Lymphomatoid Granulomatosis After Childhood Acute Lymphoblastic
Leukemia: Report of Effective Therapy
Christopher L. Moertel, MD*; Bonnie Carlson-Green, PhD‡; Jan Watterson, BA*; and
Susan C. Simonton, MD§
ABSTRACT. Lymphomatoid granulomatosis, a rare
condition in children, affects the lungs primarily but may have significant extrapulmonary manifestations, espe-cially in the central nervous system. We report a case of lymphomatoid granulomatosis with onset after the com-pletion of chemotherapy for childhood acute lympho-blastic leukemia. Two months after treatment ended, the 7-year-old girl developed splenomegaly, cervical adenop-athy, and bilateral interstitial pulmonary infiltrates. She improved on cefotaxime but experienced a seizure 1 month later. A computed tomography scan of the head was normal, but her pulmonary infiltrates had become nodular. A computed tomography– guided biopsy of 1 of the nodules revealed cellular interstitial pneumonitis. One month later, she had persistent pulmonary infil-trates, marked splenomegaly, and new seizures. Mag-netic resonance imaging of the head revealed cerebral nodules. Itraconazole was begun, and the pulmonary infiltrates resolved. Five months after her initial symp-toms, she developed tonic pupil and a decreased level of consciousness. Dexamethasone was initiated. Needle bi-opsies of the brain were carried out, yielding the diag-nosis of severe chronic inflammatory changes focally consistent with granuloma. The child redeveloped splenomegaly and fever, and then suffered an acute de-compensation with hypoxemia, tachypnea, splenomeg-aly, and cardiac gallop. Open-lung biopsy revealed lym-phomatoid granulomatosis. Lymphoma-directed therapy was initiated, and the patient had complete resolution of pulmonary and cerebral nodules 5 months later. No in-trathecal chemotherapy was administered, and radiation therapy was not necessary. Neuropsychological testing obtained after completion of therapy revealed an im-provement in attention, coordination, and fine motor speed over time. She is now in good health and attending school.Pediatrics2001;107(5). URL: http://www.pediatrics. org/cgi/content/full/107/5/e82; lymphomatoid granulomato-sis, lymphoproliferative disorder, acute lymphoblastic leuke-mia, child, second malignancy.
ABBREVIATIONS. ALL, acute lymphoblastic leukemia; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; CT, com-puted tomography; EBV, Epstein-Barr virus.
L
ymphomatoid granulomatosis, first described
by Liebow et al
1in 1972, is an extremely rare
condition in children. Although it affects the
lungs primarily, it may have significant
extrapulmo-nary manifestations, especially in the central nervous
system. We report a case of lymphomatoid
granulo-matosis with onset after the completion of
chemo-therapy for childhood acute lymphoblastic leukemia
(ALL). This patient belongs to a unique subset of
pediatric patients who have been treated for ALL
and are subsequently afflicted with this disorder. At
least 3 such cases have been described to date, in
patients 6-, 7-, and 8 years old. Two of these patients
died of their disease; 1 obtained benefit from
acyclo-vir therapy for presumed zoster and was well 7
months later.
2– 4This report is the first to provide
magnetic resonance imaging (MRI) documentation
of the course of this disease in the brain. In addition,
serial neuropsychological testing demonstrated
im-provement of disease-related impairment in cortical
processes.
CASE REPORT
A 5-year-old girl was diagnosed with ALL in September 1992. No central nervous system disease was detected. Lymphoblasts were of early B cell lineage, with only 3% CD3-positive cells in the diagnostic marrow. Treatment according to Children’s Cancer Group protocol 1881, regimen A, was completed in November 1994. No cranial radiation was given. Subsequent off-therapy bone marrow aspiration and cerebrospinal fluid (CSF) examinations were normal.
The onset of bilateral otitis media and pansinusitis was noted on January 30, 1995. At that time, the patient was febrile to 38°C, the spleen was palpable to 2 cm below the costal margin, and right cervical adenopathy was noted. A chest radiograph revealed dif-fuse bilateral interstitial pulmonary infiltrates. Complete blood count results were as follows: hemoglobin, 14.2 g/dL; platelets, 274⫻109/L; white blood cells, 4.5⫻109/L, with 13% basophils
and no blasts. The patient improved on therapy with cefotaxime, and her splenomegaly resolved. On February 22, 1995, she expe-rienced a partial complex seizure. A computed tomography (CT) scan of the head and CSF analysis were normal. The pulmonary infiltrates had become nodular, and a CT-guided needle biopsy of a nodule was obtained on March 12, 1995. The biopsy specimen was sent for consultation, and the diagnosis of cellular interstitial pneumonitis with features of lymphocytic interstitial pneumonitis was made.
