Precursor B-Cell Lymphoblastic Lymphoma ofthe Ear in a 7-Year-Old Child

Case Report

A 7-year-old girl with no significant past medical history pre-sented to a regional hospital with right-sided hearing impairment andintermittent tinnitus for 1 month. The girl had no vertigo, otorrhea, orfever. On examination, there was a bulging mass in the right externalauditory canal (EAC). Blood cell counts, basic blood chemistry, andurinalysis of the patient were normal. Pure-tone audiometry con-firmed a 40-dB conductive hearing loss in the right side. High-resolution computed tomography (CT) of the temporal bone revealedextensive soft tissue density in the right middle-ear cavity, which waspart of the EAC, and mastoid air cells (Fig 1A, arrows). The adjacentbony structures and bilateral inner ears were intact. She underwent amicroscopic excision of the right EAC lesion. Pathology revealed anepithelium-lined cyst with lymphoid stroma that contained atypicallymphocytes, with a mixed CD3 and CD20 population with hyper-plastic paracortical areas and B-cell lymphoma 2 (Bcl-2) immunore-activity in the follicle by using immunohistochemistry (IHC), whichfavored the diagnosis of reactive lymphoid stroma with huge germinalcenters. The girl was discharged to her home.

One month later, the patient had a recurrence of tinnitus andhearing impairment of the right ear with a new onset of otorrhea, andthus, she was taken to the ear, nose, and throat clinic of a medicalcenter. Otoscopy showed mild bulging of the attic of the right eardrumwith wet debris that occupied the EAC, and thus, otitis externa withotomycosis was diagnosed. After 1 month of local antifungal therapy,the symptoms persisted. Repeated high-resolution CT revealed a softtissue density that occupied the right middle-ear cleft and mastoid aircell with bony erosion of the right outer mastoid and tegmen (Fig 1B,arrows). Under the suspicion of otitis media with cholesteatoma, amicroscopic surgery was undertaken but did not identify a sac. Lasermyringotomy was also performed to ventilate the middle ear, and theauditory symptoms of the patient improved.

Five months later, the girl presented to the medical center againwith a mass bulging from the right EAC. She did not have facial palsyor enlarged cervical lymph nodes. A laryngoscopy showed normalnasopharyngeal mucosa without ulceration. Under the suspicion of amalignancy, the girl received a surgical exploration of the right middleear (Fig 1C and Data Supplement), which revealed diffuse granulationtissue overlying the epitympanum (Fig 1C, white arrow), mesotympa-num (Fig 1C, black arrow), and mastoid air cells. The granulationtissue was removed as much as possible. Microscopically, there werediffuse infiltrates of medium- to large-sized atypical lymphoid cellsunder the squamous mucosa (Fig 2A, 100�, and Fig 2B, 400�; bothwere hematoxylin and eosin [H&E] stain). The atypical cells werepositive for surface CD34 and CD79a (Fig 2C, 400�, anti-CD79astain) and nuclear terminal deoxynucleotidyl transferase (TdT; Fig2D, 400�, anti-TdT stain) and paired box protein 5 (Pax5) and

negative for CD3 and CD20 by using IHC staining. A precursor B-celllymphoblastic lymphoma (pB-LBL) was diagnosed. Head and neckmagnetic resonance imaging (MRI) showed a nasopharyngeal exten-sion of the mass.

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Fig 1.

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The patient was referred to another medical center for completestaging and protocol therapy of the pB-LBL. Positron emissiontomography (PET)/CT with [18F]fluorodeoxyglucose ([18F]FDG)revealed multiple hypermetabolic areas at the right EAC, middleand inner ear, nasopharynx (Fig 3; cursors, main tumor occupyingthe right middle and inner ear), and multiple bones includingbilateral femurs (Fig 4 ; left panel, PET/CT; right panel, confirma-tory MRI; arrows indicating metastatic lesions). A 99mTc-methylene diphosphonate whole-body bone scan also showedincreased tracer activity in the right temporal skull and right femur.Bone marrow studies including morphology, flow cytometry, andcytogenetics showed no evidence of lymphoma involvement. Stage4 pB-LBL with multiple bony metastases was confirmed.

