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Temporal bone histopathology after treatment by a large amount of cisplatin: A case study
Temporal bone histopathology after treatment by a large amount of cisplatin: A case study PO-WEN CHENG, MD, KIMITAKA KAGA, MD, SATORU KOYAMA, MD, and KENJI KONDO, MD, Taipei, Taiwan, and Tokyo, Japan
Cisplatin (Cis-diamminedichloroplatinum) has been used as a chemotherapeutic agent to treat many kinds of malignancies since 1978. The major toxic effects include nephrotoxicity, peripheral neuropathy, hypomagnesia, nausea, vomiting, myelosuppression, and ototoxicity. Because of ototoxicity, high-tone sensorineural hearing loss is not uncommon after cisplatin treatment. Although the uncontested histopathologic hallmark for high-tone sensorineural deafness is the striking loss of outer hair cells in the basal turn of the cochlea,1,2 few human temporal bone studies have been reported,1-4 and there still exists some uncertainty for other pathologic findings of cisplatin ototoxicity. In order to clarify the effect of cisplatin on hearing loss and histologic changes of temporal bone, we report a case with detailed hearing evaluations and temporal bone histopathology after treatment by a relatively high cumulative dosage of cisplatin. We also counted hair cells and cells in stria vascularis in reconstructed organs of Corti at the same time. CASE REPORT A 17-year-old adolescent girl came to the orthopedic department because she found a mass on her left ventral foot of 1 year’s duration. Biopsy specimens showed Ewing sarcoma. Bilateral multiple pulmonary metastases were also identified by imaging studies. A tumor resection was done on the fourth metatarsal bone. She was then treated by 8 courses of From the Department of Otolaryngology (Dr Cheng), Far Eastern Memorial Hospital, Taipei, the Department of Otolaryngology (Drs Cheng, Kaga, and Kondo), University of Tokyo, and the Department of Otolaryngology (Dr Koyama), Teikyo University School of Medicine, Tokyo. Dr Cheng was supported by Far Eastern Medical Foundation to study as a research fellow in Japan. Reprint requests: Po-Wen Cheng, MD, Department of Otolaryngology, Far Eastern Memorial Hospital, 21, Section 2, Nan-Ya South Road, Pan Chiao, Taipei, Taiwan; e-mail, [email protected]. Otolaryngol Head Neck Surg 2001;125:411-3. Copyright © 2001 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2001/$35.00 + 0 23/78/117408 doi:10.1067/mhn.2001.117408
chemotherapy with cisplatin as a major component during the next 16 months. Audiogram showed normal hearing before chemotherapy. Subsequently, she complained of hearing loss and continuous tinnitus after two courses of cisplatin with a cumulative dosage of 400 mg. Audiogram revealed bilateral mild to moderate high-tone (4K and 8K Hz) sensorineural deafness. After 3 courses of cisplatin with a total dosage of 570 mg, audiogram showed moderate high-tone sensorineural deafness. After 8 courses of cisplatin with a total dosage of 1379 mg, repeated audiogram showed a progressive deterioration of moderate mid-tone (2K Hz) and high-tone sensorineural deafness (Fig 1A). She had no history of vertigo. She also received palliative radiotherapy with a total dose of 40 Gy to locally control pulmonary metastases. She died of respiratory insufficiency 19 months after clinical diagnosis. Temporal bones were removed at autopsy 2 hours after her death, fixed by 10% formalin, embedded in celloidin, serially sectioned at 20 µm in horizontal plane, stained with hematoxylin-eosin, and observed under light microscope. Histopathology of temporal bone serial sections Right ear. The external auditory meatus and middle ear were normal. The epithelium and innervation of the otolith organs and semicircular canals seemed normal. In cytocochleogram (Fig 1B), there was mild to severe loss of outer hair cells in the first 13 mm of the basal turn and 3 areas of apical turn, but no loss of inner hair cells throughout the cochlea. Mild degeneration of stria vascularis was found in some areas of all turns (Fig 2A). Spiral ganglion cells and peripheral fibers in the osseous spiral lamina showed no remarkable change. Left ear. The external auditory meatus and middle ear were unremarkable. The vestibular organs appeared normal. In cytocochleogram (Fig 1B), there was complete loss of outer hair cells in the first 10 mm of basal turn and mild to severe loss in the other areas (Fig 2B). Loss of inner hair cells was noticed at two locations, one in the first 8 mm and the other at 11 mm of cochlea. There was mild degeneration of stria vascularis in the basal and upper turns. Unlike the right ear, the left had a mild decrease of spiral ganglion cells (Fig 2C) and denervation of myelinated dendritic fibers in the basal turn (Fig 2D). 411
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B Fig 1. A, Audiograms before chemotherapy, after 2 courses (400 mg), 3 courses (570 mg), and 8 courses (1379 mg) of cisplatin. B, Cytocochleogram hair cells and cells in stria vascularis were counted in reconstructed organs of Corti.
