ORIGINAL ARTICLE
Childhood Lymphomatoid Granulomatosis: A Report of 2 Cases and Review of the Literature Zwanique C. A. Tacke, MSc,* M. Judith Eikelenboom, MD, PhD,w R. Jeroen Vermeulen, MD, PhD,w Marjo S. van der Knaap, MD, PhD,w Anne M. Euser, MD, PhD,z Paul van der Valk, MD, PhD,y and Gertjan J. L. Kaspers, MD, PhD*
Summary: Lymphomatoid granulomatosis (LG) is a B-cell type lymphoproliferative disease. It mainly affects the lungs but may have extrapulmonary manifestations, especially in the central nervous system. The purpose of this study was to review the pediatric cases in the literature and add 2 new cases to the existing literature. A review of the literature was performed on children (0 to 18 years of age at diagnosis) with pathologically proven LG. We found 47 case reports, which, together with 2 new cases, were systematically analyzed. The median age was 12 years. The main symptoms were general, pulmonary, and neurological. Approximately one third of the patients were immunocompromised. High mortality rate was observed. Pediatric LG is a rare disease, which appears to be more frequently seen in immunocompromised patients, especially patients with leukemia. The disease has a high mortality rate; therefore, aggressive therapy according to a highgrade B-cell lymphoma protocol is justified. Key Words: lymphomatoid granulomatosis, children, Epstein-Barr virus, B-cell lymphoma, CNS
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L
ymphomatoid granulomatosis (LG) is an uncommon lymphoproliferative disorder first described by Liebow and colleagues in 1972.1 LG is rare in children; it mainly occurs in the fourth and fifth decade of life. The incidence of LG is unknown. LG has been described as an angiocentric and angiodestructive proliferative disease mainly affecting the lung,1 but other organs such as the central nervous system (CNS) can be involved as well.2 Pathologic features include a polymorphic infiltrate of lymphocytes, plasma cells and histiocytes, and atypical lymphoreticular cells.1 LG can be histologically staged into 3 grades, based on cytologic atypia, extent of necrosis, and retention of polymorphous cellular infiltrate.3 LG is a B-cell type disease and can occur in immunocompromised patients.4,5 The diagnosis is often delayed or only made at autopsy. The prognosis is poor and mortality varies from 38% to 64%,2 although long-lasting remissions have been described.6,7 Recently 2 children with LG were seen in our hospital. Received for publication May 11, 2013; accepted November 14, 2013. From the *Division of Pediatric Oncology/Hematology; Departments of wChild Neurology; yPathology, VU University Medical Center, Amsterdam; and zDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. Z.C.A.T and M.J.E. contributed equally. The authors declare no conflict of interest. Reprints: Gertjan J. L. Kaspers, MD, PhD, Division of Pediatric Oncology/Hematology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands (e-mail: gjl.kaspers@ vumc.nl). Copyright r 2013 by Lippincott Williams & Wilkins
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Because the disease is rare, especially in children, the literature about prognosis and the choice of therapy is limited. The purpose of this study was to review all pediatric patients with LG reported in the literature.
METHODS A systematic review of the literature was performed, limited to papers in English and children aged between 0 to 18 years. PubMed was searched for: LG and/or angiocentric B-cell lymphoma. One case report was found in a reference of another article.8 Some of the patients were reported more than once and for those patients the case report with most information was included.9–13 Some patients suffered from T-cell lymphomas and were therefore not included.14–16 One case report concerned a patient outside the age limit and one case report described a patient with lymphomatoid papulosis.17,18 Both case reports were excluded. In total, 47 children with pathologically proven LG were found and together with our 2 cases, we had reports on 49 children. We recorded characteristics listed in Table 1. Involvement of organs was based on biopsy and/or abnormalities on imaging and clinical findings. All clinical data were analyzed by SPSS 16.0 using descriptive statics.
CASE REPORTS Case Report I A 10-month-old baby girl without a medical history was admitted to the hospital with fever and seizures. Viral encephalitis was suspected and intravenous (IV) antiviral drug therapy (aciclovir) was started. She developed a status epilepticus and was transported to our hospital. She was treated with phenytoin and midazolam IV and intubated. She subsequently developed hepatosplenomegaly, a status epilepticus, and declined neurologically. Magnetic resonance imaging (MRI) of the brain revealed multiple lesions, especially in the gray matter (Fig. 1). T1-weighted images with gadolinium revealed enhancement of the leptomeninges and some of the focal parenchymal lesions. Treatment with methylprednisolone IV resulted in a neurological improvement. However, she deteriorated again and MRI showed progression of the lesions with new lesions in the cerebral white matter. She died 4 months after her initial symptoms. Autopsy revealed large lymphomatoid infiltrations mainly in the brain and lungs but also in the liver and spleen. The infiltrates consisted of a majority of small cells (largely CD3-positive and CD5-positive) and scattered large, blastic cells that were CD20-positive and CD79a-positive; a fair number of macrophages/histiocytes were present and stained positive for CD68-positive cells. The B cells were positive for EBV (by EBER RNA in situ hybridization). There was no necrosis in the infiltrates, or in the surrounding brain parenchyma. There was only minimal extension of lymphoid cells in the brain tissue that showed mild gliosis. The final diagnosis was LG grade 1.
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TABLE 1. Childhood Lymphomatoid Granulomatosis (LG): Review of Clinical and Pathologic Data
Age at Localization (Clinically EBV Tumor Patient Diagnosis Suspected and/or Proven by Status/ Number (y)/Sex Biopsy or Autopsy) Grade
Follow-up (mo)/Status at Last Follow-up
Medical History
Therapy
Lung*, CNS*, liver*, spleen*
+ /1
NA
Steroids
4/death
10/F
CNSw
/1
Steroids, chemo, anti-CD20
9/death
319 420
12/M 7/F
CNSw Lungw, CNSw, kidneyz
NA/NA /NA
521 613
15/M 17/M
Skinw Lungz, CNSw, liverw, spleenw
+ /NA NA/NA
Necrotic and granulomatous skin lesions, pancytopenia, hemophagocytosis NA ALL treatment complete before admission Wiskott-Aldrich syndrome NA
722
1/M
NA/NA
823 924
4/M 18/F
Lung*,w, liver*, kidney*, glands*, LNN*,w Lungw, CNSw Lung*,w, CNS*
NA/NA NA/NA
106 117 1225 138 149 159 165
14/F 10/M 12/M 14/M 10/M 7/M 10/M
Lungw, CNSz Lungw, glandw, eyez, kidneyz Lung*,w, LNN*,w CNSz, skinw Lung*,w, liver*,w Lung*,w, CNS*, intestinal* Lungw, liverz, kidneyz
NA/1 NA/NA + /NA NA/NA /NA /NA + /2
1726 1827
18/M 16/F
Lungz, CNSz, skinw CNSz, pleuraw
1928 2029 2130
14/F 16/M 4/M
Lungw, CNSw Lungw Lungz, skinw
+ /NA NA/1 /NA
2215 2331
4/F 17/F
LNNw CNSw
+ /NA NA/3
Lungw Lungw, CNSw Lungw, skinw, glandsw CNSz, liverz Lung*,w, liver*, glands*, CNS* Lungw, CNSz, liverz Lungw, skinw, liverz, spleenz, LNNw Lungz, CNSw kidneyz, LNNz Lungw, LNNz Lungw Lung*,w, CNS*, skin*,w Lung*,w, CNS*, skin* Lung*,w, URT*´w Lung*,w Kidneyw Skinw, spleenz Lung* Lungw, earw, paranasal sinusw Lungw Lungw Lungw, CNSz, liverz, bone marrowz, LNNz
+ /1 NA/NA NA/NA
1 (this study) 2 (this study)
2432 251 2633
1/F
4/M 8/F 6/F
2734
13/F
2835 2936
16/M 12/M
3037
10/F
3138 3239 3340 3441 3511 3642 3743 3844 3945 4012
