micronodular infiltrates in lungs, spleen and liver, an erythematous rash, gastric
M AN U
ulceration, and oral lesions. Both eosinophils and the clonal T cells were detected in biopsied liver, stomach, oral mucosa, and bone marrow, and BAL fluid contained abundant eosinophils. Polyclonal hypergammaglobulinemia and elevated serum TARC were present. Diagnosis of L-HES was proposed, but neither corticosteroids nor
TE D
chemotherapy (CHOP regimen) were effective. Within months, the patient developed rapidly progressing enlargement of the tongue, although eosinophil levels were well controlled by mepolizumab. At this time, histological analysis of the
EP
tongue showed the same atypical T cell subset, but no eosinophils, and investigators considered that the patient had progressed to peripheral CD30+ T-cell lymphoma,
AC C
exactly one year after initial presentation.
At this point, the authors should have concluded that the initial diagnosis of L-HES was incorrect, and that this patient had T-cell lymphoma from the start, causing paraneoplastic hypereosinophilia. The resulting “reactive” hypereosinophilic syndrome (HESR 2), characterized by pulmonary and stomatological complications, initially dominated the clinical presentation, and delayed recognition of lymphoma. The reactive eosinophils were indeed abundant in BAL fluid, and in the wall of an
2
ACCEPTED MANUSCRIPT occluded capillary in a necrotic gingival lesion; their direct involvement in decreased pulmonary function and local microvascular thrombosis, through release of various mediators acting on bronchial and vascular smooth muscle tone, capillary permeability, and coagulation, is highly likely 3. However, eosinophils were not
RI PT
responsible for the entire spectrum of complications, as clearly evidenced by the final tongue biopsy.
SC
The belief that lymphoma was driving disease from presentation is supported by several arguments. First, this patient’s disease distribution is consistent with the extra-
M AN U
nodal localisations typically observed in peripheral T-cell lymphoma (PTCL) (skin, liver, lungs, bone marrow, gastrointestinal tract). It is unfortunate that results of complete blood count and peripheral blood phenotyping are not reported, because blood hypereosinophilia associated with the presence of circulating clonal cells represent
TE D
the cornerstone for diagnosis of L-HES 4. Second, presence of morphologically atypical T cells in tissues throughout disease course is not characteristic of L-HES, but rather suggests underlying malignancy. Even in L-HES patients with peripheral blood
EP
lymphocytosis due to markedly expanded phenotypically abnormal clonal T cell subsets, and/or tissue-infiltrating CD3-CD4+ T cells, lymphocytes are small and
AC C
indistinguishable from normal cells 5. Third, the TCR gene rearrangement pattern is identical at presentation and at the time overt T-cell lymphoma is recognized at all studied sites, arguing strongly in favor of a disease continuum, and fourth, disease course is unrelenting and short, contrasting with protracted transformation of clonal T cells in patients with L-HES who eventually develop lymphoma 4. Typical chronology of L-HES progression is illustrated in a paper by Vaklavas et al 5, describing a patient with a CD3-CD4+ T cell clone found in blood and biopsied skin, who developed peripheral T-cell lymphoma involving the skin, tongue and soft palate more than 8
3
ACCEPTED MANUSCRIPT years after presentation. Fifth, patients with HES and elevated serum TARC (and more specifically patients with L-HES) almost invariably respond to corticosteroid treatment 6,
which was not the case of this patient. Sixth, expression of CD30 by the infiltrating T
cells is compatible with a diagnosis of peripheral T-cell lymphoma, and rather
RI PT
atypical for L-HES. Indeed, CD30 positivity is a defining feature of systemic and cutaneous anaplastic large cell lymphoma, and can be observed in other T cell malignancies 7-9, whereas CD3-CD4+ T cells typically associated with L-HES were
SC
CD30-negative in cases where this marker was specifically investigated 10-12 (and unpublished observation in 3 patients from our cohort). It could be argued that CD30
M AN U
expression is not restricted to malignant T cells 13; however, its continuous expression by atypical T cells in various tissues in this case and outgrowth of CD30+ cells at the final stage of disease, clearly indicate that these were not reactive by-stander cells.
