VOLUME

30

NUMBER

21

JULY

20

2012

JOURNAL OF CLINICAL ONCOLOGY

Precursor B-Cell Lymphoblastic Lymphoma of

the Ear in a 7-Year-Old Child
Case Report
A 7-year-old girl with no significant past medical history presented to a regional hospital with right-sided hearing impairment and
intermittent tinnitus for 1 month. The girl had no vertigo, otorrhea, or
fever. On examination, there was a bulging mass in the right external
auditory canal (EAC). Blood cell counts, basic blood chemistry, and
urinalysis of the patient were normal. Pure-tone audiometry confirmed a 40-dB conductive hearing loss in the right side. Highresolution computed tomography (CT) of the temporal bone revealed
extensive soft tissue density in the right middle-ear cavity, which was
part of the EAC, and mastoid air cells (Fig 1A, arrows). The adjacent
bony structures and bilateral inner ears were intact. She underwent a
microscopic excision of the right EAC lesion. Pathology revealed an
epithelium-lined cyst with lymphoid stroma that contained atypical
lymphocytes, with a mixed CD3 and CD20 population with hyperplastic paracortical areas and B-cell lymphoma 2 (Bcl-2) immunoreactivity in the follicle by using immunohistochemistry (IHC), which
favored the diagnosis of reactive lymphoid stroma with huge germinal
centers. The girl was discharged to her home.
One month later, the patient had a recurrence of tinnitus and
hearing impairment of the right ear with a new onset of otorrhea, and
thus, she was taken to the ear, nose, and throat clinic of a medical
center. Otoscopy showed mild bulging of the attic of the right eardrum
with wet debris that occupied the EAC, and thus, otitis externa with
otomycosis was diagnosed. After 1 month of local antifungal therapy,
the symptoms persisted. Repeated high-resolution CT revealed a soft
tissue density that occupied the right middle-ear cleft and mastoid air
cell with bony erosion of the right outer mastoid and tegmen (Fig 1B,
arrows). Under the suspicion of otitis media with cholesteatoma, a
microscopic surgery was undertaken but did not identify a sac. Laser
myringotomy was also performed to ventilate the middle ear, and the
auditory symptoms of the patient improved.
Five months later, the girl presented to the medical center again
with a mass bulging from the right EAC. She did not have facial palsy
or enlarged cervical lymph nodes. A laryngoscopy showed normal
nasopharyngeal mucosa without ulceration. Under the suspicion of a
malignancy, the girl received a surgical exploration of the right middle
ear (Fig 1C and Data Supplement), which revealed diffuse granulation
tissue overlying the epitympanum (Fig 1C, white arrow), mesotympanum (Fig 1C, black arrow), and mastoid air cells. The granulation
tissue was removed as much as possible. Microscopically, there were
diffuse infiltrates of medium- to large-sized atypical lymphoid cells
under the squamous mucosa (Fig 2A, 100, and Fig 2B, 400; both
were hematoxylin and eosin [H&E] stain). The atypical cells were
positive for surface CD34 and CD79a (Fig 2C, 400, anti-CD79a
stain) and nuclear terminal deoxynucleotidyl transferase (TdT; Fig
2D, 400, anti-TdT stain) and paired box protein 5 (Pax5) and
e184

2012 by American Society of Clinical Oncology

D I A G N O S I S

I N

O N C O L O G Y

Fig 1.

negative for CD3 and CD20 by using IHC staining. A precursor B-cell
lymphoblastic lymphoma (pB-LBL) was diagnosed. Head and neck
magnetic resonance imaging (MRI) showed a nasopharyngeal extension of the mass.
Journal of Clinical Oncology, Vol 30, No 21 (July 20), 2012: pp e184-e187

Downloaded from jco.ascopubs.org on January 17, 2015. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

Diagnosis in Oncology

Fig 2.