18/M 4/F 16/M 18/F 8/F 16/M 4/M 17/F 9/M 7/M
4146 4246 438
18/M 2/F 14/M
4447
12/F
4548
15/M
r
Lungz, LNNw, URTw, temporal bonez Lungz, CNSz, skinw
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/2 /NA
Surgery Steroids, chemo
NA 66/alive
Anti-CD20 Steroids, chemo, RT, surgery Steroids, chemo
18/alive 51/alive
EBV infection, hypogammaglobulinemia NA Steroids, chemo, RT Multiple asymptomatic Steroids, chemo, RT congenital skeletal anomalies NA Steroids, chemo NA Steroids, chemo Wiskott-Aldrich syndrome Steroids, chemo NA NA Defects in B-cell function Steroids, chemo Defects in B-cell function Steroids, chemo AML Steroids, chemo, IFN NA IFN SLE with renal transplant Steroids, chemo (EBV-positive donor) NA Steroids NA NA Hemolytic anemia, skin Chemo, allogeneic nodules, obstructive cord stem cell pulmonary disease, EBV transplant infection ALL Steroids, RT NA Steroids, chemo, IFN NA NA NA Steroids ALL Steroids, chemo
8/death NA/death 14/death 163/alive 108/alive 36/death 2/death 4/death 2/death 18/alive 22/death 36/alive NA NA 12/alive
21/alive NA NA 27/alive 13/death
NA/NA
NA
Steroids
5/death
NA/NA NA/NA
NA NA
Chemo Steroids, chemo
NA 72/alive
/1
NA
Surgery
4/alive
+ /NA NA/3 + /3 NA/NA NA/NA NA/NA NA/NA NA/2 NA/NA + /2
NA NA Recurrent oral candidiasis NA ALL NA NA NA ALL ALL
NA 24/alive 17/death 25/death 2/death 7/death NA 40/alive NA/death 12/deathy
NA/NA NA/NA NA/NA
NA NA Evans syndrome and splenectomy
/3
NA
NA Steroids, surgery Steroids, IFN Steroids, chemo Steroids Steroids NA Steroids, chemo Steroids Antiviral and antibiotics Chemo Steroids, chemo Steroids, chemo, RT, bone marrow transplant Steroids, chemo, RT
NA/NA
NA
Steroids, chemo
4/alive 3/death 36/alive 44/death 1/death
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TABLE 1. (continued) Age at Localization (Clinically EBV Tumor Patient Diagnosis Suspected and/or Proven by Status/ Number (y)/Sex Biopsy or Autopsy) Grade
Medical History
Therapy
NA Crohn
Steroids, chemo, RT, surgery Steroids, chemo
+ /2
NA
NA
+ /3
Griscelli syndrome II
Immunosuppressive treatment
4649
16/M
CNSw
/NA
4750
17/F
+ /3
4851
3/F
4952
11/F
Lungw, CNSz, liverz, oropharynxw Lungz, liverz, stomachw, skinz Lungw
Follow-up (mo)/Status at Last Follow-up 6/alive 48/alive 2/death NA/death
*Autopsy. wBiopsy site. zClinically suspected. yDeath from ALL, LG in remission. ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; chemo, chemotherapy; CNS, central nervous system; EBV, Epstein-Barr virus; IFN, interferon a 2-b; LNN, lymph nodes; NA, not available; RT, radiotherapy; SLE, systemic lupus erythematosus; URT, upper respiratory tract.
Case Report II A 10-year-old girl, with a history of necrotic and granulomatous skin lesions, pancytopenia, and hemophagocytosis, complained of fatigue, double vision, clumsiness, and facial asymmetry. On physical examination she had involvement of several cranial nerves. MRI of the brain showed multiple hyperintense focal lesions in the white and gray matter. Cerebrospinal fluid pathology showed lymphocytosis. Ultrasonography of the abdomen showed a hepatosplenomegaly. Bone marrow biopsy showed hypocellularity suggestive of aplastic anemia. A brain biopsy was performed and a diagnosis of LG (grade 1; no EBV-positive cells; Fig. 2) was tentatively made 3 months after the presentation, on the basis of the mixed infiltrates, with predominant small T ells, scattered blastic B cells with absent clonality, and admixed histiocytes, despite the negative EBER. The presence of only blastic T cells excludes reactive conditions, and absence of clonality makes a T-cell-rich diffuse large B-cell lymphoma less likely, favouring the diagnosis of LG. She was treated with vincristine, cyclophosphamide, and dexamethasone. MRI of the brain first improved but later-on, the lesions progressed. A second brain biopsy was performed, which showed a relapse of LG. Therapy was intensified with a modified non-Hodgkin lymphoma protocol, but her condition deteriorated and treatment was started with anti-CD20 IV and intrathecally. She died 9 months after she was diagnosed with LG. Autopsy showed a bronchopneumonia and in the brain, it showed a perivascular infiltration of T cells and phagocytes and loss of neurons and ischemic ganglion cell destruction.
RESULTS The findings of all 49 patients are summarized in Table 1. Median age of the patients at diagnosis was 12 years (range, 0 to 18 y). The male: female ratio was 1.2:1. Median time interval from onset of symptoms to diagnosis was 3 months (range, 1 to 96 mo).
Symptoms and Localization Main symptoms were pulmonary (66% of patients) and neurological (47%), but general symptoms as fever and weight loss were observed in 62%. Most commonly involved organs were lung (82% of patients), CNS (51%), liver (25%), skin (22%), lymph nodes (16%), kidney (13%), and spleen (8%).
Diagnostics Chest x-ray was used to detect pulmonary lesions in 67% of patients, chest computed tomography (CT) in 30%
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of them. The most frequent abnormalities were diffuse bilateral lesions, sometimes nodular. In 33% of the cases CSF was investigated, often demonstrating hypercellularity and elevated glucose and protein level. MRI of the brain was obtained in 37% of patients, most frequently showing multifocal lesions.
Pathology LG was proven in 45 patients during life and in 4 patients at autopsy (case 1, 35, 36, 39). In 23 patients, tumor tissue was examined for EBV, of which 13 (57%) were diagnosed positive for EBV. Eighteen patients (37%) were histologically classified. The lesions were graded as grade I in 6 patients (33%), grade II in 5 (28%), and grade III in 7 (39%).
Therapy In 24 patients (49%) steroids and chemotherapy were started as initial therapy. In addition, 4 received radiotherapy, 2 radiotherapy and surgery, and 2 interferon a-2b. Ten patients (22%) were administered steroids without chemotherapy, of which one patient also received radiotherapy, one underwent surgery, and one was administered with interferon a-2b. Treatment was heterogenous in the other patients and included anti-CD20 and allogeneic stem cell transplantation. One patient received antibiotic and antiviral treatment only; chemotherapy combined with steroids was recommended, but the parents declined the treatment proposal (case 40). In 6 patients, therapy was not described in detail.
Follow-up The median duration of follow-up since the first clinical presentation was 15.5 months (range, 2 to 163 mo). Thirteen patients were lost to follow-up or follow-up was not described. Of the remaining 36 patients, 18 (50%) were alive and 18 patients (50%) had died. The median interval between diagnosis and death was 8 months. Outcome was studied in relation to organ involvement. Skin involvement, either solitary or generalized, had the highest mortality rate (64%), followed by lung (60%), CNS (57%), and liver (55%) involvement. From the 24 patients with steroids and chemotherapy as therapy, 11 were alive and 12 had died, 1 was lost to follow-up. r
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FIGURE 1. Magnetic resonance images of a 10-month-old girl (case 1) with lymphomatoid granulomatosis with multifocal and diffuse lesions in the brain parenchyma, especially in the cortex of the parietal, temporal, and occipital lobes (A, FLAIR; B and C, T2-weighted images) at presentation. T1-weighted images with gadolinium revealed enhancement of the leptomeninges and some of the focal parenchymal lesions (not shown). Three months later, the images show progression with cystic degeneration (D, FLAIR; E and F, T2-weighted images). FLAIR indicates fluid-attenuated inversion recovery.