DISCUSSION
In order to monitor cisplatin ototoxicity for this patient, hearing was evaluated by repeated audiograms before and after its usage. Like previous works, we found progressive hearing loss initially invaded the high-frequency range (4K and 8K) and then also affected the mid-frequency area (2K) after we continued to treat this patient with cisplatin. However, as the cumulative dosage increased from 570 mg to 1379 mg, more than double dosage, a further significant hearing loss was limited to the high frequencies, and it seemed to approach a maximum threshold shift or plateau. In cytocochleogram, there was total loss of the outer hair cells in the first 10 mm of left cochlea, which could explain why she had an impaired hearing level of around 60 to 65 dB in the corresponding high frequencies. As we know, deafness after cisplatin is mainly attributed to the loss of outer hair cells. Because all outer hair cells had already been lost in the first 10 mm of left basal turn in our patient, we predicted that a hearing plateau had been reached in the high-frequency range and appeared to fall to around 60 to 65 dB hearing level. This hypothesis was in accordance with the previous report.5
In this temporal bone study, more serious destruction was found in left cochlea than in right cochlea, including loss of inner and outer hair cells, decrease of spiral ganglion cells, and denervation of myelinated dendritic fibers in the basal turns. These findings, especially loss of outer hair cells, might explain why her hearing level on the left side was worse by 5 to 10 dB than on the right side over the frequencies of 2K, 4K, and 8K, because the basal turn was the responsible site for these frequencies. After treatment by cisplatin, degeneration of stria vascularis, predominately in the upper turns, was never reported,2,4 but we found degeneration might be equally involved throughout all turns of cochlea without a significant preference. It was predicted that decrease of spiral ganglion cells and denervation of myelinated dendritic fibers might have resulted from the loss of hair cells because the decrease of ganglion cells and denervation of the fibers only occurred on the most destructed area of hair cells in our study. One article showed a case manifesting with acute and transient vertigo after a cumulative dosage of 620 mg of cisplatin. Temporal bone pathologic examination revealed severe degeneration of the maculae and cristae in both ears.3 However, our case did not show any
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Fig 2. Histopathology of the temporal bones. A, Atrophy of stria vascularis (arrowhead) in the middle turn of right cochlea. B, Total loss of inner (arrowhead) and outer (arrow) hair cells in the basal turn of left cochlea. C, Decrease of spiral ganglion cells (arrowheads) in the basal turn of modiolar section of left cochlea. D, Denervation of myelinated dendritic fibers (arrowhead) in osseous spiral lamina and a totally degenerative organ of Corti (arrow) in the basal turn of left cochlea. Hematoxylin-eosin stain; original magnifications ×8 (C), ×20 (A and D), and ×80 (B).
degenerative changes in the vestibular organs, even with the higher dosage of cisplatin. This means that the cochlea is more susceptible to cisplatin ototoxicity than the vestibular organs. In addition to being one of few temporal bone studies, this case is valuable in that our patient received the highest cumulative dosage of cisplatin ever reported, and it demonstrated chronologic hearing deterioration and cytocochleogram in stria vascularis for the first time. We thank Ms E. Saito and N Furuya for technical assistance of temporal bone serial sections at the Department of Otolaryngology in Teikyo University.
REFERENCES 1. Strauss M, Towfighi J, Lord S, et al. Cis-platinum ototoxicity: clinical experience and temporal bone histopathology. Laryngoscope 1983;93:1554-9. 2. Hinojosa R, Riggs LC, Strauss M, et al. Temporal bone histopathology of cisplatin ototoxicity. Am J Otol 1995;16:73140. 3. Wright CG, Schaefer SD. Inner ear histopathology in patients treated with cis-platinum. Laryngoscope 1982;92:1408-13. 4. Hoistad DL, Ondrey FG, Mutlu C, et al. Histopathology of human temporal bone after cis-platinum, radiation, or both. Otolaryngol Head Neck Surg 1998;118:825-32. 5. Kopelman J, Budnick AS, Sessions RB, et al. Ototoxicity of high-dose cisplatin by bolus administration in patients with advanced cancers and normal hearing. Laryngoscope 1988; 98:858-64.