The patient was referred to another medical center for complete

staging and protocol therapy of the pB-LBL. Positron emission
tomography (PET)/CT with [18F]fluorodeoxyglucose ([18F]FDG)
revealed multiple hypermetabolic areas at the right EAC, middle
and inner ear, nasopharynx (Fig 3; cursors, main tumor occupying
the right middle and inner ear), and multiple bones including
bilateral femurs (Fig 4 ; left panel, PET/CT; right panel, confirmatory MRI; arrows indicating metastatic lesions). A 99mTcmethylene diphosphonate whole-body bone scan also showed
increased tracer activity in the right temporal skull and right femur.
Bone marrow studies including morphology, flow cytometry, and
cytogenetics showed no evidence of lymphoma involvement. Stage
4 pB-LBL with multiple bony metastases was confirmed.
After an episode of tumor lysis syndrome that was successfully
treated with aggressive hydration and recombinant urate oxidase,
the girl began systemic chemotherapy with Taiwan Pediatric Oncology Groups regimen for pB-LBL (TPOG-98-T-LBL Arm B),
which was based on protocols of the Berlin-Frankfurt-Mnster
cooperative group.1,2 The patient became symptom free after the
first cycle of chemotherapy, and the tumors showed complete
www.jco.org

response on follow-up PET/CT 3 months later and on MRI of the

lower extremities 6 months later. She has been disease free for 2
years after the diagnosis and still on maintenance therapy.
Discussion
In this patient, the acute onset of conductive hearing loss and
recurrent auditory symptoms suggested an obstructive lesion in the
middle ear and/or EAC. Probable causes included otitis media with
effusion, cholesteatoma, infections, foreign bodies, trauma, and neoplasms. Although these symptoms rarely cause permanent hearing
impairment,3 their treatment strategies vary significantly, and sometimes diagnosis is not easy. Otitis media with effusion and cholesteatoma are relatively common in children, even in the absence of acute
middle-ear inflammation.4 In contrast, infrequent middle ear tumors
can cause symptoms and signs that are identical with those of otitis
media.5 A pathologic examination of the first EAC tumor excision
revealed the infiltration of atypical lymphocytes, but an IHC panel of
common lymphocytic markers could not identify the nature of the
underlying clonal disease.
2012 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on January 17, 2015. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

e185

Liu et al

Fig 3.

Because of the history of EAC surgery and antibiotic use,

otomycosis was diagnosed in the second hospital. More than 80%
of cases with otomycosis should respond to topical antifungal
agents.6 Although recurrent or residual otomycosis is not uncommon, the poor response of the patient to antifungal treatment
warranted a repeated CT scan, which showed more extensive lesions in the middle ear with bony invasion, which were suspected
to be otitis media with cholesteatoma.
Acquired cholesteatomas are abnormal collections of squamous
epithelium and keratin debris that form retraction pockets involving

Fig 4.
e186

2012 by American Society of Clinical Oncology

the middle ear.7 Although histologically benign, acquired cholesteatomas can expand and destroy bones, the presentation of which was
compatible with the findings on the second CT scan. The second
microscopic surgery did not find a sac. Instead, a myringotomy was
performed to drain and to release the middle-ear pressure for symptom relief.
The recurrence of an EAC tumor reminded us of a malignancy.
Pediatric ear tumors are rare but of a variety of pathology from benign
tumors such as papilloma and osteoma to malignant carcinomas and
lymphomas.8 In Epstein-Barr virus endemic areas such as Taiwan, the
nasopharyngeal extension of the primary tumor raised the concern of
nasopharyngeal cancer, although the disease has usually been seen in
adolescent boys.9 Overall, the definite diagnosis of an ear tumor still
relied on histopathology. The diffuse lymphoid infiltration with abnormal expression of precursor B-cell markers led us to the diagnosis
of pB-LBL.
Lymphoblastic lymphomas (LBLs) are precursor lymphoid neoplasms with less than 25% lymphoblasts in the bone marrow.10 More
than 60% of patients with LBLs are younger than age 18 years,11 and
they account for one fourth of all childhood non-Hodgkins lymphomas in industrialized countries.1,12 The majority of LBLs are of T
lineage and frequently present with a mass in the anterior mediastinum,13 whereas pB-LBLs constitute less than 10% of LBLs14,15 and
predominantly involve extranodal sites including the skin, soft tissue,
and bones.11,16,17 An pB-LBL of the ear is extremely rare.16,18,19 The
current WHO classification13 considered pB-LBL and precursor
B-cell acute lymphoblastic leukemia as the same category of lymphoid neoplasms.16
JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on January 17, 2015. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