Medical History In 20 patients, comorbidity or a positive medical history was reported. Leukemia was observed in 7 children. Two patients had been treated for acute lymphoid leukemia, and one patient had acute myeloid leukemia and completed therapy just 1 month before the first symptoms of LG occurred. Four patients developed LG during treatment of acute lymphoid leukemia. Two patients were known to have the Wiskott-Aldrich syndrome. One patient had a persistent EBV infection and hypogammaglobulinemia. Two patients, siblings, had subtle defects in B-cell function with mild suppression of serum immunoglobulin G-levels. Two patients had skin lesions before admission, of which one also had pancytopenia with some hemophagocytosis and the other had hemolytic anemia, a previous EBV infection, and an 18-months history of inflammatory and obstructive pulmonary disease. One r
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patient had a history of recurrent oral candidiasis for 3 years before developing LG. One patient had end-stage renal disease as a result of systemic lupus erythematosus and had a renal transplant from an EBV-positive donor. One patient was known with Evans syndrome and underwent a splenectomy. One patient had the Crohn disease and the other had the Griscelli syndrome type 2.
DISCUSSION Until now, no systematic review of childhood case reports of LG has been published. LG occurs most often at middle age and is rarely seen during childhood.2 We report a total of 47 pediatric patients found in the English literature since the first description of LG in 1972 and added 2 newly identified patients of our own hospital. It has been suggested that LG is a T-cell disease because of www.jpho-online.com |
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FIGURE 2. The immunohistologic findings of a 10-year-old girl (case 2) with lymphomatoid granulomatosis. A, Brain biopsy showing a perivascular cuff of predominantly lymphoid cells, with a mixture of B cells and T cells in this CD20 (= anti-B-cell antibody)-staining (CD20, 10 objective). B, Higher magnification of perivascular infiltrate. There is a predominance of small lymphocytic cells, with occasional blasts, that is, large cells with nuclei showing a vesicular, lighter chromatin (hematoxylin-eosin, 25 objective). C, Some area as (B) (adjacent section) stained for CD20. The positive cells are a minority, but the blasts are positively stained, (CD20, 25 objective). D, Section from the autopsy of this patient showing localization of the process in the basal ganglia (hematoxylin-eosin, 2.5 objective).
immunohistochemical evidence of massive T-lymphocyte infiltration.53 Recent studies using more sensitive immunophenotyping and EBV RNA in situ hybridization rather support the concept that LG is an EBV-positive B-cell lymphoproliferative disorder, with a large number of reactive Tcell infiltrates.40,54,55 Although the classification of the WHO is clear, there are cases at least very similar to LG but without EBV positivity.31,56 Some case reports in the literature appeared to be clearly T-cell lymphomas and were, therefore, excluded from this review. Publication bias is likely present in our study, but this disease is so rare that a prospective study design for children with LG is virtually impossible. Symptoms at presentation are diverse but differ from those reported in adults.1,2 We found a higher incidence of neurological symptoms but a lower incidence of general malaise and weight loss, although pulmonary symptoms occur at the same rate.2 Hepatosplenomegaly and lymphadenopathy are frequent findings in adults,2 but are even more common in children. The abnormalities observed on chest x-ray and chest CT resemble the abnormalities observed in adult reports.57,58 In the case of pulmonary symptoms, at least a chest x-ray should be obtained and a chest CT should be considered. MRI of the brain in the case of CNS involvement identified multifocal T2-hyperintense lesions in some cases with surrounding edema. Multifocal intraparenchymal lesions were also the most common abnormalities in another recent study focusing on brain abnormalities in LG.59 In view of the high incidence of CNS involvement, a brain MRI should be considered in all children suspected of or diagnosed with LG. Although the MRI appearance of LG of the brain varies, multifocal white and gray matter lesions with enhancement are most frequent.
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Multiple organ involvement is more frequent in children than solitary organ involvement. Therefore, when LG is suspected in a child, each tract should be examined for proper staging. A definitive diagnosis of LG can only be made by histopathologic examination of involved tissues. EBV was positive in 50% of the 20 tested patients, which is frequent but less often than in other studies.54,60 Histologically, the nodular lesions consist of polymorphic infiltrates of lymphocytes around blood vessels and focal sites of necrosis within the lymphomatoid infiltrates with, depending on their grade, large atypical cells.31,61 Histopathologic grading is important in the prognosis and treatment of patients with LG. Involvement of the CNS is considered an adverse prognostic sign,2 but we could not confirm this. Outcome in our study was also independent of EBV status, although EBV status was determined in only half of the cases. Histologic gradation did not correlate with mortality, but the small numbers limit firm conclusions. Fourteen of the 46 patients were immunocompromised, either by treatment for another condition such as leukemia, or by an underlying immunodeficiency. This indicates that the immune system plays a role in the etiology of LG. Remarkably, one pair of siblings with LG was found with a B-cell function defect, which suggests a possible genetic condition or an environmental provoking factor.9 It is not possible to advice an optimal therapy for LG based on the data of this review. Most of the patients were treated with corticosteroids, either as single agent or combined with chemotherapeutic agents. Radiotherapy has been used for CNS involvement, as recently a distinction in treatment recommendations is made between low-grade and highgrade LG. Immunomodulatory therapy like interferon a is used for low-grade disease and multi-agent chemotherapy r
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for high-grade lesions. This is partly based on the understanding that low-grade LG is immune system-dependent and high-grade LG consists of EBV-positive large atypical B cells and together with its clinical aggressiveness be approached as diffuse large B-cell lymphoma using intensive chemotherapy.62
19. Paspala AB, Sundaram C, Purohit AK, et al. Exclusive CNS involvement by lymphomatoid granulomatosis in a 12-year-old boy: a case report. Surg Neurol. 1999;51:258–260. 20. Moertel CL, Carlson-Green B, Watterson J, et al. Lymphomatoid granulomatosis after childhood acute lymphoblastic leukemia; report of effective therapy. Pediatrics. 2001;107:E82, Available at: http://pediatrics.aappublications.org/cgi/reprint/ 107/5/e82. Accessed February 16, 2009. 21. Sebire NJ, Haselden S, Malone M, et al. Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol. 2003;56:555–557. 22. Lehman TJ, Church JA, Isaacs H. Lymphomatoid granulomatosis in a 13 month-old infant. J Rheumatol. 1989;16: 235–238. 23. Whelan HT, Moore P. Central nervous system lymphomatoid granulomatosis. Pediatr Neurosci. 1987;13:113–117. 24. Verity MA, Wolfson WL. Cerebral lymphomatoid granulomatosis. A report of two cases, with disseminated necrotizing leukoencephalopathy in one. Acta Neuropathol. 1976;15: 117–124. 25. Ilowite NT, Fligner CL, Ochs HD, et al. Pulmonary angiitis with atypical lymphoreticular infiltrates in Wiskott-Aldrich syndrome: possible relationship of lymphomatoid granulomatosis and EBV infection. Clin Immunol Immunopathol. 1986;41:479–484. 26. Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol. 2001;25:1111–1120. 27. Cachat F, Meagher-Villemure K, Guignard JP. Lymphomatoid granulomatosis in a renal transplant patient. Pediatr Nephrol. 2003;18:838–842. 