After an episode of tumor lysis syndrome that was successfullytreated with aggressive hydration and recombinant urate oxidase,the girl began systemic chemotherapy with Taiwan Pediatric On-cology Group’s regimen for pB-LBL (TPOG-98-T-LBL Arm B),which was based on protocols of the Berlin-Frankfurt-Münstercooperative group.1,2 The patient became symptom free after thefirst cycle of chemotherapy, and the tumors showed complete

response on follow-up PET/CT 3 months later and on MRI of thelower extremities 6 months later. She has been disease free for 2years after the diagnosis and still on maintenance therapy.

Discussion

In this patient, the acute onset of conductive hearing loss andrecurrent auditory symptoms suggested an obstructive lesion in themiddle ear and/or EAC. Probable causes included otitis media witheffusion, cholesteatoma, infections, foreign bodies, trauma, and neo-plasms. Although these symptoms rarely cause permanent hearingimpairment,3 their treatment strategies vary significantly, and some-times diagnosis is not easy. Otitis media with effusion and cholestea-toma are relatively common in children, even in the absence of acutemiddle-ear inflammation.4 In contrast, infrequent middle ear tumorscan cause symptoms and signs that are identical with those of otitismedia.5 A pathologic examination of the first EAC tumor excisionrevealed the infiltration of atypical lymphocytes, but an IHC panel ofcommon lymphocytic markers could not identify the nature of theunderlying clonal disease.

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Fig 2.

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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 antifungalagents.6 Although recurrent or residual otomycosis is not uncom-mon, the poor response of the patient to antifungal treatmentwarranted a repeated CT scan, which showed more extensive le-sions in the middle ear with bony invasion, which were suspectedto be otitis media with cholesteatoma.

Acquired cholesteatomas are abnormal collections of squamousepithelium and keratin debris that form retraction pockets involving

the middle ear.7 Although histologically benign, acquired cholesteato-mas can expand and destroy bones, the presentation of which wascompatible with the findings on the second CT scan. The secondmicroscopic surgery did not find a sac. Instead, a myringotomy wasperformed to drain and to release the middle-ear pressure for symp-tom relief.

The recurrence of an EAC tumor reminded us of a malignancy.Pediatric ear tumors are rare but of a variety of pathology from benigntumors such as papilloma and osteoma to malignant carcinomas andlymphomas.8 In Epstein-Barr virus endemic areas such as Taiwan, thenasopharyngeal extension of the primary tumor raised the concern ofnasopharyngeal cancer, although the disease has usually been seen inadolescent boys.9 Overall, the definite diagnosis of an ear tumor stillrelied on histopathology. The diffuse lymphoid infiltration with ab-normal expression of precursor B-cell markers led us to the diagnosisof pB-LBL.

Lymphoblastic lymphomas (LBLs) are precursor lymphoid neo-plasms with less than 25% lymphoblasts in the bone marrow.10 Morethan 60% of patients with LBLs are younger than age 18 years,11 andthey account for one fourth of all childhood non-Hodgkin’s lympho-mas in industrialized countries.1,12 The majority of LBLs are of Tlineage and frequently present with a mass in the anterior mediasti-num,13 whereas pB-LBLs constitute less than 10% of LBLs14,15 andpredominantly 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 Thecurrent WHO classification13 considered pB-LBL and precursorB-cell acute lymphoblastic leukemia as the same category of lym-phoid neoplasms.16

Fig 3.

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Fig 4.