TE D
Besides the above characteristics indicating the early presence of occult peripheral T-cell lymphoma, the biomarkers that were instrumental in the authors’ initial conclusion that the patient had L-HES (i.e. CD3-CD4+ phenotype, and increased
EP
serum TARC) are by no means specific for this condition and should in fact be considered as suggestive of T-cell lymphoma unless strong evidence against this
AC C
diagnosis is provided 14. Indeed, these perturbations may be associated with various forms of lymphoma, including Sezary Syndrome, angioimmunblastic T-cell lymphoma, HTLV-associated adult T cell leukemia lymphoma, and CD30+ anaplastic T-cell lymphoma 15-18. This would not be the first case wherein diagnosis of CD30+ T-cell lymphoma is delayed because of the magnitude of paraneoplastic eosinophilia and eosinophilic infiltrates 19, and even eosinophil-mediated obliteration of small blood vessels with development of necrotic lesions has already been reported in this setting 20.
4
ACCEPTED MANUSCRIPT
This case report underscores the care that should be taken when evaluating patients with persistent hypereosinophilia. Correct appraisal of the clinical situation involves specific diagnostic check-points, and diagnosis of L-HES must be made in a stepwise
RI PT
manner, carefully ruling out differential diagnoses along the way (Figure 1). The first step consists in establishing the presence of a “hypereosinophilic syndrome” in a patient with hypereosinophilia; i.e. whether eosinophils are deleterious.
SC
According to the most recent definition 2, this term qualifies any pathological
condition associated with persistent hypereosinophilia wherein eosinophils are
M AN U
primarily involved in organ damage. Increased eosinophils must therefore be present in damaged tissues (and generally in peripheral blood as well), in absence of any other potential explanation for the observed functional and/or structural abnormalities. An obvious correlate is that lowering eosinophil counts (more or less
TE D
rapidly depending on severity of clinical manifestations) must be a therapeutic goal. Elucidation of the cause of hypereosinophilia, and classification of the HES as reactive, primary (neoplastic), or idiopathic, is essential for appropriate
EP
management, and this generally involves two sequential steps. Investigations are first conducted to detect the presence of underlying drug allergy,
AC C
parasitic infections, cancer (often adenocarcinoma), hematologic malignancies, and various other clinically well-defined disorders known to be associated with hypereosinophilia, such as eosinophilic granulomatosis with polyangiitis (EGPA) and allergic broncho-pulmonary aspergillosis (ABPA). The hematologic malignancies that must be considered at this stage are those wherein malignant myeloid or lymphoid cells are readily detectable in peripheral blood and/or biopsied tissues and can be distinguished on the basis of abnormal morphology, phenotype, clonality, and/or karyotype. Diagnosis is relatively straight-forward; examples include chronic
5
ACCEPTED MANUSCRIPT myelogenous or myelomonocytic leukemia, Hodgkin lymphoma, cutaneous/peripheral T-cell lymphoma, and systemic mastocytosis. The next series of investigations aim to detect occult etiologies of apparently unexplained hypereosinophilia, including most significantly FIP1L1-PDGFRA+ chronic
RI PT
eosinophilic leukemia (CEL) and L-HES. Distinguishing these disorders from truly idiopathic HES is meaningful for treatment (i.e. imatinib mesylate as first choice for FIP1L1-PDGFRA+ CEL) and follow-up (i.e. repeated evaluation for lymphoma in L-HES) However, both are infrequent and the diagnostic tools are expensive and require
SC
21.
expertise, so they should be reserved for “second-line” investigations, once more
M AN U
common and/or readily detectable causes of hypereosinophilia have been ruled out.
In the present case, there was indeed a hypereosinophilic syndrome, but the first line
TE D
of diagnostic tests pointed strongly towards peripheral T-cell lymphoma. None of the second-line tests contradicted this diagnosis. An attempt to lower eosinophil levels with corticosteroids was reasonable because of the severity of pulmonary and
EP
vascular manifestations directly related to the eosinophilic infiltrates, but should not have delayed treatment directed towards the abnormal T cells. Initiation of CHOP-
AC C
chemotherapy 3 months after presentation does indicate that the authors were concerned about malignancy, but the subsequent decision to treat with anti-IL-5 antibodies represents a surprising de-escalation in this regard. Mepolizumab’s efficacy has been established for patients with corticosteroid-responsive HES 22 (including L-HES) but this patient had corticosteroid-resistant disease associated with atypical T cells. Furthermore, the fact that the oral lesions progressed rapidly, at the time eosinophils were finally controlled by treatment, raises an important issue pertaining to the eventual impact of reactive (paraneoplastic) hypereosinophilia on
6
ACCEPTED MANUSCRIPT homeostatic control of clonal T cells 23. CD30-targeted therapy with brentuximab vedotin would have been a more interesting alternative, directed against disease mechanisms further upstream.
