Case Study

Concurrent and Clonally Related Pediatric

Follicular Lymphoma and Burkitt Lymphoma
in a 5-Year-Old Boy
Aaron C. Shaver, MD, PhD,1* David Zimmerman, MD,2 Mingya Liu, MS,3
Cindy Vnencak-Jones, PhD,1 Annette S. Kim, MD, PhD1,4
Laboratory Medicine 47:1:43-47

DOI: 10.1093/labmed/lmv014

ABSTRACT
involving the MYC gene. To our knowledge, this case is the first reported
Pediatric follicular lymphoma shares morphologic similarities with the
instance of transformation of follicular lymphoma of any sort into true
adult form of the disease but lacks other classic features of adult
Burkitt lymphoma and the first reported instance of acquisition of MYC
lymphoma, including t(14;18) translocation, BCL2 overexpression, and
abnormalities in pediatric follicular lymphoma.
transformation to aggressive higher-grade lymphoma. Herein, we report
a novel case in which a 5-year-old boy (ethnicity unknown) had follicular
Keywords: transformed B-cell lymphoma, pediatric follicular lymphoma,
lymphoma, along with concurrent high-grade and clonally related
Burkitt lymphoma, IgH rearrangement, MYC translocation, fluorescence
disease that fulfilled all of the morphologic, immunophenotypic, and
in situ hybridization
genetic criteria for Burkitt lymphoma, including a t(8;14) translocation

Case Report and fine needle aspiration of a right cervical node at an

outside institution. Review of the pathologic characteristics
The patient was a 5-year-old boy (ethnicity unknown), born
of the bilateral tonsils was performed at our institution,
at 27 weeks’ gestational age, with a medical history
Vanderbilt University Medical Center (VUMC), including
including complications of prematurity and pyloric stenosis
morphologic, immunohistochemical, and molecular
and no history of previous malignant neoplasms. Before he
analysis.
arrived at Vanderbilt Children’s Hospital (VCH), he had
experienced 5 weeks of bilateral tonsillar swelling and
Hematoxylin-eosin (H&E)–stained histologic sections of the
cervical lymphadenopathy. He had no history of systemic
right tonsil of the patient showed partially preserved tonsillar
symptoms, such as fever, night sweats, or weight loss. His
tissue with follicular hyperplasia. A significant portion of the
cervical and tonsillar swelling failed to resolve with
tissue was completely effaced by an atypical lymphoid
antibiotic treatment, so he underwent bilateral tonsillectomy
infiltrate composed of large, back-to-back follicular
structures (Image 1). These abnormal follicles were made up
of sheets of medium-to-large abnormal cells with oval to
Abbreviations slightly irregular nuclei, vesicular chromatin, central small
VCH, Vanderbilt Children’s Hospital; VUMC, Vanderbilt University nucleoli, and scant-to-moderate amounts of cytoplasm.
Medical Center; H&E, hematoxylin-eosin; IGH, immunoglobulin heavy
Mantle zones were markedly attenuated or absent, and
chain; PCR, polymerase chain reaction; CT, computed tomography; PET,
positron emission technology; WHO, World Health Organization; DLBCL, occasional scattered tingible-body macrophages and mitotic
diffuse large B-cell lymphoma; FISH, fluorescence in situ hybridization figures were apparent. In a single well-defined portion of the
1 specimen, the infiltrate was sheet-like rather than nodular
Department of Pathology, Microbiology, and Immunology, Vanderbilt
University, 2Forensic Medical, 3Genetics Associates, Nashville, TN, and and displayed a distinct “starry sky” pattern at low power,
4
Current address Department of Pathology, Brigham and Women’s with increased tingible body macrophages admixed with a
Hospital, Boston, MA population of medium-sized cells with round nuclei, dense
*To whom correspondence should be addressed. chromatin, multiple small peripheral nucleoli, scant
aaron.shaver@vanderbilt.edu cytoplasm, and abundant mitotic and apoptotic figures.