Diagnosis in Oncology

The use of IHC is important to establish the diagnosis of lymphoid malignancies. Because CD20 is variably expressed in B-cell
non-Hodgkins lymphoma and only in 54% to 62% of pB-LBLs,11,16
another preB- or B-cell marker such as CD79a, CD19, or Pax520
should also be checked in the pediatric population when a lymphocytic malignancy is suspected. In contrast, cytogenetic analysis or
fluorescence in situ hybridization may support the diagnosis of LBL by
showing recurrent chromosomal abnormalities that have been observed in preB- or T-cell ALL, although normal karyotype or different breakpoints have also been noted.11,17,21 In our patient, a
cytogenetic study of the bone marrow showed normal karyotype, but
a cytogenetic study or fluorescence in situ hybridization of the primary
tumor was not performed at the first two hospitals.
PET/CT with [18F]FDG has served as a useful modality in the
diagnosis and follow-up of lymphomas. In a large series of 1,093
lymphoma patients, 94% of patients showed [18F]FDG avidity, including all six patients with LBL.22 In our patient, PET/CT showed the
nasopharyngeal extension of the ear tumor and multiple bony metastases, both of which provided critical information for staging.
In conclusion, pB-LBL of the ear is extremely rare and usually
needs to be discerned from infectious or inflammatory causes. The
accurate diagnosis relies on a high index of suspicion with incorporating precursor lymphocytic markers as a part of IHC studies, especially
in the pediatric population or in lesions with marked lymphoid hyperplasia or infiltration. In addition, [18F]FDG PET/CT provides valuable
information in patients with suspected lymphoma, especially in lymphomas that originated from unusual extranodal sites.

Yen-Lin Liu
Academia Sinica and National Taiwan University, Taipei; Buddhist Tzu Chi
General Hospital, Taipei Branch, Xindian, New Taipei, Taiwan

Chun-Liang Tung
Chiayi Christian Hospital, Chia-Yi City, Taiwan

Yung-Li Yang, Dong-Tsamn Lin, and Kai-Hsin Lin

National Taiwan University Hospital, Taipei, Taiwan

Hsueh Lu Liao
Chiayi Christian Hospital, Chia-Yi City, Taiwan

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES
1. Yang CP, Hung JJ, Jaing TH, et al: Treatment results of the TPOG-NHL92
protocols for childhood non-Hodgkins lymphomas in Taiwan: A report from the
Taiwan Pediatric Oncology Group (TPOG). Acta Paediatr Taiwan 41:193-204,
2000
2. Schrappe M, Reiter A, Zimmermann M, et al: Long-term results of four
consecutive trials in childhood ALL performed by the ALL-BFM study group from
1981 to 1995: Berlin-Frankfurt-Munster. Leukemia 14:2205-2222, 2000