RI PT
This case report illustrates the current knowledge-gap regarding pathogenesis and diagnosis of clonal T cell disorders, and the complex relationships that exist between indolent clinically benign disease forms and more invasive malignant conditions.
SC
Natural disease course and the potential impact of external factors including
therapeutic compounds are difficult to grasp, because these disorders are both
M AN U
uncommon and heterogeneous. A likely scenario is that clinically “benign” T cell lymphoproliferative disease may follow different paths in individual patients depending on the occurrence of additional “hits” that eventually compromise homeostasis and favor malignant outgrowth of a T cell sub-clone, whereas in others,
TE D
the immune “anti-tumor” response or other mechanisms may control disease. Although the emergence of complex karyotypes at the time full-blown malignancy develops is classical in this setting, the intermediate stages are often cytogenetically
EP
unremarkable, and may be associated with epigenetic changes, or point mutations. Clearly, long-term multi-centric prospective follow-up of patients presenting with
AC C
clonal T cell disorders is essential for a better understanding of their natural history and hence for improved therapeutic management.
7
ACCEPTED MANUSCRIPT References
1.
d'Elbee JM, Parrens M, Mercie P, Longy Boursier M, Dieval C, de Mascarel A, et al.
Hypereosinophilic syndrome - lymphocytic variant transforming into peripheral T-cell
oral radiology. 2013; 116(3): e185-90. 2.
RI PT
lymphoma with severe oral manifestations. Oral surgery, oral medicine, oral pathology and
Valent P, Klion AD, Horny HP, Roufosse F, Gotlib J, Weller PF, et al. Contemporary
consensus proposal on criteria and classification of eosinophilic disorders and related
3.
SC
syndromes. The Journal of allergy and clinical immunology. 2012.
Valent P, Gleich GJ, Reiter A, Roufosse F, Weller PF, Hellmann A, et al. Pathogenesis
review of hematology. 2012; 5(2): 157-76. 4.
M AN U
and classification of eosinophil disorders: a review of recent developments in the field. Expert
Roufosse F, Cogan E, Goldman M. Lymphocytic variant hypereosinophilic syndromes.
Immunol Allergy Clin North Am. 2007; 27(3): 389-413.
Vaklavas C, Tefferi A, Butterfield J, Ketterling R, Verstovsek S, Kantarjian H, et al.
TE D
5.
'Idiopathic' eosinophilia with an Occult T-cell clone: prevalence and clinical course. Leuk Res. 2007; 31(5): 691-4. 6.
Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, et al.
EP
Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 2009. Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, et al. CD30(+) anaplastic
AC C
7.
large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000; 96(12): 3681-95. 8.
Brugnoni D, Airo P, Tosoni C, Taglietti M, Lodi-Rizzini F, Calzavara-Pinton P, et al. CD3-
CD4+ cells with a Th2-like pattern of cytokine production in the peripheral blood of a patient with cutaneous T-cell lymphoma. Leukemia. 1997; 11(11): 1983-5. 9.
Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis,
new variants, and simulators. Journal of cutaneous pathology. 2006; 33 Suppl 1: 58-70.
8
ACCEPTED MANUSCRIPT 10.
Brugnoni D, Airo P, Rossi G, Bettinardi A, Simon HU, Garza L, et al. A case of
hypereosinophilic syndrome is associated with the expansion of a CD3-CD4+ T-cell population able to secrete large amounts of interleukin-5. Blood. 1996; 87(4): 1416-22. 11.
Ravoet M, Sibille C, Gu C, Libin M, Haibe-Kains B, Sotiriou C, et al. Molecular profiling of
RI PT
CD3-CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways. Blood. 2009; 114(14): 2969-83. 12.
Roumier AS, Grardel N, Lai JL, Becqueriaux I, Ghomari K, de Lavareille A, et al.
Hypereosinophilia with abnormal T cells, trisomy 7 and elevated TARC serum level.
13.
SC
Haematologica. 2003; 88(7): ECR24.
Werner B, Massone C, Kerl H, Cerroni L. Large CD30-positive cells in benign, atypical
14.
M AN U
lymphoid infiltrates of the skin. Journal of cutaneous pathology. 2008; 35(12): 1100-7. Roufosse F. Hypereosinophilic syndrome variants: diagnostic and therapeutic
considerations. Haematologica. 2009; 94(9): 1188-93. 15.
Edelman J, Meyerson HJ. Diminished CD3 expression is useful for detecting and
enumerating Sezary cells. Am J Clin Pathol. 2000; 114(3): 467-77.
