American Journal of Otolaryngology - Head and Neck Medicine and Surgery
Volume 32, Issue 1 , Pages 13-18, January 2011

Pathologic correlations of otologic symptoms in acute lymphocytic leukemia☆

  • Kyoichi Terao, MD, PhD

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • International Hearing Foundation, Minneapolis, Minnesota, USA
    • Department of Otolaryngology, Kinki University School of Medicine, Osaka, Japan
    • ,
  • Sebahattin Cureoglu, MD

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • Paparella Ear Head and Neck Institute, Minneapolis, Minnesota, USA
    • Corresponding Author InformationCorresponding author. Department of Otolaryngology, University of Minnesota, Room 210, Lions Research Building, 2001, 6th Street, SE, Minneapolis, MN 55455, USA. Tel.: +1 612 626 9883; fax: +1 612 626 9871.
    • ,
  • Patricia A. Schachern, BS

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • ,
  • Michael M. Paparella, MD

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • International Hearing Foundation, Minneapolis, Minnesota, USA
    • Paparella Ear Head and Neck Institute, Minneapolis, Minnesota, USA
    • ,
  • Norimasa Morita, MD, PhD

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • International Hearing Foundation, Minneapolis, Minnesota, USA
    • ,
  • Shigenobu Nomiya, MD, PhD

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • International Hearing Foundation, Minneapolis, Minnesota, USA
    • ,
  • Taro Inagaki, MD, PhD

      Affiliations

    • Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
    • International Hearing Foundation, Minneapolis, Minnesota, USA
    • ,
  • Kazunori Mori, MD, PhD

      Affiliations

    • Department of Otolaryngology, Kinki University School of Medicine, Osaka, Japan
    • ,
  • Kiyotaka Murata, MD, PhD

      Affiliations

    • Department of Otolaryngology, Kinki University School of Medicine, Osaka, Japan

Received 30 June 2009 published online 21 December 2009.

Article Outline

Abstract 

Objectives

To assess the clinicopathologic correlations of otologic complaints in patients with acute lymphocytic leukemia.

Design

Otologic complaints and histologic findings were evaluated in 25 temporal bones of 13 acute lymphocytic leukemia patients.

Results

Nine patients had a history of otologic complaints, including hearing loss, otalgia, otorrhea, and vertigo in 5, 3, 3, and 2 patients, respectively. Hemorrhage was most commonly observed in the middle ear (6 patients, 9 temporal bones) and was also observed in cochlea (4 patients, 4 temporal bones), and vestibule (6 patients, 6 temporal bones). Leukemic infiltration was observed in the petrous apex (13 patients, 24 temporal bones), middle ear (7 patients, 14 temporal bones), cochlea (3 patients, 4 temporal bones), vestibule (3 patients, 4 temporal bones), and internal auditory canal (5 patients, 8 temporal bones). Inflammatory changes were observed in the cochlea (5 patients, 8 temporal bones) and vestibule (5 patients, 8 temporal bones). Middle ear effusion containing floating tumor cells was observed in 4 temporal bones of 3 patients. Irreversible histopathologic changes of the middle ear, such as the destruction of the ossicles, perforation of the tympanic membrane, and granulation tissues were observed in 5 temporal bones of 4 patients.

Conclusions

Ear involvement is common in acute lymphocytic leukemia patients. With prolonged survival due to the progress of treatment, the diagnosis and treatment of nonhematopoietic system symptoms, such as ear problems due to acute lymphocytic leukemia, have become more important.

 

Back to Article Outline

1. Introduction 

It is reported that patients with leukemia occasionally have hearing loss, tinnitus, and/or vertigo as initial clinical complaints or during follow-up [1], [2], [3], [4]. The proportion of patients with leukemia having definite otologic signs or symptoms was reported to be 32% by Shanbrom and Finch [2] (1958) and 48% by Paparella et al [3] (1973). In contrast, leukemic infiltration of the ear is infrequent in the clinical setting, and only anecdotal cases have been reported to date [5], [6]. Clinicians need to clearly understand the clinicopathologic correlations of otologic symptoms in patients with leukemia. A human temporal bone study of a large number of cases specific to acute lymphocytic leukemia (ALL) has not been conducted. This study was performed in a large number of temporal bones from patients with ALL to determine the histopathologic correlations of clinical findings.