28. Hareema A. Lymphomatoid granulomatosis: unusual presentation in a pediatric patient. Pediatr Devel Pathol. 2003;6:106–107. 29. Mazzie JP, Price AP, Khullar P, et al. Lymphomatoid granulomatosis in a pediatric patient. Clin Imaging. 2004; 28:209–213. 30. LeSueur BW, Ellsworth L, Bangert JL, et al. Lymphomatoid granulomatosis in a 4-year-old boy. Pediatr Dermatol. 2000; 17:369–372. 31. Katszenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34:35–48. 32. Medeiros LJ, Jaffe ES, Chen YY, et al. Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions. Am J Surg Pathol. 1992;16:439–447. 33. Be´ka´ssy AN, Cameron R, Garwicz S, et al. Lymphomatoid granulomatosis during treatment of acute lymphoblastic leukemia in a 6-year old girl. Am J Pediatr Hematol Oncol. 1985;7:377–380. 34. Prapphal N, Limudomporn S, Watana D, et al. Lymphomatoid granulomatosis with upper airway obstruction: a case report. J Med Assoc Thai. 1991;74:526–530. 35. Capone PM, Mechtler LL, Bates VE, et al. Multiple giant intracranial aneurysms associated with lymphomatoid granulomatosis. A magnetic resonance imaging and angiographic study. J Neuroimaging. 1994;4:109–111. 36. Gu¨ven A, Baskin D. Lymphomatoid granulomatosis in a boy with long-term follow-up. Pediatr Hematol Oncol. 2001;18: 377–382. 37. Kendi AT, McKinney AM, Clark HB, et al. A pediatric case of low-grade lymphomatoid granulomatosis presenting with a cerebellar mass. Am J Neuroradiol. 2007;28:1803–1805. 38. Hu X, Selbs E, Drexler S. An 18-year-old man with persistent cough and bilateral lower lung infiltration. Epstein-Barr viruspositive lymphoproliferative disorder consistent with lymphomatoid granulomatosis. Arch Pathol Lab Med. 2006;130:E44–E46. 39. Karnak I, Ciftci AO, Talim B, et al. Pulmonary lymphomatoid granulomatosis in a 4 year old. J Pediatr Surg. 1999;34: 1033–1035. 40. Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral
REFERENCES 1. Liebow AA, Carington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol. 1972;3:457–558. 2. Katzenstein AL, Carrington MD, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43:360–373. 3. Lipford EH, Margolick JB, Longo DL, et al. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood. 1988;72:1674–1681. 4. Anders KH, Latte H, Chang BS, et al. Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome. Hum Pathol. 1989;20:326–334. 5. Oren H, Irken G, Kargi A, et al. A pediatric case of lymphomatoid granulomatosis with onset after completion of chemotherapy for acute myeloid leukemia. J Pediatr Hematol Oncol. 2003;25:163–165. 6. Mizuno T, Takanashi Y, Onodera H, et al. A case of lymphomatoid granulomatous/angiocentric immunoproliferative lesion with long clinical course and diffuse brain involvement. J Neurol Sci. 2003;213:67–76. 7. Pearson AD, Craft AW, Howe JM. Choroidal involvement in lymphomatoid granulomatosis. Br J Opthalmol. 1991;75: 688–689. 8. Bernstein ML, Reece ER, de Chadarere´vian JP, et al. Bonemarrow transplant in lymphomatoid granulomatosis. Report of a case. Cancer. 1986;58:969–972. 9. Rogers BB, Browning I, Rosenblatt H, et al. A familial lymphoproliferative disorder presenting with primary pulmonary manifestations. Am Rev R Dis. 1992;145:203–208. 10. Rimsza LM, Rimsza ME, Gilbert-Barness E. Pathological cases of the month. Lymphomatoid granulomatosis. Am J Dis Child. 1993;147:693–694. 11. Cohen SR, Landing BH, Siegel S, et al. Lymphomatoid granulomatosis in a child with acute lymphatic leukemia in remission. Ann Otol Rhinol Laryngol Suppl. 1978;87:5–10. 12. Scully RE, Mark EJ, McNeely WF, et al. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 40-1987. A seven-year-old boy with acute lymphocytic leukemia in remission, with abnormalities of the ears, paranasal sinuses, and lungs. N Eng J Med. 1987;317: 879–890. 13. Podlas HB, Gritzman MC, Thomaides S, et al. CT of CNS lesions in lymphomatoid granulomatosis: case report. Am J Neuroradiol. 1988;9:592–594. 14. Mrusek S, Marx A, Kummerle-Deschner J, et al. Development of granulomatous common variable immunodeficiency subsequent to infection with Toxoplasma gondii. Clin Exp Immunol. 2004;137:578–583. 15. Drut R, Drut RM. Angiocentric immunoproliferative lesion and angiocentric lymphoma of lymph node in children. A report of two cases. J Clin Pathol. 2005;58:550–552. 16. Mosqueda-Taylor A, Menenes-Garcia A, Za´rate-Osorno A, et al. Angiocentric lymphomas of the palate: clinico-pathological considerations in 12 cases. J Oral Pathol Med. 1997;26:93–97. 17. Leedman PJ, Matz LR, Pullan P. Endocrine dysfunction in lymphomatoid granulomatosis. Aust N Z J Med. 1989;19: 97–102. 18. Rogers M, de Launey J, Kemp A, et al. Lymphomatoid papulosis in an 11-month-old infant. Pediatr Dermatol. 1984;2: 124–130. r
2013 Lippincott Williams & Wilkins
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Tacke et al
41. 42. 43. 44.
45. 46. 47. 48. 49.
50.
51.
infection of B lymphocytes and response to interferon-alfa 2b. Blood. 1996;87:4531–4537. Patton WF, Lynch JP 3rd. Lymphomatoid granulomatosis. Clinicopathologic study of four cases and literature review. Medicine (Baltimore). 1982;61:1–12. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid Granulomatosis. Prospective clinical and therapeutic experience over 10 years. N Eng J Med. 1982;306:68–74. Hunter S, Samir A, Eisner B, et al. Diagnosis of renal lymphoma by percutaneous image guided biopsy: experience with 11 cases. J Urol. 2006;176:1952–1956. Takeshita M, Akamatsu M, Ohshima K, et al. Angiocentric immunoproliferative lesions of the skin show lobular panniculitis and are mainly disorders of large granular lymphocytes. Hum Pathol. 1995;26:1321–1328. Drut R. Angiocentric B-cell lymphoma of the lung in an immunocompromised boy. Pediatr Pathol. 1988;8:395–400. Colby TV, Carrington CB. Pulmonary lymphomas simulating lymphomatoid granulomatosis. Am J Surg Pathol. 1982;6:19–32. C¸akmak O¨, Kutluk T, Akyol MU, et al. Angiocentric lymphoma involving the temporal bone in a child. Eur Arch Otorhinolaryngol. 1999;256:262–265. Halvani A, Owlia MB, Sami R. Lymphomatoid granulomatosis with splenomegaly and pancytopenia. Zhongguo Fei Ai Za Zhi. 2010;13:84–86. Gupta T, Wadasadawala T, Shet T, et al. Isolated central nervous system involvement by lymphomatoid granulomatosis in an adolescent: a case report and review of literature. Pediatr Hematol Oncol. 2010;27:150–159. Destombe S, Bouron-DalSoglio D, Rougemont AL, et al. Lymphomatoid granulomatosis: a unique complication of Crohn disease and its treatment in pediatrics. J Pediatr Gastroenterol Nutr. 2010;50:559–561. Uccini S, Testi AM, Al-Badri SF, et al. Gastric perforation as a primary manifestation of lymphomatoid granulomatosis. Pediatr Blood Cancer. 2011;57:178–179.
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52. Szczawinska-Poplonyk A, Kycler Z, Breborowicz A, et al. Pulmonary lymphomatoid anulomatosis in Griscelli syndrome type 2. Viral Immunol. 2011;24:471–473. 53. Nichols PW, Koss M, Levine AM, et al. Lymphomatoid granulomatosis: a T-cell disorder? Am J Med. 1982;72:467–471. 54. Myers JL, Kurtin PJ, Katzenstein AA, et al. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol. 1995;19:1300–1312. 55. Guinee D, Jaffe E, Kingma D, et al. Pulmonary Lymphomatoid granulomatosis. Evidence for a proliferation of EpsteinBarr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol. 1994;18:753–764. 56. Pittaluga S, Wilson WH, Jaffe ES, et al. WHO classification of tumours of heamatopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008:247–249. 57. Lee JS, Tuder R, Lynch D. Lymphomatoid granulomatosis: radiographic features and pathological correlations. Am J Roentgenol. 2000;175:1335–1339. 58. Dee PM, Arora NS, Innes DJ. The pulmonary manifestations of lymphomatoid granulomatosis. Radiology. 1982;143: 613–618. 59. Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology. 2005;237:265–273. 60. Katzenstein AL, Peiper S. detection of Epstein-Barr virus genomes in lymphomatoid granulomatosis: analyses of 29 cases using the polymerase chain reaction technique. Mod Pathol. 1990;3:435–441. 61. Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Cancer Surv. 1997;30:233–248. 62. Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep. 2012;7:208–215.