C American Society for Clinical Pathology, 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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Image 1
Photomicrographs from the areas of follicular lymphoma (panels A, C, E, G) and Burkitt lymphoma (panels B, D, F, H) from the patient’s right tonsil.
A, The follicular lymphoma consists of large, homogeneous follicles with attenuated mantle and marginal zones, arranged in a back-to-back fashion
(hematoxylin-eosin staining, original magnification 40). B, The Burkitt lymphoma has a diffuse, infiltrative pattern, without follicular architecture and
with an increased number of tingible-body macrophages, giving the lesion the classic “starry sky” pattern (hematoxylin-eosin staining, original
magnification 100). C and D, Immunohistochemical stains for CD10 highlight the respective morphologic patterns in the follicular (panel C) and
infiltrative (panel D) portions of the lesion (original magnification 100). E, At higher power, the follicular portion of the specimen contains cells that
are intermediate to large in size, with vesicular chromatin, central nucleoli, and scattered small lymphocytes and macrophages (hematoxylin-eosin,
original magnification 400). F, Burkitt lymphoma is composed of medium-sized, irregular cells with dense, coarse chromatin and abundant
apoptotic figures and macrophages (hematoxylin-eosin staining, original magnification 400). G and H, The Ki-67 proliferative index in the follicular
area, at approximately 80% (panel G), is lower and shows more variable staining than in the Burkitt lymphoma panel (panel H), where the Ki-67 index
is > 95% with strong staining. (original magnification 400).

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44 DOI: 10.1093/labmed/lmv014
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Sections of the left tonsil demonstrated no evidence of the
atypical lymphoid processes seen in the right tonsil.
Immunohistochemical studies (Image 1) demonstrated that
the neoplastic cells in the follicular portion of the specimen
were B lymphocytes that tested negative for CD3, positive for
CD10, CD20, and BCL6, and dimly positive for BCL2 in a
subset of cells. The Ki-67 proliferative index in this area was
approximately 80%, with a mix of light- and dark-staining
cells. Immunohistochemical stains in the denser, “starry sky”
portion of the specimen highlighted the sheet-like, infiltrative
low-power pattern of this area, with no evidence of follicular
architecture. The cells here tested positive for CD10, CD20,
and BCL6, and were negative for CD3 and BCL2. The Ki-67
index was greater than 95%, with consistently strong staining.
No evidence of the t(14;18) IGH@/BCL2 translocation was
detected in any of 200 cells probed in each of the lesions,
although the IGH@ fluorescent probe of this set revealed
evidence of a translocation involving IGH@ but not BCL2 in
86 of 200 cells (43%) probed (Image 2A and 2C) in the
“starry sky” region. In this same region, the t(8;14) MYC/
IGH@ translocation was detected in 109 of 200 (54.5%) cells
probed (Image 2B). All cells assayed in the follicular area
tested negative for the t(8;14) translocation (Image 2D). We
performed polymerase chain reaction (PCR)–based IGH@
VDJ rearrangement studies separately on tissue isolated
from areas of Burkitt morphology and of follicular
morphology. In each case, the findings of these studies
demonstrated an identical clonal pattern of IGH@
rearrangement (Image 2E), which indicated that the 2
processes were derived from the same genetic clone.
Staging workup, including computed tomography (CT) scan,
positron emission technology (PET) scan, lumbar puncture,
and bone marrow biopsy, revealed no evidence of further
disease. The patient was subsequently treated with
combination chemotherapy (cyclophosphamide, vincristine,
prednisone, methotrexate, hydrocortisone, and doxorubicin)
and remained free of clinical or radiographic evidence of
disease 60 months after initial diagnosis (point of last
documented clinical followup).
Discussion
Although they share a common name, histogenic cell of
origin, and certain morphologic features, adult and pediatric
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Case Study
follicular lymphoma are distinct clinicopathologic entities.
Adult follicular lymphoma is relatively common, whereas
pediatric follicular lymphoma is much rarer.1,2
Adult follicular lymphoma is classically associated with the
t(14;18)(q32;q21) translocation involving the IGH@ and BCL2
genes in 85% to 90% of cases, with associated upregulation
of BCL2. In contrast, this translocation and BCL2 positivity
via immunohistochemical testing are consistently absent in
the pediatric disease. The clinical course of adult follicular
lymphoma is determined to a large degree by its
morphologic grade, which depends on the proportion of
large, centroblastic cells in the neoplastic population;
transformation to large B-cell lymphoma can occur, with
concomitant adverse prognostic consequences.3,4
In contrast, the course of pediatric follicular lymphoma is
generally benign, with long event-free survival and infrequent
relapses, and is seemingly independent of the initial
morphologic grade.5-8 Definitive transformation to large-cell
lymphoma after an initial diagnosis of pediatric follicular
lymphoma is not documented in the literature, to our
knowledge; only 1 series to date has included cases with
concurrent large-cell lymphoma at the time of diagnosis,
seemingly without impact on clinical course.7
Herein, we report a clinical case that represents, to our
knowledge, the first published identification of
transformation of follicular lymphoma, whether pediatric or
adult, into true Burkitt lymphoma, as confirmed by
morphologic testing, immunophenotyping, and the presence
of the classical t(8;14) translocation without a rearrangement
of BCL2 or BCL6. The case we report is of pediatric follicular
lymphoma in the tonsil of a 5-year-old boy, with co-occurring
Burkitt lymphoma confirmed by molecular studies to be
clonally related to the follicular lymphoma. As with most
pediatric follicular lymphomas, this case was not associated
with t(14;18).
Although MYC abnormalities are classically associated with
Burkitt lymphoma—in particular, the t(8;14) translocation
involving IGH@—large-cell transformations of follicular
lymphoma that acquire a MYC translocation almost never
fulfill the diagnostic qualifications for true Burkitt lymphoma,
mostly due to the high frequency of the t(14;18) translocation
in adult follicular lymphoma. These cases are often referred to
in the older literature as “Burkitt-like lymphoma” or “atypical
Burkitt lymphoma.” However, in current studies, such cases
would be more properly referred to as “double-hit”
Lab Medicine 2016;47:1;43–47 45
DOI: 10.1093/labmed/lmv014
 Case Study