Back to Article Outline

2. Materials and methods 

Autopsy reports of 1000 patients from the temporal bone collection at the University of Minnesota were screened to select cases with ALL. Twenty-five temporal bones from 13 patients were obtained.

Clinical details of these 13 patients were as follows. All the patients were white. There were 8 males and 5 females in this group with an age range of 3 to 67 years and an average age of 17.5 years. Five patients received chemotherapy and radiation therapy, 7 received chemotherapy, and 1 received only palliative therapy. Five patients were administered ototoxic drugs. Eleven patients died of infection, 1 of hemorrhage, and 1 of hepatic coma. The range of survival was 1 to 64 months with an average survival period of 24.3 months.

Temporal bones were removed at autopsy less than 24 hours after death and were fixed in formalin solution. Each bone was decalcified, embedded in celloidin, and serially sectioned in the horizontal plane at a thickness of 20 μm. Every 10th section was stained with hematoxylin-eosin and mounted on a glass slide. We examined each temporal bone under light microscopy for the presence of leukemic infiltration, hemorrhage, and inflammatory changes, and noted the anatomic site of involvement. Clinical records were reviewed to retrieve the clinical course, treatment methods, and clinical otologic complaints reported after the initial diagnosis of leukemia. We reviewed autopsy reports to determine the proportion of other organs with leukemic cells and then considered the histopathologic correlations of clinical findings.

Back to Article Outline

3. Results 

Nine patients (69.2%) had one or more otologic complaints according to the clinical reports (Table 1). Hearing loss was the most common complaint. Sensorineural hearing loss was noted in 1 patient and conductive hearing loss in 1 patient, but the type of hearing loss was not clear in 3 patients. Four patients (30.8%) had no clinical otologic complaints. Six patients had otalgia, otorrhea, and/or ear bleeding. One patient had undergone surgery for acute mastoiditis, at which time ALL relapse was diagnosed. One patient had an ear tube inserted for exudative otitis media, and 4 other patients were treated conservatively for otitis externa and otitis media.

Table 1. Otologic complaints
Otologic complaintsNo. (%) of patients
Hearing loss5 (38.5)
Otorrhea4 (30.8)
Otalgia4 (30.8)
None4 (30.8)
Vertigo2 (15.4)
Ear bleeding1 (7.7)

The incidence of the histopathologic findings grouped according to their anatomic site in temporal bones of patients with ALL, is shown in Table 2. Histopathologic findings of 9 patients (69.2%) were similar on both sides. Leukemic infiltration was observed most commonly in the marrow spaces of the petrous apex (13 patients, 24 temporal bones), including the marrow spaces of the ossicles (2 patients, 4 temporal bones) and the endochondral layer of the bony labyrinth (2 patients, 4 temporal bones). Leukemic infiltration was observed in the submucous membranes of the external auditory canal, tympanic membrane, middle ear, and mastoid. Infiltration was also observed inside and outside of the submucous vessels. Because of leukemic infiltration and congestion, the swelling of the external auditory canal was observed in 1 temporal bone, and that of the tympanic membrane in 5 temporal bones of 3 patients. Leukemic infiltration of the cochlea, vestibule, and internal auditory canal was observed in 4 temporal bones of 3 patients, 2 of whom complained of vertigo (Fig. 1). Leukemic infiltration of the internal auditory canal was observed in the perineural and endoneural sheaths of the seventh and/or eighth cranial nerves. Leukemic cells were observed in the cerebrospinal fluid (CSF) of 3 patients with leukemic infiltration of the internal auditory canal, one of whom had severe sensorineural hearing loss in both ears (Fig. 2). Although leukemic infiltration of the facial canal was observed, none of these cases had exhibited facial paralysis. All patients had leukemic infiltration in some areas of temporal bones.