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Childhood Lymphomatoid Granulomatosis: A Report of 2 Cases and Review of the Literature Zwanique C. A. Tacke, MSc,* M. Judith Eikelenboom, MD, PhD,w R. Jeroen Vermeulen, MD, PhD,w Marjo S. van der Knaap, MD, PhD,w Anne M. Euser, MD, PhD,z Paul van der Valk, MD, PhD,y and Gertjan J. L. Kaspers, MD, PhD*
Summary: Lymphomatoid granulomatosis (LG) is a B-cell type lymphoproliferative disease. It mainly affects the lungs but may have extrapulmonary manifestations, especially in the central nervous system. The purpose of this study was to review the pediatric cases in the literature and add 2 new cases to the existing literature. A review of the literature was performed on children (0 to 18 years of age at diagnosis) with pathologically proven LG. We found 47 case reports, which, together with 2 new cases, were systematically analyzed. The median age was 12 years. The main symptoms were general, pulmonary, and neurological. Approximately one third of the patients were immunocompromised. High mortality rate was observed. Pediatric LG is a rare disease, which appears to be more frequently seen in immunocompromised patients, especially patients with leukemia. The disease has a high mortality rate; therefore, aggressive therapy according to a highgrade B-cell lymphoma protocol is justified. Key Words: lymphomatoid granulomatosis, children, Epstein-Barr virus, B-cell lymphoma, CNS
(J Pediatr Hematol Oncol 2014;36:e416–e422)
L
ymphomatoid granulomatosis (LG) is an uncommon lymphoproliferative disorder first described by Liebow and colleagues in 1972.1 LG is rare in children; it mainly occurs in the fourth and fifth decade of life. The incidence of LG is unknown. LG has been described as an angiocentric and angiodestructive proliferative disease mainly affecting the lung,1 but other organs such as the central nervous system (CNS) can be involved as well.2 Pathologic features include a polymorphic infiltrate of lymphocytes, plasma cells and histiocytes, and atypical lymphoreticular cells.1 LG can be histologically staged into 3 grades, based on cytologic atypia, extent of necrosis, and retention of polymorphous cellular infiltrate.3 LG is a B-cell type disease and can occur in immunocompromised patients.4,5 The diagnosis is often delayed or only made at autopsy. The prognosis is poor and mortality varies from 38% to 64%,2 although long-lasting remissions have been described.6,7 Recently 2 children with LG were seen in our hospital. Received for publication May 11, 2013; accepted November 14, 2013. From the *Division of Pediatric Oncology/Hematology; Departments of wChild Neurology; yPathology, VU University Medical Center, Amsterdam; and zDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. Z.C.A.T and M.J.E. contributed equally. The authors declare no conflict of interest. Reprints: Gertjan J. L. Kaspers, MD, PhD, Division of Pediatric Oncology/Hematology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands (e-mail: gjl.kaspers@ vumc.nl). Copyright r 2013 by Lippincott Williams & Wilkins
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Because the disease is rare, especially in children, the literature about prognosis and the choice of therapy is limited. The purpose of this study was to review all pediatric patients with LG reported in the literature.
METHODS A systematic review of the literature was performed, limited to papers in English and children aged between 0 to 18 years. PubMed was searched for: LG and/or angiocentric B-cell lymphoma. One case report was found in a reference of another article.8 Some of the patients were reported more than once and for those patients the case report with most information was included.9–13 Some patients suffered from T-cell lymphomas and were therefore not included.14–16 One case report concerned a patient outside the age limit and one case report described a patient with lymphomatoid papulosis.17,18 Both case reports were excluded. In total, 47 children with pathologically proven LG were found and together with our 2 cases, we had reports on 49 children. We recorded characteristics listed in Table 1. Involvement of organs was based on biopsy and/or abnormalities on imaging and clinical findings. All clinical data were analyzed by SPSS 16.0 using descriptive statics.
CASE REPORTS Case Report I A 10-month-old baby girl without a medical history was admitted to the hospital with fever and seizures. Viral encephalitis was suspected and intravenous (IV) antiviral drug therapy (aciclovir) was started. She developed a status epilepticus and was transported to our hospital. She was treated with phenytoin and midazolam IV and intubated. She subsequently developed hepatosplenomegaly, a status epilepticus, and declined neurologically. Magnetic resonance imaging (MRI) of the brain revealed multiple lesions, especially in the gray matter (Fig. 1). T1-weighted images with gadolinium revealed enhancement of the leptomeninges and some of the focal parenchymal lesions. Treatment with methylprednisolone IV resulted in a neurological improvement. However, she deteriorated again and MRI showed progression of the lesions with new lesions in the cerebral white matter. She died 4 months after her initial symptoms. Autopsy revealed large lymphomatoid infiltrations mainly in the brain and lungs but also in the liver and spleen. The infiltrates consisted of a majority of small cells (largely CD3-positive and CD5-positive) and scattered large, blastic cells that were CD20-positive and CD79a-positive; a fair number of macrophages/histiocytes were present and stained positive for CD68-positive cells. The B cells were positive for EBV (by EBER RNA in situ hybridization). There was no necrosis in the infiltrates, or in the surrounding brain parenchyma. There was only minimal extension of lymphoid cells in the brain tissue that showed mild gliosis. The final diagnosis was LG grade 1.
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TABLE 1. Childhood Lymphomatoid Granulomatosis (LG): Review of Clinical and Pathologic Data
Age at Localization (Clinically EBV Tumor Patient Diagnosis Suspected and/or Proven by Status/ Number (y)/Sex Biopsy or Autopsy) Grade
Follow-up (mo)/Status at Last Follow-up
Medical History
Therapy
Lung*, CNS*, liver*, spleen*
+ /1
NA
Steroids
4/death
10/F
CNSw
/1
Steroids, chemo, anti-CD20
9/death
319 420
12/M 7/F
CNSw Lungw, CNSw, kidneyz
NA/NA /NA
521 613
15/M 17/M
Skinw Lungz, CNSw, liverw, spleenw
+ /NA NA/NA
Necrotic and granulomatous skin lesions, pancytopenia, hemophagocytosis NA ALL treatment complete before admission Wiskott-Aldrich syndrome NA
722
1/M
NA/NA
823 924
4/M 18/F
Lung*,w, liver*, kidney*, glands*, LNN*,w Lungw, CNSw Lung*,w, CNS*
NA/NA NA/NA
106 117 1225 138 149 159 165
14/F 10/M 12/M 14/M 10/M 7/M 10/M
Lungw, CNSz Lungw, glandw, eyez, kidneyz Lung*,w, LNN*,w CNSz, skinw Lung*,w, liver*,w Lung*,w, CNS*, intestinal* Lungw, liverz, kidneyz
NA/1 NA/NA + /NA NA/NA /NA /NA + /2
1726 1827
18/M 16/F
Lungz, CNSz, skinw CNSz, pleuraw
1928 2029 2130
14/F 16/M 4/M
Lungw, CNSw Lungw Lungz, skinw
+ /NA NA/1 /NA
2215 2331
4/F 17/F
LNNw CNSw
+ /NA NA/3
Lungw Lungw, CNSw Lungw, skinw, glandsw CNSz, liverz Lung*,w, liver*, glands*, CNS* Lungw, CNSz, liverz Lungw, skinw, liverz, spleenz, LNNw Lungz, CNSw kidneyz, LNNz Lungw, LNNz Lungw Lung*,w, CNS*, skin*,w Lung*,w, CNS*, skin* Lung*,w, URT*´w Lung*,w Kidneyw Skinw, spleenz Lung* Lungw, earw, paranasal sinusw Lungw Lungw Lungw, CNSz, liverz, bone marrowz, LNNz
+ /1 NA/NA NA/NA
1 (this study) 2 (this study)
2432 251 2633
1/F
4/M 8/F 6/F
2734
13/F
2835 2936
16/M 12/M
3037
10/F
3138 3239 3340 3441 3511 3642 3743 3844 3945 4012