By March 24, 1995, the patient had developed marked spleno-megaly and additional seizures. Bone marrow and CSF were obtained; no evidence of leukemia or infiltrative process was noted. An MRI scan of the head revealed multiple gadolinium-avid cerebral nodules at the junction of the cerebral gray and white matter in a general distribution (Fig 1). Given the persis-tence of the nodular pulmonary infiltrates, emperic itraconazole was started. Over the next several weeks, continued improvement and resolution of the pulmonary infiltrates was noted (Fig 2). From the Departments of *Hematology/Oncology, ‡Child and Family
Ser-vices, and §Pathology, Children’s Hospitals and Clinics, St Paul, Minnesota. Received for publication Sep 5, 2000; accepted Jan 12, 2001.
Reprint requests to (C.L.M.) 345 N Smith Ave, St Paul, MN 55102. E-mail: chris.moertel@childrenshc.org
PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad-emy of Pediatrics.
However, on June 5, 1995, the patient acutely developed a tonic pupil on the left (dilated pupil and slow reaction to light and darkness, with photophobia), followed 3 days later by a decreased level of consciousness, bulbar speech, and drooling. Complete blood count revealed: hemoglobin, 10.9 g/dL; platelets, 168 ⫻ 109/L; and white blood cells, 2.5⫻109/L (46% neutrophils, 44%
lymphocytes, 10% monocytes). CSF revealed: protein, 79 mg/dL; glucose, 50 mg/dL; red blood cells, 1/mm3; and white blood cells,
7/mm3(100% lymphocytes). Dexamethasone (50 mg/m2/day
di-vided into 6-hour intervals) was administered, with improvement of neurologic symptoms. The dexamethasone was then quickly tapered to 10 mg/m2/day. On June 9, 1995, a fine-needle
aspira-tion of the spleen was obtained that was nondiagnostic. Four stereotactic needle biopsies of a brain nodule conducted on June 13, 1995 showed an atypical lymphoid infiltrate (Fig 3). The majority of lymphocytes were positive for CD3 with virtually no cells positive for L26 (CD20). Strong positivity for CD68 was present within macrophages. The biopsy specimens were referred for outside consultation yielding a diagnosis of severe chronic inflammatory changes focally consistent with granuloma. Addi-tional stains for acid-fast organisms and toxoplasmosis were neg-ative. Ultrastructural findings showed no evidence of significant demyelination or viral infection. Full clinical recovery was noted by June 17, 1995, and dexamethasone was tapered.
On July 18, 1995, the patient redeveloped splenomegaly and fever. Neck pain, hesitant speech, and yawning followed, and she was again treated with dexamethasone. This was slowly tapered, but on August 22, 1995, she suffered an acute decompensation with hypoxemia, tachypnea, poor color, splenomegaly, diffuse rales, and cardiac gallop. An echocardiogram revealed poor car-diac function with a shortening fraction of 20%. An MRI of the head revealed new frontal and parietal lesions, similar in character to those previously seen. A CT of the abdomen revealed new wedge-shaped densities in the kidneys, consistent with vascular
occlusion. The following day an open-lung biopsy was obtained, which demonstrated an atypical angiocentric lymphoproliferative process, suggestive of lymphomatoid granulomatosis (Fig 4). The perivascular atypical lymphocyte population was positive for CD45, CD3, and CD20, the majority being CD3-positive. Pathol-ogy consultation confirmed the immunohistologic diagnosis of lymphomatoid granulomatosis. Cultures of lung tissue were neg-ative for routine bacterial and acid-fast organisms, fungi, and viruses. Polymerase chain reaction analysis of frozen lung biopsy tissue showed no clonal rearrangement of the immunoglobulin heavy chain (IgHJH), T cell receptor-chain, and T cell receptor
␥-chain genes. Serology for Epstein-Barr virus (EBV) was negative. Serologies and cultures for cytomegalovirus were indicative of past infection, with no evidence of current activation. Serologies for histoplasmosis, cryptococcus, and blastomyces were likewise negative. EBV in situ hybridization analysis, conducted on tissue from the lung biopsy with intact RNA, was negative.
Lymphoma-directed chemotherapy was initiated on August 31, 1995 and consisted of intravenous cyclophosphamide, intravenous vincristine, oral prednisone, and intravenous methotrexate.5The
patient exhibited immediate and continued clinical improvement, and by January 16, 1996, complete resolution of nodules in the cerebrum and chest was noted. Cardiac function returned to nor-mal. The spleen, still palpable, was markedly diminished in size. Chemotherapy ended on March 20, 1996, by which time the splenomegaly had resolved.
Neuropsychological testing was performed in February 1997, 11 months after completion of treatment for lymphomatoid gran-ulomatosis. Testing revealed a decrease in overall intelligence quotient scores compared with baseline testing completed during treatment for her ALL in 1992. Follow-up neuropsychological testing was administered in March 1998, showing an improve-ment in attention, fine motor speed, and coordination, although still showing deficits compared with same-aged peers.
Fig 1. Serial T1-weighted MRIs with gadolinium enhancement:A, at initia-tion of therapy;B, 3 months after initi-ation of therapy;C, 1 year from diag-nosis; andD, off therapy.
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At her last medical follow-up in August 2000, the patient con-tinued to be in good health. She had been off anticonvulsants for 41 months. She attends school in a mainstream class and receives special education services as needed under the “other health im-paired” classification. Stimulant medication (methylphenidate) for attention problems has been beneficial.