Cisplatin (Cis-diamminedichloroplatinum) has been used as a chemotherapeutic agent to treat many kinds of malignancies since 1978. The major toxic effects include nephrotoxicity, peripheral neuropathy, hypomagnesia, nausea, vomiting, myelosuppression, and ototoxicity. Because of ototoxicity, high-tone sensorineural hearing loss is not uncommon after cisplatin treatment. Although the uncontested histopathologic hallmark for high-tone sensorineural deafness is the striking loss of outer hair cells in the basal turn of the cochlea,1,2 few human temporal bone studies have been reported,1-4 and there still exists some uncertainty for other pathologic findings of cisplatin ototoxicity. In order to clarify the effect of cisplatin on hearing loss and histologic changes of temporal bone, we report a case with detailed hearing evaluations and temporal bone histopathology after treatment by a relatively high cumulative dosage of cisplatin. We also counted hair cells and cells in stria vascularis in reconstructed organs of Corti at the same time. CASE REPORT A 17-year-old adolescent girl came to the orthopedic department because she found a mass on her left ventral foot of 1 year’s duration. Biopsy specimens showed Ewing sarcoma. Bilateral multiple pulmonary metastases were also identified by imaging studies. A tumor resection was done on the fourth metatarsal bone. She was then treated by 8 courses of From the Department of Otolaryngology (Dr Cheng), Far Eastern Memorial Hospital, Taipei, the Department of Otolaryngology (Drs Cheng, Kaga, and Kondo), University of Tokyo, and the Department of Otolaryngology (Dr Koyama), Teikyo University School of Medicine, Tokyo. Dr Cheng was supported by Far Eastern Medical Foundation to study as a research fellow in Japan. Reprint requests: Po-Wen Cheng, MD, Department of Otolaryngology, Far Eastern Memorial Hospital, 21, Section 2, Nan-Ya South Road, Pan Chiao, Taipei, Taiwan; e-mail, [email protected]. Otolaryngol Head Neck Surg 2001;125:411-3. Copyright © 2001 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2001/$35.00 + 0 23/78/117408 doi:10.1067/mhn.2001.117408
chemotherapy with cisplatin as a major component during the next 16 months. Audiogram showed normal hearing before chemotherapy. Subsequently, she complained of hearing loss and continuous tinnitus after two courses of cisplatin with a cumulative dosage of 400 mg. Audiogram revealed bilateral mild to moderate high-tone (4K and 8K Hz) sensorineural deafness. After 3 courses of cisplatin with a total dosage of 570 mg, audiogram showed moderate high-tone sensorineural deafness. After 8 courses of cisplatin with a total dosage of 1379 mg, repeated audiogram showed a progressive deterioration of moderate mid-tone (2K Hz) and high-tone sensorineural deafness (Fig 1A). She had no history of vertigo. She also received palliative radiotherapy with a total dose of 40 Gy to locally control pulmonary metastases. She died of respiratory insufficiency 19 months after clinical diagnosis. Temporal bones were removed at autopsy 2 hours after her death, fixed by 10% formalin, embedded in celloidin, serially sectioned at 20 µm in horizontal plane, stained with hematoxylin-eosin, and observed under light microscope. Histopathology of temporal bone serial sections Right ear. The external auditory meatus and middle ear were normal. The epithelium and innervation of the otolith organs and semicircular canals seemed normal. In cytocochleogram (Fig 1B), there was mild to severe loss of outer hair cells in the first 13 mm of the basal turn and 3 areas of apical turn, but no loss of inner hair cells throughout the cochlea. Mild degeneration of stria vascularis was found in some areas of all turns (Fig 2A). Spiral ganglion cells and peripheral fibers in the osseous spiral lamina showed no remarkable change. Left ear. The external auditory meatus and middle ear were unremarkable. The vestibular organs appeared normal. In cytocochleogram (Fig 1B), there was complete loss of outer hair cells in the first 10 mm of basal turn and mild to severe loss in the other areas (Fig 2B). Loss of inner hair cells was noticed at two locations, one in the first 8 mm and the other at 11 mm of cochlea. There was mild degeneration of stria vascularis in the basal and upper turns. Unlike the right ear, the left had a mild decrease of spiral ganglion cells (Fig 2C) and denervation of myelinated dendritic fibers in the basal turn (Fig 2D). 411
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B Fig 1. A, Audiograms before chemotherapy, after 2 courses (400 mg), 3 courses (570 mg), and 8 courses (1379 mg) of cisplatin. B, Cytocochleogram hair cells and cells in stria vascularis were counted in reconstructed organs of Corti.