18/M 4/F 16/M 18/F 8/F 16/M 4/M 17/F 9/M 7/M
4146 4246 438
18/M 2/F 14/M
4447
12/F
4548
15/M
r
Lungz, LNNw, URTw, temporal bonez Lungz, CNSz, skinw
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/2 /NA
Surgery Steroids, chemo
NA 66/alive
Anti-CD20 Steroids, chemo, RT, surgery Steroids, chemo
18/alive 51/alive
EBV infection, hypogammaglobulinemia NA Steroids, chemo, RT Multiple asymptomatic Steroids, chemo, RT congenital skeletal anomalies NA Steroids, chemo NA Steroids, chemo Wiskott-Aldrich syndrome Steroids, chemo NA NA Defects in B-cell function Steroids, chemo Defects in B-cell function Steroids, chemo AML Steroids, chemo, IFN NA IFN SLE with renal transplant Steroids, chemo (EBV-positive donor) NA Steroids NA NA Hemolytic anemia, skin Chemo, allogeneic nodules, obstructive cord stem cell pulmonary disease, EBV transplant infection ALL Steroids, RT NA Steroids, chemo, IFN NA NA NA Steroids ALL Steroids, chemo
8/death NA/death 14/death 163/alive 108/alive 36/death 2/death 4/death 2/death 18/alive 22/death 36/alive NA NA 12/alive
21/alive NA NA 27/alive 13/death
NA/NA
NA
Steroids
5/death
NA/NA NA/NA
NA NA
Chemo Steroids, chemo
NA 72/alive
/1
NA
Surgery
4/alive
+ /NA NA/3 + /3 NA/NA NA/NA NA/NA NA/NA NA/2 NA/NA + /2
NA NA Recurrent oral candidiasis NA ALL NA NA NA ALL ALL
NA 24/alive 17/death 25/death 2/death 7/death NA 40/alive NA/death 12/deathy
NA/NA NA/NA NA/NA
NA NA Evans syndrome and splenectomy
/3
NA
NA Steroids, surgery Steroids, IFN Steroids, chemo Steroids Steroids NA Steroids, chemo Steroids Antiviral and antibiotics Chemo Steroids, chemo Steroids, chemo, RT, bone marrow transplant Steroids, chemo, RT
NA/NA
NA
Steroids, chemo
4/alive 3/death 36/alive 44/death 1/death
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TABLE 1. (continued) Age at Localization (Clinically EBV Tumor Patient Diagnosis Suspected and/or Proven by Status/ Number (y)/Sex Biopsy or Autopsy) Grade
Medical History
Therapy
NA Crohn
Steroids, chemo, RT, surgery Steroids, chemo
+ /2
NA
NA
+ /3
Griscelli syndrome II
Immunosuppressive treatment
4649
16/M
CNSw
/NA
4750
17/F
+ /3
4851
3/F
4952
11/F
Lungw, CNSz, liverz, oropharynxw Lungz, liverz, stomachw, skinz Lungw
Follow-up (mo)/Status at Last Follow-up 6/alive 48/alive 2/death NA/death
*Autopsy. wBiopsy site. zClinically suspected. yDeath from ALL, LG in remission. ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; chemo, chemotherapy; CNS, central nervous system; EBV, Epstein-Barr virus; IFN, interferon a 2-b; LNN, lymph nodes; NA, not available; RT, radiotherapy; SLE, systemic lupus erythematosus; URT, upper respiratory tract.
Case Report II A 10-year-old girl, with a history of necrotic and granulomatous skin lesions, pancytopenia, and hemophagocytosis, complained of fatigue, double vision, clumsiness, and facial asymmetry. On physical examination she had involvement of several cranial nerves. MRI of the brain showed multiple hyperintense focal lesions in the white and gray matter. Cerebrospinal fluid pathology showed lymphocytosis. Ultrasonography of the abdomen showed a hepatosplenomegaly. Bone marrow biopsy showed hypocellularity suggestive of aplastic anemia. A brain biopsy was performed and a diagnosis of LG (grade 1; no EBV-positive cells; Fig. 2) was tentatively made 3 months after the presentation, on the basis of the mixed infiltrates, with predominant small T ells, scattered blastic B cells with absent clonality, and admixed histiocytes, despite the negative EBER. The presence of only blastic T cells excludes reactive conditions, and absence of clonality makes a T-cell-rich diffuse large B-cell lymphoma less likely, favouring the diagnosis of LG. She was treated with vincristine, cyclophosphamide, and dexamethasone. MRI of the brain first improved but later-on, the lesions progressed. A second brain biopsy was performed, which showed a relapse of LG. Therapy was intensified with a modified non-Hodgkin lymphoma protocol, but her condition deteriorated and treatment was started with anti-CD20 IV and intrathecally. She died 9 months after she was diagnosed with LG. Autopsy showed a bronchopneumonia and in the brain, it showed a perivascular infiltration of T cells and phagocytes and loss of neurons and ischemic ganglion cell destruction.
RESULTS The findings of all 49 patients are summarized in Table 1. Median age of the patients at diagnosis was 12 years (range, 0 to 18 y). The male: female ratio was 1.2:1. Median time interval from onset of symptoms to diagnosis was 3 months (range, 1 to 96 mo).
Symptoms and Localization Main symptoms were pulmonary (66% of patients) and neurological (47%), but general symptoms as fever and weight loss were observed in 62%. Most commonly involved organs were lung (82% of patients), CNS (51%), liver (25%), skin (22%), lymph nodes (16%), kidney (13%), and spleen (8%).
Diagnostics Chest x-ray was used to detect pulmonary lesions in 67% of patients, chest computed tomography (CT) in 30%
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of them. The most frequent abnormalities were diffuse bilateral lesions, sometimes nodular. In 33% of the cases CSF was investigated, often demonstrating hypercellularity and elevated glucose and protein level. MRI of the brain was obtained in 37% of patients, most frequently showing multifocal lesions.
Pathology LG was proven in 45 patients during life and in 4 patients at autopsy (case 1, 35, 36, 39). In 23 patients, tumor tissue was examined for EBV, of which 13 (57%) were diagnosed positive for EBV. Eighteen patients (37%) were histologically classified. The lesions were graded as grade I in 6 patients (33%), grade II in 5 (28%), and grade III in 7 (39%).
Therapy In 24 patients (49%) steroids and chemotherapy were started as initial therapy. In addition, 4 received radiotherapy, 2 radiotherapy and surgery, and 2 interferon a-2b. Ten patients (22%) were administered steroids without chemotherapy, of which one patient also received radiotherapy, one underwent surgery, and one was administered with interferon a-2b. Treatment was heterogenous in the other patients and included anti-CD20 and allogeneic stem cell transplantation. One patient received antibiotic and antiviral treatment only; chemotherapy combined with steroids was recommended, but the parents declined the treatment proposal (case 40). In 6 patients, therapy was not described in detail.
Follow-up The median duration of follow-up since the first clinical presentation was 15.5 months (range, 2 to 163 mo). Thirteen patients were lost to follow-up or follow-up was not described. Of the remaining 36 patients, 18 (50%) were alive and 18 patients (50%) had died. The median interval between diagnosis and death was 8 months. Outcome was studied in relation to organ involvement. Skin involvement, either solitary or generalized, had the highest mortality rate (64%), followed by lung (60%), CNS (57%), and liver (55%) involvement. From the 24 patients with steroids and chemotherapy as therapy, 11 were alive and 12 had died, 1 was lost to follow-up. r
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FIGURE 1. Magnetic resonance images of a 10-month-old girl (case 1) with lymphomatoid granulomatosis with multifocal and diffuse lesions in the brain parenchyma, especially in the cortex of the parietal, temporal, and occipital lobes (A, FLAIR; B and C, T2-weighted images) at presentation. T1-weighted images with gadolinium revealed enhancement of the leptomeninges and some of the focal parenchymal lesions (not shown). Three months later, the images show progression with cystic degeneration (D, FLAIR; E and F, T2-weighted images). FLAIR indicates fluid-attenuated inversion recovery.