Roufosse F, Garaud S, de Leval L. Lymphoproliferative disorders associated with
TE D
16.
hypereosinophilia. Semin Hematol. 2012; 49(2): 138-48. 17.
Serke S, van Lessen A, Hummel M, Szczepek A, Huhn D, Stein H. Circulating CD4+ T
EP
lymphocytes with intracellular but no surface CD3 antigen in five of seven patients
180-7. 18.
AC C
consecutively diagnosed with angioimmunoblastic T-cell lymphoma. Cytometry. 2000; 42(3):
Willemze R. Cutaneous T-cell lymphoma: epidemiology, etiology, and classification.
Leukemia & lymphoma. 2003; 44 Suppl 3: S49-54. 19.
Powers ML, Watson BW, Frater JL, Kreisel F, Hassan A. Peripheral eosinophilia
camouflaging anaplastic large cell lymphoma. International journal of surgical pathology. 2011; 19(3): 405-8. 20.
Aractingi S, Bachmeyer C, Pautier P, Barboteu M, Meignin V, Daniel MT, et al. Necrotic
cutaneous lesions induced by hypereosinophilic syndrome secondary to a T-cell lymphoma. Journal of the American Academy of Dermatology. 2002; 46(5 Suppl): S133-6.
9
ACCEPTED MANUSCRIPT 21.
Klion AD. How I treat hypereosinophilic syndromes. Blood. 2009; 114(18): 3736-41.
22.
Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, et al. Treatment
of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008; 358(12): 1215-28. Harfi I, Schandene L, Dremier S, Roufosse F. Eosinophils affect functions of in vitro-
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23.
AC C
EP
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SC
activated human CD3-CD4+ T cells. Journal of translational medicine. 2013; 11: 112.
10
ACCEPTED MANUSCRIPT
Blood : > 1.5 G/L and/or Tissue : “excessive”
Figure 1. Diagnostic evaluation of persistent hypereosinophilia.
1
2
YES
AC C
EP
SC
TE D
Eosinophil reduction with corticosteroids • Not mandatory (depends on severity of complications and ability to treat underlying disease rapidly) • Not always effective (esp. in case of myeloproliferative disease)
M AN U
YES
Treatment of underlying disease
Imatinib mesylateb (all cases) Corticosteroids (if complications present)
What is the cause of hypereosinophilia ? First-line evaluations • Drug and travel history • CBC and blood smear • Parasite serology, search for eggs/larvae • Evaluation for cancer and lymphoma (family and personal risk factors, physical examination, imaging) • Biopsy of any enlarged lymph node, skin lesion, or organ with structural or functional abnormality (incl. bone marrow) • Various additional tests depending on clinical manifestations (Aspergillus-specific Ig, ANCA, serum tryptase, etc) Common underlying cause identified
RI PT
Is there a hypereosinophilic syndrome ? • Eosinophilic infiltrates in tissue biopsies and/or imaging showing abnormalities highly typical of eosinophil-mediated damage (e.g. rupture of mitral valve chordae tendinae, ventricular thrombus) • Tissue/organ dysfunction, damage • No other explanation than presence of eosinophils
a
Eosinophilia
NO
3
Second-line evaluations • PCR/FISH for FIP1L1-PDGFRA • Detailed T cell phenotyping, TCR gene rearrangementa • Other cytogenetic abnormalities (JAK2 mutation, rare rearrangements involving PDGFRA, PDGFRB)
FIP1L1-PDGFRA+ CEL L-HES
if imaging or biopsies suggest lymphoma at previous check-point, these evaluations should be done earlier ; serum TARC remains experimental and has not yet been validated b detailed recommendations for management of these disorders is available in reference 21
S2212-4403(14)00641-5
DOI:
10.1016/j.oooo.2014.04.018
Reference:
OOOO 958
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 22 April 2014 Accepted Date: 23 April 2014
Please cite this article as: Roufosse F, Peripheral T-cell lymphoma developing after diagnosis of lymphocytic variant hypereosinophilic syndrome: misdiagnosed lymphoma or natural disease progression?, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/ j.oooo.2014.04.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Peripheral T-cell lymphoma developing after diagnosis of lymphocytic variant hypereosinophilic syndrome: misdiagnosed lymphoma or natural disease progression?
RI PT
Roufosse F.
Department of Internal Medicine, Hôpital Erasme, Brussels, and Institute for Medical
SC
Immunology, Gosselies; Université Libre de Bruxelles, Brussels, Belgium.