DISCUSSION
In order to monitor cisplatin ototoxicity for this patient, hearing was evaluated by repeated audiograms before and after its usage. Like previous works, we found progressive hearing loss initially invaded the high-frequency range (4K and 8K) and then also affected the mid-frequency area (2K) after we continued to treat this patient with cisplatin. However, as the cumulative dosage increased from 570 mg to 1379 mg, more than double dosage, a further significant hearing loss was limited to the high frequencies, and it seemed to approach a maximum threshold shift or plateau. In cytocochleogram, there was total loss of the outer hair cells in the first 10 mm of left cochlea, which could explain why she had an impaired hearing level of around 60 to 65 dB in the corresponding high frequencies. As we know, deafness after cisplatin is mainly attributed to the loss of outer hair cells. Because all outer hair cells had already been lost in the first 10 mm of left basal turn in our patient, we predicted that a hearing plateau had been reached in the high-frequency range and appeared to fall to around 60 to 65 dB hearing level. This hypothesis was in accordance with the previous report.5
In this temporal bone study, more serious destruction was found in left cochlea than in right cochlea, including loss of inner and outer hair cells, decrease of spiral ganglion cells, and denervation of myelinated dendritic fibers in the basal turns. These findings, especially loss of outer hair cells, might explain why her hearing level on the left side was worse by 5 to 10 dB than on the right side over the frequencies of 2K, 4K, and 8K, because the basal turn was the responsible site for these frequencies. After treatment by cisplatin, degeneration of stria vascularis, predominately in the upper turns, was never reported,2,4 but we found degeneration might be equally involved throughout all turns of cochlea without a significant preference. It was predicted that decrease of spiral ganglion cells and denervation of myelinated dendritic fibers might have resulted from the loss of hair cells because the decrease of ganglion cells and denervation of the fibers only occurred on the most destructed area of hair cells in our study. One article showed a case manifesting with acute and transient vertigo after a cumulative dosage of 620 mg of cisplatin. Temporal bone pathologic examination revealed severe degeneration of the maculae and cristae in both ears.3 However, our case did not show any
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Fig 2. Histopathology of the temporal bones. A, Atrophy of stria vascularis (arrowhead) in the middle turn of right cochlea. B, Total loss of inner (arrowhead) and outer (arrow) hair cells in the basal turn of left cochlea. C, Decrease of spiral ganglion cells (arrowheads) in the basal turn of modiolar section of left cochlea. D, Denervation of myelinated dendritic fibers (arrowhead) in osseous spiral lamina and a totally degenerative organ of Corti (arrow) in the basal turn of left cochlea. Hematoxylin-eosin stain; original magnifications ×8 (C), ×20 (A and D), and ×80 (B).
degenerative changes in the vestibular organs, even with the higher dosage of cisplatin. This means that the cochlea is more susceptible to cisplatin ototoxicity than the vestibular organs. In addition to being one of few temporal bone studies, this case is valuable in that our patient received the highest cumulative dosage of cisplatin ever reported, and it demonstrated chronologic hearing deterioration and cytocochleogram in stria vascularis for the first time. We thank Ms E. Saito and N Furuya for technical assistance of temporal bone serial sections at the Department of Otolaryngology in Teikyo University.
REFERENCES 1. Strauss M, Towfighi J, Lord S, et al. Cis-platinum ototoxicity: clinical experience and temporal bone histopathology. Laryngoscope 1983;93:1554-9. 2. Hinojosa R, Riggs LC, Strauss M, et al. Temporal bone histopathology of cisplatin ototoxicity. Am J Otol 1995;16:73140. 3. Wright CG, Schaefer SD. Inner ear histopathology in patients treated with cis-platinum. Laryngoscope 1982;92:1408-13. 4. Hoistad DL, Ondrey FG, Mutlu C, et al. Histopathology of human temporal bone after cis-platinum, radiation, or both. Otolaryngol Head Neck Surg 1998;118:825-32. 5. Kopelman J, Budnick AS, Sessions RB, et al. Ototoxicity of high-dose cisplatin by bolus administration in patients with advanced cancers and normal hearing. Laryngoscope 1988; 98:858-64.