Image 2
Results of fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) testing of a
specimen from the patient, a 5-year-old boy. A, FISH study results demonstrate no evidence of a t(14;18)
IGH@/BCL2 translocation. B, The results of further FISH studies reveal the presence of a t(8;14) MYC/
IGH@ rearrangement in the areas of Burkitt lymphoma. C, A nucleus from the Burkitt area of the tumor
reveals multiple copies of the IGH@ probe but no additional copies of BCL2, consistent with an IGH@
rearrangement with a non-BCL2 partner. D, The results of further FISH studies reveal no evidence of the
MYC/IGH@ translocation in the areas of follicular lymphoma. E, PCR amplification of the IGH@ locus
shows the presence of identical clonal IGH VDJ rearrangements in separate reactions performed on tissue
isolated from the follicular (lane FL) and Burkitt (lane BL) portions of the lesion (a Phi X Hinf I size ladder is
present in lane L for reference).

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46 DOI: 10.1093/labmed/lmv014
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lymphomas;9,10 in the World Health Organization (WHO) 2008
classification scheme, they would be classified depending on
their morphologic and immunophenotypic profile as diffuse
large B-cell lymphoma (DLBCL) or within the new diagnostic
category of “B-cell lymphoma, unclassifiable, with features
intermediate between DLBCL and Burkitt lymphoma.”4 These
lymphomas are genetically distinct from Burkitt lymphoma
and also may differ in their immunophenotype, morphologic
appearance, and clinical course, which is typically much
worse than that of Burkitt lymphoma.10
Compared with the profound prognostic effect that
translocations of MYC have on prognosis in adult lymphomas,
the effect of such translocations on pediatric lymphomas is
less understood. Although no cases of pediatric follicular
lymphoma with an associated MYC translocation have been
reported in the literature, MYC translocations have been
reported to be more common in pediatric DLBCL
(approximately 37% of cases) than in the adult counterpart.11-13
The prognostic significance of MYC translocation in pediatric
DLBCL is unclear, with 1 report11 showing no difference in
event-free survival between the cases of DLBCL without or
without MYC translocation, whereas another study14
demonstrated a significant decrease in survival associated
with MYC aberrations.
Presentation of clonally related follicular lymphoma, adult or
pediatric, and true Burkitt lymphoma with t(8;14) has not
previously been described. The case we described herein
highlights the potential biologic relationship between these 2
malignancies of germinal center B-cells. The clinical
significance of this joint presentation of the 2 related
lymphomas is unclear; however, in this patient, there have
been no adverse outcomes to date as a result.
This case further highlights the clinical distinction between
the seemingly similar entities of adult and pediatric follicular
lymphoma: the former typically cannot transform to a true
Burkitt lymphoma, whereas the latter theoretically may be
able to do so. As recent studies1,2 bring added attention to
the occurrence of the pediatric variant of follicular lymphoma
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Case Study
in the adult population, this distinction will likely be
increasingly important. LM
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Lab Medicine 2016;47:1;43–47 47
DOI: 10.1093/labmed/lmv014