Table 2. Temporal bone pathologic findings
AreaLeukemic infiltrationHemorrhageInflammatory changes
No. (%) of patients (n = 13)No. (%) of TBs (n = 25)No. (%) of patients (n = 13)No. (%) of TBs (n = 25)No. (%) of patients (n = 13)No. (%) of TBs (n = 25)
External ear4 (30.8)7 (28.0)1 (7.7)2 (8.0)00
TM6 (46.2)8 (32.0)1 (7.7)2 (8.0)1 (7.7)1 (4.0)
Middle ear7 (53.8)14 (56.0)6 (46.2)9 (36.0)4 (30.8)5 (20.0)
Mastoid6 (46.2)10 (40.0)4 (30.8)5 (20.0)2 (15.4)2 (8.0)
Cochlea3 (23.1)4 (16.0)4 (30.8)4 (16.0)5 (38.5)8 (32.0)
Vestibule3 (23.1)4 (16.0)6 (46.2)6 (24.0)5 (38.5)8 (32.0)
Modiolus2 (15.4)3 (12.0)1 (7.7)1 (4.0)00
Facial nerve4 (30.8)7 (28.0)2 (15.4)3 (12.0)00
IAC5 (38.5)8 (32.0)6 (46.2)7 (28.0)00
Petrous apex13 (100 )24 (96.0)1 (7.7)1 (4.0)00

TB indicates temporal bone; TM, tympanic membrane; IAC, internal auditory canal.

  • View full-size image.
  • Fig. 1. 

    Temporal bone of a 17-year-old male who complained of vertigo. Leukemic infiltration is observed in the scala tympani of the basal turn (A). Aggregation of tumor cells is evident (B). Hematoxylin-eosin, original magnification ×40 (A), ×400 (B).

  • View full-size image.
  • Fig. 2. 

    Temporal bone of a 15-year-old male adolescent who complained of gradually progressive hearing loss. Leukemic infiltration is observed in both the cochlear and vestibular nerves (A). Aggregation of tumor cells is observed in the endoneural sheath of the cochlear nerve (B). Hematoxylin-eosin, original magnification ×100 (A), ×400 (B).

Hemorrhage was observed most commonly in the middle ear (6 patients, 9 temporal bones) in the submucous membranes, with hypervascularization, capillary dilatation, and numerous red blood cells in the capillaries. It was occasionally also observed in the middle ear cavity. Hemorrhage of the inner ear was observed mainly in the perilymph. Extensive hemorrhage in the cochlea and vestibule was observed in 2 temporal bones of 2 patients, one of whom complained of vertigo and otalgia (Fig. 3). One patient who died of subarachnoid hemorrhage had extensive hemorrhage in the internal auditory canal and modiolus. Sixteen temporal bones of 12 patients showed various degrees of hemorrhage.

  • View full-size image.
  • Fig. 3. 

    Temporal bone of a 16-year-old male who complained of vertigo. There is extensive hemorrhage in the scala vestibuli, scala tympani, and modiolus, but not in the cochlear duct. There is ballooning of the Reissner's membrane. Hematoxylin-eosin, original magnification ×20.

Inflammatory changes were observed most commonly in the cochlea (5 patients, 8 temporal bones) and the vestibule (5 patients, 8 temporal bones). Serous labyrinthitis was observed in 8 temporal bones of 5 patients, and purulent labyrinthitis was observed in 1 temporal bone (Fig. 4). Four of these patients complained of hearing loss, one of whom showed severe degeneration of the organ of Corti. Inflammatory changes of the middle ear were observed in the submucous membranes with leukemic infiltration and hemorrhage. Middle ear effusion was observed in 5 temporal bones of 4 patients; the pathologic findings indicated effusion containing floating tumor cells in 4 temporal bones of 3 patients, and leukemic infiltration around the eustachian tube in all of temporal bones. Five temporal bones of 4 patients had the following irreversible histopathologic changes: hyperplastic epithelium of the middle ear with proliferation of ciliated and goblet cells in one temporal bone, destruction of the ossicles in 2 temporal bones of 2 patients, perforation of the tympanic membrane in 2 temporal bones of 2 patients, and granulation tissues of the middle ear in 4 temporal bones of 3 patients.

  • View full-size image.
  • Fig. 4. 

    Temporal bone of an 11-year-old female adolescent who complained of hearing loss. The round window membrane was involved in inflammatory changes (A). Numerous red blood cells, lymphocytes, polymorphonuclear leukocytes, and fibrocytes are observed. (B). Hematoxylin-eosin, original magnification ×20 (A), ×400 (B).

Four patients had no otologic complaints and poor pathologic findings including those of leukemic infiltration only observed in the petrous apex along with scanty hemorrhage in the middle or inner ear. None of them had inflammatory changes.