Medical History In 20 patients, comorbidity or a positive medical history was reported. Leukemia was observed in 7 children. Two patients had been treated for acute lymphoid leukemia, and one patient had acute myeloid leukemia and completed therapy just 1 month before the first symptoms of LG occurred. Four patients developed LG during treatment of acute lymphoid leukemia. Two patients were known to have the Wiskott-Aldrich syndrome. One patient had a persistent EBV infection and hypogammaglobulinemia. Two patients, siblings, had subtle defects in B-cell function with mild suppression of serum immunoglobulin G-levels. Two patients had skin lesions before admission, of which one also had pancytopenia with some hemophagocytosis and the other had hemolytic anemia, a previous EBV infection, and an 18-months history of inflammatory and obstructive pulmonary disease. One r
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patient had a history of recurrent oral candidiasis for 3 years before developing LG. One patient had end-stage renal disease as a result of systemic lupus erythematosus and had a renal transplant from an EBV-positive donor. One patient was known with Evans syndrome and underwent a splenectomy. One patient had the Crohn disease and the other had the Griscelli syndrome type 2.
DISCUSSION Until now, no systematic review of childhood case reports of LG has been published. LG occurs most often at middle age and is rarely seen during childhood.2 We report a total of 47 pediatric patients found in the English literature since the first description of LG in 1972 and added 2 newly identified patients of our own hospital. It has been suggested that LG is a T-cell disease because of www.jpho-online.com |
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FIGURE 2. The immunohistologic findings of a 10-year-old girl (case 2) with lymphomatoid granulomatosis. A, Brain biopsy showing a perivascular cuff of predominantly lymphoid cells, with a mixture of B cells and T cells in this CD20 (= anti-B-cell antibody)-staining (CD20, 10 objective). B, Higher magnification of perivascular infiltrate. There is a predominance of small lymphocytic cells, with occasional blasts, that is, large cells with nuclei showing a vesicular, lighter chromatin (hematoxylin-eosin, 25 objective). C, Some area as (B) (adjacent section) stained for CD20. The positive cells are a minority, but the blasts are positively stained, (CD20, 25 objective). D, Section from the autopsy of this patient showing localization of the process in the basal ganglia (hematoxylin-eosin, 2.5 objective).
immunohistochemical evidence of massive T-lymphocyte infiltration.53 Recent studies using more sensitive immunophenotyping and EBV RNA in situ hybridization rather support the concept that LG is an EBV-positive B-cell lymphoproliferative disorder, with a large number of reactive Tcell infiltrates.40,54,55 Although the classification of the WHO is clear, there are cases at least very similar to LG but without EBV positivity.31,56 Some case reports in the literature appeared to be clearly T-cell lymphomas and were, therefore, excluded from this review. Publication bias is likely present in our study, but this disease is so rare that a prospective study design for children with LG is virtually impossible. Symptoms at presentation are diverse but differ from those reported in adults.1,2 We found a higher incidence of neurological symptoms but a lower incidence of general malaise and weight loss, although pulmonary symptoms occur at the same rate.2 Hepatosplenomegaly and lymphadenopathy are frequent findings in adults,2 but are even more common in children. The abnormalities observed on chest x-ray and chest CT resemble the abnormalities observed in adult reports.57,58 In the case of pulmonary symptoms, at least a chest x-ray should be obtained and a chest CT should be considered. MRI of the brain in the case of CNS involvement identified multifocal T2-hyperintense lesions in some cases with surrounding edema. Multifocal intraparenchymal lesions were also the most common abnormalities in another recent study focusing on brain abnormalities in LG.59 In view of the high incidence of CNS involvement, a brain MRI should be considered in all children suspected of or diagnosed with LG. Although the MRI appearance of LG of the brain varies, multifocal white and gray matter lesions with enhancement are most frequent.
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Multiple organ involvement is more frequent in children than solitary organ involvement. Therefore, when LG is suspected in a child, each tract should be examined for proper staging. A definitive diagnosis of LG can only be made by histopathologic examination of involved tissues. EBV was positive in 50% of the 20 tested patients, which is frequent but less often than in other studies.54,60 Histologically, the nodular lesions consist of polymorphic infiltrates of lymphocytes around blood vessels and focal sites of necrosis within the lymphomatoid infiltrates with, depending on their grade, large atypical cells.31,61 Histopathologic grading is important in the prognosis and treatment of patients with LG. Involvement of the CNS is considered an adverse prognostic sign,2 but we could not confirm this. Outcome in our study was also independent of EBV status, although EBV status was determined in only half of the cases. Histologic gradation did not correlate with mortality, but the small numbers limit firm conclusions. Fourteen of the 46 patients were immunocompromised, either by treatment for another condition such as leukemia, or by an underlying immunodeficiency. This indicates that the immune system plays a role in the etiology of LG. Remarkably, one pair of siblings with LG was found with a B-cell function defect, which suggests a possible genetic condition or an environmental provoking factor.9 It is not possible to advice an optimal therapy for LG based on the data of this review. Most of the patients were treated with corticosteroids, either as single agent or combined with chemotherapeutic agents. Radiotherapy has been used for CNS involvement, as recently a distinction in treatment recommendations is made between low-grade and highgrade LG. Immunomodulatory therapy like interferon a is used for low-grade disease and multi-agent chemotherapy r
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for high-grade lesions. This is partly based on the understanding that low-grade LG is immune system-dependent and high-grade LG consists of EBV-positive large atypical B cells and together with its clinical aggressiveness be approached as diffuse large B-cell lymphoma using intensive chemotherapy.62
19. Paspala AB, Sundaram C, Purohit AK, et al. Exclusive CNS involvement by lymphomatoid granulomatosis in a 12-year-old boy: a case report. Surg Neurol. 1999;51:258–260. 20. Moertel CL, Carlson-Green B, Watterson J, et al. Lymphomatoid granulomatosis after childhood acute lymphoblastic leukemia; report of effective therapy. Pediatrics. 2001;107:E82, Available at: http://pediatrics.aappublications.org/cgi/reprint/ 107/5/e82. Accessed February 16, 2009. 21. Sebire NJ, Haselden S, Malone M, et al. Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol. 2003;56:555–557. 22. Lehman TJ, Church JA, Isaacs H. Lymphomatoid granulomatosis in a 13 month-old infant. J Rheumatol. 1989;16: 235–238. 23. Whelan HT, Moore P. Central nervous system lymphomatoid granulomatosis. Pediatr Neurosci. 1987;13:113–117. 24. Verity MA, Wolfson WL. Cerebral lymphomatoid granulomatosis. A report of two cases, with disseminated necrotizing leukoencephalopathy in one. Acta Neuropathol. 1976;15: 117–124. 25. Ilowite NT, Fligner CL, Ochs HD, et al. Pulmonary angiitis with atypical lymphoreticular infiltrates in Wiskott-Aldrich syndrome: possible relationship of lymphomatoid granulomatosis and EBV infection. Clin Immunol Immunopathol. 1986;41:479–484. 26. Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol. 2001;25:1111–1120. 27. Cachat F, Meagher-Villemure K, Guignard JP. Lymphomatoid granulomatosis in a renal transplant patient. Pediatr Nephrol. 2003;18:838–842. 