M AN U
Corresponding author: Dr. Florence Roufosse
Erasme Hospital, Department of Internal Medicine 808 Route de Lennik
Phone : 00 32 2 555 3806
Fax : 00 32 2 555 3211
EP
Email : [email protected]
TE D
B-1070 Brussels, Belgium
AC C
The author has no conflict of interest to declare.
Word count: 1500 References: 23 Figures: 1
1
ACCEPTED MANUSCRIPT Dear Editor,
We would like to comment on the recent case report submitted by d’Elbée et al 1, and seize this opportunity to underline the diagnostic complexity of distinguishing
RI PT
lymphocytic variant hypereosinophilic syndrome (L-HES) from T-cell lymphoma.
The authors report the case of a patient with hypereosinophilia and a phenotypically
SC
aberrant (CD3-CD4+CD30+) clonal T cell population, presenting clinically with
micronodular infiltrates in lungs, spleen and liver, an erythematous rash, gastric
M AN U
ulceration, and oral lesions. Both eosinophils and the clonal T cells were detected in biopsied liver, stomach, oral mucosa, and bone marrow, and BAL fluid contained abundant eosinophils. Polyclonal hypergammaglobulinemia and elevated serum TARC were present. Diagnosis of L-HES was proposed, but neither corticosteroids nor
TE D
chemotherapy (CHOP regimen) were effective. Within months, the patient developed rapidly progressing enlargement of the tongue, although eosinophil levels were well controlled by mepolizumab. At this time, histological analysis of the
EP
tongue showed the same atypical T cell subset, but no eosinophils, and investigators considered that the patient had progressed to peripheral CD30+ T-cell lymphoma,
AC C
exactly one year after initial presentation.
At this point, the authors should have concluded that the initial diagnosis of L-HES was incorrect, and that this patient had T-cell lymphoma from the start, causing paraneoplastic hypereosinophilia. The resulting “reactive” hypereosinophilic syndrome (HESR 2), characterized by pulmonary and stomatological complications, initially dominated the clinical presentation, and delayed recognition of lymphoma. The reactive eosinophils were indeed abundant in BAL fluid, and in the wall of an
2
ACCEPTED MANUSCRIPT occluded capillary in a necrotic gingival lesion; their direct involvement in decreased pulmonary function and local microvascular thrombosis, through release of various mediators acting on bronchial and vascular smooth muscle tone, capillary permeability, and coagulation, is highly likely 3. However, eosinophils were not
RI PT
responsible for the entire spectrum of complications, as clearly evidenced by the final tongue biopsy.
SC
The belief that lymphoma was driving disease from presentation is supported by several arguments. First, this patient’s disease distribution is consistent with the extra-
M AN U
nodal localisations typically observed in peripheral T-cell lymphoma (PTCL) (skin, liver, lungs, bone marrow, gastrointestinal tract). It is unfortunate that results of complete blood count and peripheral blood phenotyping are not reported, because blood hypereosinophilia associated with the presence of circulating clonal cells represent
TE D
the cornerstone for diagnosis of L-HES 4. Second, presence of morphologically atypical T cells in tissues throughout disease course is not characteristic of L-HES, but rather suggests underlying malignancy. Even in L-HES patients with peripheral blood
EP
lymphocytosis due to markedly expanded phenotypically abnormal clonal T cell subsets, and/or tissue-infiltrating CD3-CD4+ T cells, lymphocytes are small and
AC C
indistinguishable from normal cells 5. Third, the TCR gene rearrangement pattern is identical at presentation and at the time overt T-cell lymphoma is recognized at all studied sites, arguing strongly in favor of a disease continuum, and fourth, disease course is unrelenting and short, contrasting with protracted transformation of clonal T cells in patients with L-HES who eventually develop lymphoma 4. Typical chronology of L-HES progression is illustrated in a paper by Vaklavas et al 5, describing a patient with a CD3-CD4+ T cell clone found in blood and biopsied skin, who developed peripheral T-cell lymphoma involving the skin, tongue and soft palate more than 8
3
ACCEPTED MANUSCRIPT years after presentation. Fifth, patients with HES and elevated serum TARC (and more specifically patients with L-HES) almost invariably respond to corticosteroid treatment 6,
which was not the case of this patient. Sixth, expression of CD30 by the infiltrating T
cells is compatible with a diagnosis of peripheral T-cell lymphoma, and rather
RI PT
atypical for L-HES. Indeed, CD30 positivity is a defining feature of systemic and cutaneous anaplastic large cell lymphoma, and can be observed in other T cell malignancies 7-9, whereas CD3-CD4+ T cells typically associated with L-HES were
SC
CD30-negative in cases where this marker was specifically investigated 10-12 (and unpublished observation in 3 patients from our cohort). It could be argued that CD30
M AN U
expression is not restricted to malignant T cells 13; however, its continuous expression by atypical T cells in various tissues in this case and outgrowth of CD30+ cells at the final stage of disease, clearly indicate that these were not reactive by-stander cells.