DISCUSSION
The initial published series of 40 patients with
lymphomatoid granulomatosis by Liebow et al
1in-cluded only 1 child, aged 8.5 years. A subsequent
series added 116 cases, with 12 of 152 patients (8%)
⬍
20 years old.
6Although the primary pulmonary
manifestations of this disorder are central to the
di-agnosis, extrapulmonary manifestations, as were
present in our patient’s case, may be quite
signifi-cant.
1,6,7Involvement of the nervous system (67%),
skin (39%), kidney (32%), spleen (18%), liver (12%),
heart (11%), and lymph nodes (8%) has been
de-scribed.
6The T cell origin of the disorder was first
sug-gested by Nichols et al
8and was elegantly confirmed
by Lipford and colleagues
9in 1988. A subsequent
study of 4 patients confirmed T cell predominance
but suggested that the process was dependent on an
Fig 2. Serial chest radiographs showing evolution of nodular pulmonary infil-trates: A, normal radiograph during therapy for ALL;B, bilateral interstitial infiltrates at onset of lymphomatoid granulomatosis;C, at initiation of ther-apy for lymphomatoid granulomatosis; and D, 2 months after completion of therapy.
Fig 3. Needle biopsy of frontal lobe of brain, revealing pleomorphic perivas-cular infiltrate. Original magnification: 400⫻; hematoxylin and eosin stain.
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EBV-associated B cell lymphoproliferative
phenom-enon.
10A more recent series of 16 cases determined
the proliferation index of B cells, T cells, and
histio-cytes in lymphomatoid granulomatosis lesions,
us-ing combined immunohistochemistry for CD20,
CD3, CD68, and CD57 with DNA topoisomerase II as
a marker of proliferation.
11The authors found a
sig-nificantly higher proliferation index in B cells
com-pared with the other cell populations. The average B
cell proliferation index in the high-grade (grade III)
lesions was similar to that in large cell
non-Hodgkin’s B cell lymphomas.
11It should be
empha-sized that our patient had no evidence of EBV
infec-tion, based on serology and in situ hybridization of
pathologic lung tissue. Our patient demonstrates
that, as has also been shown in the posttransplant
lymphoproliferative disorders, EBV need not be
present to incite this illness.
12Fauci and colleagues
7described their experience
with 15 patients with lymphomatoid
granulomato-sis, one who was 16 years old. Thirteen patients
received therapy with cyclophosphamide and
pred-nisone; 7 had long-lasting complete remissions. Of
those who did not respond to therapy and
subse-quently died, the majority developed malignant
lym-phoma. Fauci et al
7noted that early treatment with
immunosuppressive therapy markedly decreased
the previously high mortality rate (65%–90%) of
lym-phomatoid granulomatosis.
We confirm that cyclophosphamide and
cortico-steroid-based therapy is effective, and note that
cor-ticosteroids alone produced only temporary benefit
in our patient. Central nervous system benefits
ob-tained without such directed therapy as cranial
radi-ation or intrathecal chemotherapy were remarkable
in this case, and well documented by serial
neuro-psychological testing and MRI.
Our patient’s diagnosis was delayed in this case
because of a number of factors: 1) the patient
re-sponded to empiric antibiotic therapy; 2) limited
ma-terial was obtained from the needle biopsies, making
histopathologic review difficult; and 3) the biopsies
were all obtained when the patient was being treated
with glucocorticoid therapy, which may have
ob-scured the diagnosis early in the patient’s course.
Awareness of the features of this syndrome in the
appropriate clinical context may lead to earlier
rec-ognition and prompt institution of appropriate
ther-apy.
Childhood
lymphomatoid
granulomatosis
should be considered in the clinicopathologic
diag-nosis of upper respiratory tract symptomatology
with concurrent nodular pulmonary infiltrates and
central nervous system manifestations, especially in
the setting of past diagnosis of and treatment for
ALL with apparent long-term remission.
ACKNOWLEDGMENTS
This work was supported in part by the Pine Tree Apple Tennis Classic Oncology Research Fund.
We thank the following individuals who have made the prep-aration of this manuscript possible: Nancy Battaglia; Timothy Greiner, MD; Thomas Gross, MD; and Jere´ Wasko.
We also thank Joanne Hilden, MD, and Peter Helseth, MD, for their thoughtful reviews of the manuscript.
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DOI: 10.1542/peds.107.5.e82
2001;107;e82
Pediatrics
Christopher L. Moertel, Bonnie Carlson-Green, Jan Watterson and Susan C. Simonton
Leukemia: Report of Effective Therapy
Lymphomatoid Granulomatosis After Childhood Acute Lymphoblastic
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DOI: 10.1542/peds.107.5.e82
2001;107;e82
Pediatrics
Christopher L. Moertel, Bonnie Carlson-Green, Jan Watterson and Susan C. Simonton
Leukemia: Report of Effective Therapy
Lymphomatoid Granulomatosis After Childhood Acute Lymphoblastic
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