Liu et al

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The use of IHC is important to establish the diagnosis of lym-phoid malignancies. Because CD20 is variably expressed in B-cellnon-Hodgkin’s lymphoma and only in 54% to 62% of pB-LBLs,11,16

another pre–B- or B-cell marker such as CD79a, CD19, or Pax520

should also be checked in the pediatric population when a lympho-cytic malignancy is suspected. In contrast, cytogenetic analysis orfluorescence in situ hybridization may support the diagnosis of LBL byshowing recurrent chromosomal abnormalities that have been ob-served in pre–B- or T-cell ALL, although normal karyotype or differ-ent breakpoints have also been noted.11,17,21 In our patient, acytogenetic study of the bone marrow showed normal karyotype, buta cytogenetic study or fluorescence in situ hybridization of the primarytumor was not performed at the first two hospitals.

PET/CT with [18F]FDG has served as a useful modality in thediagnosis and follow-up of lymphomas. In a large series of 1,093lymphoma patients, 94% of patients showed [18F]FDG avidity, in-cluding all six patients with LBL.22 In our patient, PET/CT showed thenasopharyngeal extension of the ear tumor and multiple bony metas-tases, both of which provided critical information for staging.

In conclusion, pB-LBL of the ear is extremely rare and usuallyneeds to be discerned from infectious or inflammatory causes. Theaccurate diagnosis relies on a high index of suspicion with incorporat-ing precursor lymphocytic markers as a part of IHC studies, especiallyin the pediatric population or in lesions with marked lymphoid hyper-plasia or infiltration. In addition, [18F]FDG PET/CT provides valuableinformation in patients with suspected lymphoma, especially in lym-phomas that originated from unusual extranodal sites.

Yen-Lin LiuAcademia Sinica and National Taiwan University, Taipei; Buddhist Tzu ChiGeneral Hospital, Taipei Branch, Xindian, New Taipei, Taiwan

Chun-Liang TungChiayi Christian Hospital, Chia-Yi City, Taiwan

Yung-Li Yang, Dong-Tsamn Lin, and Kai-Hsin LinNational Taiwan University Hospital, Taipei, Taiwan

Hsueh Lu LiaoChiayi Christian Hospital, Chia-Yi City, Taiwan

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conflicts of interest.

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protocols for childhood non-Hodgkin’s lymphomas in Taiwan: A report from theTaiwan Pediatric Oncology Group (TPOG). Acta Paediatr Taiwan 41:193-204,2000

2. Schrappe M, Reiter A, Zimmermann M, et al: Long-term results of fourconsecutive trials in childhood ALL performed by the ALL-BFM study group from1981 to 1995: Berlin-Frankfurt-Munster. Leukemia 14:2205-2222, 2000

3. Parving A: Epidemiology of hearing loss and aetiological diagnosis ofhearing impairment in childhood. Int J Pediatr Otorhinolaryngol 5:151-165, 1983

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5. Kletzker GR, Smith PG, McIntire LD, et al: Presentation and managementof 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 treatmentimplications. Otolaryngol Head Neck Surg 135:787-791, 2006

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12. Wright D, McKeever P, Carter R: Childhood non-Hodgkin lymphomas in theUnited Kingdom: Findings from the UK Children’s Cancer Study Group. J ClinPathol 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 haematopoieticand lymphoid tissues (ed 4). Lyon, France, International Agency for Research onCancer, 2008, pp 167-178

14. Borowitz MJ, Croker BP, Metzgar RS: Lymphoblastic lymphoma with thephenotype of common acute lymphoblastic leukemia. Am J Clin Pathol 79:387-391, 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 lymphoblasticlymphoma: A predominantly extranodal tumor with low propensity for leukemicinvolvement. Am J Surg Pathol 24:1480-1490, 2000

17. Millot F, Robert A, Bertrand Y, et al: Cutaneous involvement in childrenwith acute lymphoblastic leukemia or lymphoblastic lymphoma: The Children’sLeukemia Cooperative Group of the European Organization of Research andTreatment of Cancer (EORTC). Pediatrics 100:60-64, 1997

18. Zanation AM, Ebert CS Jr, Coffey CS, et al: Precursor B-cell lymphoblasticlymphoma 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. JLaryngol Otol 117:205-207, 2003

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DOI: 10.1200/JCO.2011.40.7544; published online ahead of print atwww.jco.org on June 18, 2012

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