TE D
Besides the above characteristics indicating the early presence of occult peripheral T-cell lymphoma, the biomarkers that were instrumental in the authors’ initial conclusion that the patient had L-HES (i.e. CD3-CD4+ phenotype, and increased
EP
serum TARC) are by no means specific for this condition and should in fact be considered as suggestive of T-cell lymphoma unless strong evidence against this
AC C
diagnosis is provided 14. Indeed, these perturbations may be associated with various forms of lymphoma, including Sezary Syndrome, angioimmunblastic T-cell lymphoma, HTLV-associated adult T cell leukemia lymphoma, and CD30+ anaplastic T-cell lymphoma 15-18. This would not be the first case wherein diagnosis of CD30+ T-cell lymphoma is delayed because of the magnitude of paraneoplastic eosinophilia and eosinophilic infiltrates 19, and even eosinophil-mediated obliteration of small blood vessels with development of necrotic lesions has already been reported in this setting 20.
4
ACCEPTED MANUSCRIPT
This case report underscores the care that should be taken when evaluating patients with persistent hypereosinophilia. Correct appraisal of the clinical situation involves specific diagnostic check-points, and diagnosis of L-HES must be made in a stepwise
RI PT
manner, carefully ruling out differential diagnoses along the way (Figure 1). The first step consists in establishing the presence of a “hypereosinophilic syndrome” in a patient with hypereosinophilia; i.e. whether eosinophils are deleterious.
SC
According to the most recent definition 2, this term qualifies any pathological
condition associated with persistent hypereosinophilia wherein eosinophils are
M AN U
primarily involved in organ damage. Increased eosinophils must therefore be present in damaged tissues (and generally in peripheral blood as well), in absence of any other potential explanation for the observed functional and/or structural abnormalities. An obvious correlate is that lowering eosinophil counts (more or less
TE D
rapidly depending on severity of clinical manifestations) must be a therapeutic goal. Elucidation of the cause of hypereosinophilia, and classification of the HES as reactive, primary (neoplastic), or idiopathic, is essential for appropriate
EP
management, and this generally involves two sequential steps. Investigations are first conducted to detect the presence of underlying drug allergy,
AC C
parasitic infections, cancer (often adenocarcinoma), hematologic malignancies, and various other clinically well-defined disorders known to be associated with hypereosinophilia, such as eosinophilic granulomatosis with polyangiitis (EGPA) and allergic broncho-pulmonary aspergillosis (ABPA). The hematologic malignancies that must be considered at this stage are those wherein malignant myeloid or lymphoid cells are readily detectable in peripheral blood and/or biopsied tissues and can be distinguished on the basis of abnormal morphology, phenotype, clonality, and/or karyotype. Diagnosis is relatively straight-forward; examples include chronic
5
ACCEPTED MANUSCRIPT myelogenous or myelomonocytic leukemia, Hodgkin lymphoma, cutaneous/peripheral T-cell lymphoma, and systemic mastocytosis. The next series of investigations aim to detect occult etiologies of apparently unexplained hypereosinophilia, including most significantly FIP1L1-PDGFRA+ chronic
RI PT
eosinophilic leukemia (CEL) and L-HES. Distinguishing these disorders from truly idiopathic HES is meaningful for treatment (i.e. imatinib mesylate as first choice for FIP1L1-PDGFRA+ CEL) and follow-up (i.e. repeated evaluation for lymphoma in L-HES) However, both are infrequent and the diagnostic tools are expensive and require
SC
21.
expertise, so they should be reserved for “second-line” investigations, once more
M AN U
common and/or readily detectable causes of hypereosinophilia have been ruled out.