Organs outside the hematopoietic system in which leukemic infiltration was observed, are reported according to autopsy reports in Table 3. Leukemic cells were observed in various organs. In 1 patient, leukemic cells were found only in the hematopoietic system. In temporal bones, leukemic infiltration of the middle ear was second only to that of the petrous apex.

Table 3. Leukemic infiltration of organs outside the hematopoietic system
OrganNo. (%) of patients
Middle ear7 (53.8)
Kidney7 (53.8)
Lung6 (46.2)
Brain5 (38.5)
Testis4 (30.8)
Intestine3 (23.1)
Thyroid2 (15.4)
Heart1 (7.7)
Stomach1 (7.7)
Adrenal1 (7.7)

Back to Article Outline

4. Discussion 

The incidence of otologic complaints ranges from 16.8% to 48.0% in patients with leukemia [1], [2], [3]. We found that 69.2% of patients with ALL had definite otologic complaints. This high incidence of otologic complaints was attributed to prolonged survival.

It has been reported that histopathologic findings in temporal bones from patients with leukemia can be mainly classified as leukemic infiltration, hemorrhage, and inflammatory changes [3], [7].

Leukemic infiltration of temporal bones could be caused hematogenously or through the CSF. Leukemic infiltration was observed most commonly in the marrow spaces of the petrous apex [7], which was observed in all patients. In general, leukemic cells that spread hematogenously must first pass the petrous apex before involving the middle and inner ear. Proctor and Lindsay [8] reported that the sluggish blood flow in the sinusoidal capillaries of the marrow presumably favors the deposition of tumor cells in these areas of temporal bones. In addition, Jahn et al [9] showed that subsequent metastasis, after invasion of the petrous bone, occurs by vascular permeation. The submucous vessels of the mastoid air cells are ultimately occluded with tumors. These vessels communicate with the vessels of the middle ear cleft, and the tumor cells are ultimately carried throughout the tubotympanic cavity.

Since the perineurium of the nerve in the internal auditory canal is similar to lymph vessels and communicates with the CSF, leukemic cells in the CSF would be transported to the modiolus, cochlea, vestibule, or semicircular canals through the lymph that surrounds the cochlear and vestibular nerves. This appeared likely in 3 of our patients because leukemic cells were evident in both the internal auditory canal and the CSF.

In 4 of 8 (50%) temporal bones with leukemia with middle ear effusion, floating tumor cells were detected in the effusion [10]. The incidence of effusion containing floating tumor cells in the present study was higher than that observed in this previous study [10]. In patients with leukemia with middle ear effusion, a cytologic examination is recommended.

Inflammatory changes of the middle ear apparently superimposed upon the leukemic infiltration and submucous hemorrhage. It has been reported that eustachian tube obstruction by leukemic infiltration, infiltration and hemorrhage of the submucous membranes of the middle ear, and hematotympanum may all predispose to infection [11]. These findings were also common findings in our cases. Our findings suggest that leukemic infiltration and a tendency to bleed are main causes of inflammatory changes of the middle ear. Many patients with ALL showed findings of labyrinthitis much beyond our expectations. However, the reason remains unknown.

Many researchers have reported that the most common otologic complaint due to leukemia is hearing loss [2], [3], [12], [13], as in the present study. The most common cause of conductive hearing loss may be secondary otitis media due to leukemic infiltration and hemorrhage. The control of inflammatory changes in the middle ear is very important, because many patients with inflammatory changes of the middle ear have irreversible histopathologic changes, and the most common cause of death was infection. Acute sensorineural hearing loss and/or vertigo related to leukemic infiltration of the inner ear and cranial nerves has been reported [4], [14], [15], [16], [17]. These conditions seemed likely in 3 of our patients, as 2 with vertigo and 1 with sensorineural hearing loss had leukemic infiltration of the internal auditory canal and/or the inner ear. Thus, in the follow-up of patients with leukemia, various nonspecific otologic symptoms should be kept in mind.

In a study of 273 patients with acute leukemia, the incidence of facial paralysis was 2.8% in patients with acute non-lymphocytic leukemia (213 patients) and 13.3% in patients with ALL (60 patients) [18]. The most common mechanism in leukemic facial neuropathies is the surrounding meningeal involvement of the nerve [19]. In our cases, although leukemic infiltration of the CSF, internal auditory canal, and facial canal were observed, none of them had experienced facial paralysis.