28. Hareema A. Lymphomatoid granulomatosis: unusual presentation in a pediatric patient. Pediatr Devel Pathol. 2003;6:106–107. 29. Mazzie JP, Price AP, Khullar P, et al. Lymphomatoid granulomatosis in a pediatric patient. Clin Imaging. 2004; 28:209–213. 30. LeSueur BW, Ellsworth L, Bangert JL, et al. Lymphomatoid granulomatosis in a 4-year-old boy. Pediatr Dermatol. 2000; 17:369–372. 31. Katszenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34:35–48. 32. Medeiros LJ, Jaffe ES, Chen YY, et al. Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions. Am J Surg Pathol. 1992;16:439–447. 33. Be´ka´ssy AN, Cameron R, Garwicz S, et al. Lymphomatoid granulomatosis during treatment of acute lymphoblastic leukemia in a 6-year old girl. Am J Pediatr Hematol Oncol. 1985;7:377–380. 34. Prapphal N, Limudomporn S, Watana D, et al. Lymphomatoid granulomatosis with upper airway obstruction: a case report. J Med Assoc Thai. 1991;74:526–530. 35. Capone PM, Mechtler LL, Bates VE, et al. Multiple giant intracranial aneurysms associated with lymphomatoid granulomatosis. A magnetic resonance imaging and angiographic study. J Neuroimaging. 1994;4:109–111. 36. Gu¨ven A, Baskin D. Lymphomatoid granulomatosis in a boy with long-term follow-up. Pediatr Hematol Oncol. 2001;18: 377–382. 37. Kendi AT, McKinney AM, Clark HB, et al. A pediatric case of low-grade lymphomatoid granulomatosis presenting with a cerebellar mass. Am J Neuroradiol. 2007;28:1803–1805. 38. Hu X, Selbs E, Drexler S. An 18-year-old man with persistent cough and bilateral lower lung infiltration. Epstein-Barr viruspositive lymphoproliferative disorder consistent with lymphomatoid granulomatosis. Arch Pathol Lab Med. 2006;130:E44–E46. 39. Karnak I, Ciftci AO, Talim B, et al. Pulmonary lymphomatoid granulomatosis in a 4 year old. J Pediatr Surg. 1999;34: 1033–1035. 40. Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral
REFERENCES 1. Liebow AA, Carington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol. 1972;3:457–558. 2. Katzenstein AL, Carrington MD, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43:360–373. 3. Lipford EH, Margolick JB, Longo DL, et al. Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood. 1988;72:1674–1681. 4. Anders KH, Latte H, Chang BS, et al. Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome. Hum Pathol. 1989;20:326–334. 5. Oren H, Irken G, Kargi A, et al. A pediatric case of lymphomatoid granulomatosis with onset after completion of chemotherapy for acute myeloid leukemia. J Pediatr Hematol Oncol. 2003;25:163–165. 6. Mizuno T, Takanashi Y, Onodera H, et al. A case of lymphomatoid granulomatous/angiocentric immunoproliferative lesion with long clinical course and diffuse brain involvement. J Neurol Sci. 2003;213:67–76. 7. Pearson AD, Craft AW, Howe JM. Choroidal involvement in lymphomatoid granulomatosis. Br J Opthalmol. 1991;75: 688–689. 8. Bernstein ML, Reece ER, de Chadarere´vian JP, et al. Bonemarrow transplant in lymphomatoid granulomatosis. Report of a case. Cancer. 1986;58:969–972. 9. Rogers BB, Browning I, Rosenblatt H, et al. A familial lymphoproliferative disorder presenting with primary pulmonary manifestations. Am Rev R Dis. 1992;145:203–208. 10. Rimsza LM, Rimsza ME, Gilbert-Barness E. Pathological cases of the month. Lymphomatoid granulomatosis. Am J Dis Child. 1993;147:693–694. 11. Cohen SR, Landing BH, Siegel S, et al. Lymphomatoid granulomatosis in a child with acute lymphatic leukemia in remission. Ann Otol Rhinol Laryngol Suppl. 1978;87:5–10. 12. Scully RE, Mark EJ, McNeely WF, et al. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 40-1987. A seven-year-old boy with acute lymphocytic leukemia in remission, with abnormalities of the ears, paranasal sinuses, and lungs. N Eng J Med. 1987;317: 879–890. 13. Podlas HB, Gritzman MC, Thomaides S, et al. CT of CNS lesions in lymphomatoid granulomatosis: case report. Am J Neuroradiol. 1988;9:592–594. 14. Mrusek S, Marx A, Kummerle-Deschner J, et al. Development of granulomatous common variable immunodeficiency subsequent to infection with Toxoplasma gondii. Clin Exp Immunol. 2004;137:578–583. 15. Drut R, Drut RM. Angiocentric immunoproliferative lesion and angiocentric lymphoma of lymph node in children. A report of two cases. J Clin Pathol. 2005;58:550–552. 16. Mosqueda-Taylor A, Menenes-Garcia A, Za´rate-Osorno A, et al. Angiocentric lymphomas of the palate: clinico-pathological considerations in 12 cases. J Oral Pathol Med. 1997;26:93–97. 17. Leedman PJ, Matz LR, Pullan P. Endocrine dysfunction in lymphomatoid granulomatosis. Aust N Z J Med. 1989;19: 97–102. 18. Rogers M, de Launey J, Kemp A, et al. Lymphomatoid papulosis in an 11-month-old infant. Pediatr Dermatol. 1984;2: 124–130. r
2013 Lippincott Williams & Wilkins
www.jpho-online.com |
e421
Tacke et al
41. 42. 43. 44.
45. 46. 47. 48. 49.
50.
51.
infection of B lymphocytes and response to interferon-alfa 2b. Blood. 1996;87:4531–4537. Patton WF, Lynch JP 3rd. Lymphomatoid granulomatosis. Clinicopathologic study of four cases and literature review. Medicine (Baltimore). 1982;61:1–12. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid Granulomatosis. Prospective clinical and therapeutic experience over 10 years. N Eng J Med. 1982;306:68–74. Hunter S, Samir A, Eisner B, et al. Diagnosis of renal lymphoma by percutaneous image guided biopsy: experience with 11 cases. J Urol. 2006;176:1952–1956. Takeshita M, Akamatsu M, Ohshima K, et al. Angiocentric immunoproliferative lesions of the skin show lobular panniculitis and are mainly disorders of large granular lymphocytes. Hum Pathol. 1995;26:1321–1328. Drut R. Angiocentric B-cell lymphoma of the lung in an immunocompromised boy. Pediatr Pathol. 1988;8:395–400. Colby TV, Carrington CB. Pulmonary lymphomas simulating lymphomatoid granulomatosis. Am J Surg Pathol. 1982;6:19–32. C¸akmak O¨, Kutluk T, Akyol MU, et al. Angiocentric lymphoma involving the temporal bone in a child. Eur Arch Otorhinolaryngol. 1999;256:262–265. Halvani A, Owlia MB, Sami R. Lymphomatoid granulomatosis with splenomegaly and pancytopenia. Zhongguo Fei Ai Za Zhi. 2010;13:84–86. Gupta T, Wadasadawala T, Shet T, et al. Isolated central nervous system involvement by lymphomatoid granulomatosis in an adolescent: a case report and review of literature. Pediatr Hematol Oncol. 2010;27:150–159. Destombe S, Bouron-DalSoglio D, Rougemont AL, et al. Lymphomatoid granulomatosis: a unique complication of Crohn disease and its treatment in pediatrics. J Pediatr Gastroenterol Nutr. 2010;50:559–561. Uccini S, Testi AM, Al-Badri SF, et al. Gastric perforation as a primary manifestation of lymphomatoid granulomatosis. Pediatr Blood Cancer. 2011;57:178–179.
e422 | www.jpho-online.com
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52. Szczawinska-Poplonyk A, Kycler Z, Breborowicz A, et al. Pulmonary lymphomatoid anulomatosis in Griscelli syndrome type 2. Viral Immunol. 2011;24:471–473. 53. Nichols PW, Koss M, Levine AM, et al. Lymphomatoid granulomatosis: a T-cell disorder? Am J Med. 1982;72:467–471. 54. Myers JL, Kurtin PJ, Katzenstein AA, et al. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol. 1995;19:1300–1312. 55. Guinee D, Jaffe E, Kingma D, et al. Pulmonary Lymphomatoid granulomatosis. Evidence for a proliferation of EpsteinBarr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol. 1994;18:753–764. 56. Pittaluga S, Wilson WH, Jaffe ES, et al. WHO classification of tumours of heamatopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008:247–249. 57. Lee JS, Tuder R, Lynch D. Lymphomatoid granulomatosis: radiographic features and pathological correlations. Am J Roentgenol. 2000;175:1335–1339. 58. Dee PM, Arora NS, Innes DJ. The pulmonary manifestations of lymphomatoid granulomatosis. Radiology. 1982;143: 613–618. 59. Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology. 2005;237:265–273. 60. Katzenstein AL, Peiper S. detection of Epstein-Barr virus genomes in lymphomatoid granulomatosis: analyses of 29 cases using the polymerase chain reaction technique. Mod Pathol. 1990;3:435–441. 61. Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Cancer Surv. 1997;30:233–248. 62. Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep. 2012;7:208–215.
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