In the present case, there was indeed a hypereosinophilic syndrome, but the first line
TE D
of diagnostic tests pointed strongly towards peripheral T-cell lymphoma. None of the second-line tests contradicted this diagnosis. An attempt to lower eosinophil levels with corticosteroids was reasonable because of the severity of pulmonary and
EP
vascular manifestations directly related to the eosinophilic infiltrates, but should not have delayed treatment directed towards the abnormal T cells. Initiation of CHOP-
AC C
chemotherapy 3 months after presentation does indicate that the authors were concerned about malignancy, but the subsequent decision to treat with anti-IL-5 antibodies represents a surprising de-escalation in this regard. Mepolizumab’s efficacy has been established for patients with corticosteroid-responsive HES 22 (including L-HES) but this patient had corticosteroid-resistant disease associated with atypical T cells. Furthermore, the fact that the oral lesions progressed rapidly, at the time eosinophils were finally controlled by treatment, raises an important issue pertaining to the eventual impact of reactive (paraneoplastic) hypereosinophilia on
6
ACCEPTED MANUSCRIPT homeostatic control of clonal T cells 23. CD30-targeted therapy with brentuximab vedotin would have been a more interesting alternative, directed against disease mechanisms further upstream.
RI PT
This case report illustrates the current knowledge-gap regarding pathogenesis and diagnosis of clonal T cell disorders, and the complex relationships that exist between indolent clinically benign disease forms and more invasive malignant conditions.
SC
Natural disease course and the potential impact of external factors including
therapeutic compounds are difficult to grasp, because these disorders are both
M AN U
uncommon and heterogeneous. A likely scenario is that clinically “benign” T cell lymphoproliferative disease may follow different paths in individual patients depending on the occurrence of additional “hits” that eventually compromise homeostasis and favor malignant outgrowth of a T cell sub-clone, whereas in others,
TE D
the immune “anti-tumor” response or other mechanisms may control disease. Although the emergence of complex karyotypes at the time full-blown malignancy develops is classical in this setting, the intermediate stages are often cytogenetically
EP
unremarkable, and may be associated with epigenetic changes, or point mutations. Clearly, long-term multi-centric prospective follow-up of patients presenting with
AC C
clonal T cell disorders is essential for a better understanding of their natural history and hence for improved therapeutic management.
7
ACCEPTED MANUSCRIPT References
1.
d'Elbee JM, Parrens M, Mercie P, Longy Boursier M, Dieval C, de Mascarel A, et al.
Hypereosinophilic syndrome - lymphocytic variant transforming into peripheral T-cell
oral radiology. 2013; 116(3): e185-90. 2.
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lymphoma with severe oral manifestations. Oral surgery, oral medicine, oral pathology and
Valent P, Klion AD, Horny HP, Roufosse F, Gotlib J, Weller PF, et al. Contemporary
consensus proposal on criteria and classification of eosinophilic disorders and related
3.
SC
syndromes. The Journal of allergy and clinical immunology. 2012.
Valent P, Gleich GJ, Reiter A, Roufosse F, Weller PF, Hellmann A, et al. Pathogenesis
review of hematology. 2012; 5(2): 157-76. 4.
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and classification of eosinophil disorders: a review of recent developments in the field. Expert
Roufosse F, Cogan E, Goldman M. Lymphocytic variant hypereosinophilic syndromes.
Immunol Allergy Clin North Am. 2007; 27(3): 389-413.
Vaklavas C, Tefferi A, Butterfield J, Ketterling R, Verstovsek S, Kantarjian H, et al.
TE D
5.
'Idiopathic' eosinophilia with an Occult T-cell clone: prevalence and clinical course. Leuk Res. 2007; 31(5): 691-4. 6.
Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, et al.
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Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 2009. Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, et al. CD30(+) anaplastic
AC C
7.
large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000; 96(12): 3681-95. 8.
Brugnoni D, Airo P, Tosoni C, Taglietti M, Lodi-Rizzini F, Calzavara-Pinton P, et al. CD3-
CD4+ cells with a Th2-like pattern of cytokine production in the peripheral blood of a patient with cutaneous T-cell lymphoma. Leukemia. 1997; 11(11): 1983-5. 9.
Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis,
new variants, and simulators. Journal of cutaneous pathology. 2006; 33 Suppl 1: 58-70.
8
ACCEPTED MANUSCRIPT 10.
Brugnoni D, Airo P, Rossi G, Bettinardi A, Simon HU, Garza L, et al. A case of
hypereosinophilic syndrome is associated with the expansion of a CD3-CD4+ T-cell population able to secrete large amounts of interleukin-5. Blood. 1996; 87(4): 1416-22. 11.
Ravoet M, Sibille C, Gu C, Libin M, Haibe-Kains B, Sotiriou C, et al. Molecular profiling of
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CD3-CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways. Blood. 2009; 114(14): 2969-83. 12.