3. Parving A: Epidemiology of hearing loss and aetiological diagnosis of

hearing impairment in childhood. Int J Pediatr Otorhinolaryngol 5:151-165, 1983
4. Gifford KA, Holmes MG, Bernstein HH: Hearing loss in children. Pediatr
Rev 30:207-215; quiz 216, 2009
5. Kletzker GR, Smith PG, McIntire LD, et al: Presentation and management
of uncommon lesions of the middle ear. Am J Otol 16:634-642, 1995
6. Ho T, Vrabec JT, Yoo D, et al: Otomycosis: Clinical features and treatment
implications. Otolaryngol Head Neck Surg 135:787-791, 2006
7. Isaacson G: Diagnosis of pediatric cholesteatoma. Pediatrics 120:603-608,
2007
8. Biswas D, Saha S, Bera SP: Relative distribution of the tumours of ear,
nose and throat in the paediatric patients. Int J Pediatr Otorhinolaryngol 71:801805, 2007
9. Sheen JM, Yu HR, Huang EY, et al: Nasopharyngeal carcinoma in children:
A single institutions experience. Acta Paediatr Taiwan 46:268-271, 2005
10. Borowitz MJ, Chan JKC: Introduction and overview of the classification of
the lymphoid neoplasms, in Swerdlow SH, Campo E, Harris NL, et al (eds): WHO
Classification of Tumours Of Haematopoietic and Lymphoid Tissues (ed 4). Lyon,
France, International Agency for Research on Cancer, 2008, pp 157-166
11. Maitra A, McKenna RW, Weinberg AG, et al: Precursor B-cell lymphoblastic lymphoma: A study of nine cases lacking blood and bone marrow involvement
and review of the literature. Am J Clin Pathol 115:868-875, 2001
12. Wright D, McKeever P, Carter R: Childhood non-Hodgkin lymphomas in the
United Kingdom: Findings from the UK Childrens Cancer Study Group. J Clin
Pathol 50:128-134, 1997
13. Borowitz MJ, Chan JKC: Precursor lymphoid neoplasms, in Swerdlow SH,
Campo E, Harris NL, et al (eds): WHO classification of tumours of haematopoietic
and lymphoid tissues (ed 4). Lyon, France, International Agency for Research on
Cancer, 2008, pp 167-178
14. Borowitz MJ, Croker BP, Metzgar RS: Lymphoblastic lymphoma with the
phenotype of common acute lymphoblastic leukemia. Am J Clin Pathol 79:387391, 1983
15. Chen YC, Ho CL, Kao WY, et al: Adult lymphoblastic lymphoma in Taiwan:
An analysis of treatment results of 26 patients. Ann Hematol 80:647-652, 2001
16. Lin P, Jones D, Dorfman DM, et al: Precursor B-cell lymphoblastic
lymphoma: A predominantly extranodal tumor with low propensity for leukemic
involvement. Am J Surg Pathol 24:1480-1490, 2000
17. Millot F, Robert A, Bertrand Y, et al: Cutaneous involvement in children
with acute lymphoblastic leukemia or lymphoblastic lymphoma: The Childrens
Leukemia Cooperative Group of the European Organization of Research and
Treatment of Cancer (EORTC). Pediatrics 100:60-64, 1997
18. Zanation AM, Ebert CS Jr, Coffey CS, et al: Precursor B-cell lymphoblastic
lymphoma presenting as an isolated external ear swelling in a two-year-old child.
Int J Pediatr Otorhinolaryngol 69:695-699, 2005
19. Lang EE, Walsh RM, Leader M: Primary middle-ear lymphoma in a child. J
Laryngol Otol 117:205-207, 2003
20. Torlakovic E, Torlakovic G, Nguyen PL, et al: The value of anti-pax-5
immunostaining in routinely fixed and paraffin-embedded sections: A novel pan
pre-B and B-cell marker. Am J Surg Pathol 26:1343-1350, 2002
21. Lones MA, Heerema NA, Le Beau MM, et al: Chromosome abnormalities
in advanced stage lymphoblastic lymphoma of children and adolescents: A report
from CCG-E08. Cancer Genet Cytogenet 172:1-11, 2007
22. Weiler-Sagie M, Bushelev O, Epelbaum R, et al: (18)F-FDG avidity in
lymphoma readdressed: A study of 766 patients. J Nucl Med 51:25-30, 2010

DOI: 10.1200/JCO.2011.40.7544; published online ahead of print at

www.jco.org on June 18, 2012

www.jco.org

2012 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on January 17, 2015. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

e187