Back to Article Outline

5. Conclusion 

Leukemic infiltration should be considered in ALL patients, even if otitis media is observed. Biopsy samples should include submucosal tissues. Various nonspecific otologic symptoms are possible in patients with ALL. Because leukemic infiltration of temporal bones is observed frequently in patients with ear problems, clinicians should consider the possibility of ear metastases in patients with ALL.

Back to Article Outline

Acknowledgment 

The authors thank Carolyn Sutherland for technical assistance.

Back to Article Outline

References 

  1. Druss JG. Aural manifestations of leukemia. Arch Otolaryngol Head Neck Surg. 1945;42:267–274
  2. Shanbrom E, Finch SC. The auditory manifestations of leukemia. Yale J Biol Med. 1958;31:144–156
  3. Paparella MM, Berlinger NT, Oda M, et al. Otological manifestations of leukemia. Laryngoscope. 1973;83:1510–1526
  4. Taljebini M, Linthicum FH. Hearing loss in chronic lymphocytic leukemia. Otol Neurotol. 2007;28:282–283
  5. Millot F, Klossec JM, Brizard F, et al. Recurrence of childhood acute lymphoblastic leukemia presenting as a tumor of the middle ear: a case report. J Pediatr Hematol. 1997;19:351–353
  6. Au WY, Chan CF, Chim CS, et al. External auditory canal tumor: a rare chloroma in acute promyelocytic leukemia with a complete response to arsenic trioxide. J Clin Oncol. 2001;20:3993–3995
  7. Zechner G, Altmann F. The temporal bone in leukemia histopathological studies. Ann Otol Rhinol Laryngol. 1969;78:375–387
  8. Proctor B, Lindsay JR. Tumors involving the petrous pyramid of the temporal bone. Arch Otolaryngol Head Neck Surg. 1947;46:180–194
  9. Jahn AF, Farkashidy J, Berman JM. Metastatic tumors in the temporal bone—a pathophysiologic study. J Otolaryngol. 1979;8:85–95
  10. Okura SI, Kaga K. Temporal bone pathology of leukemia and malignant lymphoma with middle ear effusion. Auris Nasus Larynx. 1994;21:1–7
  11. Wiernik PH, Serpick AA. Glanulocytic sarcoma (chloroma). Blood. 1970;35:361–369
  12. Schuknecht HF, Igarashi M, Chasin WD. Inner ear hemorrhage in leukemia. A case report. Laryngoscope. 1965;75:662–668
  13. Breccia M, Petti MC, Testi AM, et al. Ear involvement in acute promyelocytic leukemia at relapse: a disease-associated ‘sanctuary’?. Leukemia. 2002;16:1127–1130
  14. Aikawa T, Ohtani I. Temporal bone findings in central nervous system leukemia. Am J Otolaryngol. 1991;12:320–325
  15. Hoshino T, Hiraide F, Nomura Y. Metastatic tumor of the inner ear: a histopathological report. J Laryngol Otol. 1972;86:697–707
  16. LaVenuta F, Moore JA. Involvement of the inner ear in acute stem cell leukemia. Report of two cases. Ann Otol Rhinol Laryngol. 1972;81:132–137
  17. Hallpike CS, Harrison MS. Clinical and pathological observations of a case of leukemia with deafness and vertigo. J Laryngol Otol. 1950;64:427–430
  18. Sklansky BD, Jafek BW, Wiernik PH. Otolaryngologic manifestations of acute leukemia. Laryngoscope. 1974;84:210–230
  19. Ozçakar L, Akinci A, Ozgöçmen S, et al. Bell's palsy as an early manifestation of acute lymphoblastic leukemia. Ann Hematol. 2003;82:124–126

☆ This study was supported by the International Hearing Foundation, the Starkey Foundation, and the Society for Promotion of International Oto-Rhino-Laryngology.

PII: S0196-0709(09)00170-7

doi:10.1016/j.amjoto.2009.08.006

American Journal of Otolaryngology - Head and Neck Medicine and Surgery
Volume 32, Issue 1 , Pages 13-18, January 2011

Article Tools

* Image Usage & Resolution