Roumier AS, Grardel N, Lai JL, Becqueriaux I, Ghomari K, de Lavareille A, et al.
Hypereosinophilia with abnormal T cells, trisomy 7 and elevated TARC serum level.
13.
SC
Haematologica. 2003; 88(7): ECR24.
Werner B, Massone C, Kerl H, Cerroni L. Large CD30-positive cells in benign, atypical
14.
M AN U
lymphoid infiltrates of the skin. Journal of cutaneous pathology. 2008; 35(12): 1100-7. Roufosse F. Hypereosinophilic syndrome variants: diagnostic and therapeutic
considerations. Haematologica. 2009; 94(9): 1188-93. 15.
Edelman J, Meyerson HJ. Diminished CD3 expression is useful for detecting and
enumerating Sezary cells. Am J Clin Pathol. 2000; 114(3): 467-77.
Roufosse F, Garaud S, de Leval L. Lymphoproliferative disorders associated with
TE D
16.
hypereosinophilia. Semin Hematol. 2012; 49(2): 138-48. 17.
Serke S, van Lessen A, Hummel M, Szczepek A, Huhn D, Stein H. Circulating CD4+ T
EP
lymphocytes with intracellular but no surface CD3 antigen in five of seven patients
180-7. 18.
AC C
consecutively diagnosed with angioimmunoblastic T-cell lymphoma. Cytometry. 2000; 42(3):
Willemze R. Cutaneous T-cell lymphoma: epidemiology, etiology, and classification.
Leukemia & lymphoma. 2003; 44 Suppl 3: S49-54. 19.
Powers ML, Watson BW, Frater JL, Kreisel F, Hassan A. Peripheral eosinophilia
camouflaging anaplastic large cell lymphoma. International journal of surgical pathology. 2011; 19(3): 405-8. 20.
Aractingi S, Bachmeyer C, Pautier P, Barboteu M, Meignin V, Daniel MT, et al. Necrotic
cutaneous lesions induced by hypereosinophilic syndrome secondary to a T-cell lymphoma. Journal of the American Academy of Dermatology. 2002; 46(5 Suppl): S133-6.
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ACCEPTED MANUSCRIPT 21.
Klion AD. How I treat hypereosinophilic syndromes. Blood. 2009; 114(18): 3736-41.
22.
Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, et al. Treatment
of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008; 358(12): 1215-28. Harfi I, Schandene L, Dremier S, Roufosse F. Eosinophils affect functions of in vitro-
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23.
AC C
EP
TE D
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activated human CD3-CD4+ T cells. Journal of translational medicine. 2013; 11: 112.
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Blood : > 1.5 G/L and/or Tissue : “excessive”
Figure 1. Diagnostic evaluation of persistent hypereosinophilia.
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YES
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Eosinophil reduction with corticosteroids • Not mandatory (depends on severity of complications and ability to treat underlying disease rapidly) • Not always effective (esp. in case of myeloproliferative disease)
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Treatment of underlying disease
Imatinib mesylateb (all cases) Corticosteroids (if complications present)
What is the cause of hypereosinophilia ? First-line evaluations • Drug and travel history • CBC and blood smear • Parasite serology, search for eggs/larvae • Evaluation for cancer and lymphoma (family and personal risk factors, physical examination, imaging) • Biopsy of any enlarged lymph node, skin lesion, or organ with structural or functional abnormality (incl. bone marrow) • Various additional tests depending on clinical manifestations (Aspergillus-specific Ig, ANCA, serum tryptase, etc) Common underlying cause identified
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Is there a hypereosinophilic syndrome ? • Eosinophilic infiltrates in tissue biopsies and/or imaging showing abnormalities highly typical of eosinophil-mediated damage (e.g. rupture of mitral valve chordae tendinae, ventricular thrombus) • Tissue/organ dysfunction, damage • No other explanation than presence of eosinophils
a
Eosinophilia
NO
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Second-line evaluations • PCR/FISH for FIP1L1-PDGFRA • Detailed T cell phenotyping, TCR gene rearrangementa • Other cytogenetic abnormalities (JAK2 mutation, rare rearrangements involving PDGFRA, PDGFRB)
FIP1L1-PDGFRA+ CEL L-HES
if imaging or biopsies suggest lymphoma at previous check-point, these evaluations should be done earlier ; serum TARC remains experimental and has not yet been validated b detailed recommendations for management of these disorders is available in reference 21