Kyoichi Terao

Human papillomavirus DNA and p16 expression in Japanese patients with oropharyngeal squamous cell carcinoma

Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV‐related OPSCC in Japan. During the study, formalin‐fixed, paraffin‐embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno‐histochemistry. For HPV DNA‐positive, p16‐negative specimens, the methylation status of the p16 gene promoter was examined by methylation‐specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074–0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA‐positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese.

Vestibular system changes in sudden deafness with and without vertigo: a human temporal bone study.

Objective To investigate the vestibular system changes in sudden deafness with vertigo (SDwV) and sudden deafness without vertigo (SDwoV) and the cause of persistent canal paresis (CP) in SDwV patients. Study Design Retrospective study. Materials and Methods Four temporal bones from the affected ear in 4 patients with unilateral sudden deafness (SD), 2 SDwV and 2 SDwoV, were selected. Four contralateral temporal bones with normal-hearing ears were defined as the control. Morphologic findings of the labyrinth, the number of Scarpa’s ganglion cells, and the density of vestibular hair cells were investigated in all temporal bones. Clinical data and the results of vestibular tests of 11 patients with unilateral SD, as a separate group, also were investigated. Results Atrophic change of the organ of Corti, tectorial membrane, and stria vascularis in cochlea, and deposits and atrophic otoconial membrane in vestibular sense organs were seen on affected ears more than control ears. The density of Type I hair cells seemed to decrease on the saccular macula and the posterior semicircular canal crista on affected ears, and there was no remarkable difference between SDwV and SDwoV. In 1 patient with SDwoV who died 10 months after the onset of SD, there were large amount of deposits on the cupula, the atrophied otoconial membrane was peeling off from the saccular macula, and the saccular membrane collapsed to the saccular macula in the affected ear. In the clinical data, all SDwV who were examined within 2 years from the onset had CP, and all SDwV had profound hearing loss. Conclusion There is no remarkable difference between SDwV and SDwoV in the number of Scarpa’s ganglion cells and the density of vestibular hair cells. The damage of the extracellular superstructure is seen in SD with or without vertigo. The damage of extracellular superstructure is potentially one of the causes of persistent CP in patients with SD.

Cochlear changes in presbycusis with tinnitus.

OBJECTIVES The pathophysiology of tinnitus is obscure and its treatment is therefore elusive. Significant progress in this field can only be achieved by determining the mechanisms of tinnitus generation, and thus, histopathologic findings of the cochlea in presbycusis with tinnitus become crucial. We revealed the histopathologic findings of the cochlea in subjects with presbycusis and tinnitus. MATERIAL AND METHODS The subjects were divided into 2 groups, presbycusis with tinnitus (tinnitus) group and presbycusis without tinnitus (control) group, with each group comprising 8 temporal bones from 8 subjects. We quantitatively analyzed the number of spiral ganglion cells, loss of cochlear inner and outer hair cells, and areas of the stria vascularis and spiral ligament. RESULTS There was a significantly greater loss of outer hair cells in the tinnitus group compared with the control group in the basal and upper middle turns. The stria vascularis was more atrophic in the tinnitus group compared with the control group in the basal turn. CONCLUSIONS Tinnitus is more common in patients with presbycusis who have more severe degeneration of outer hair cells and stria vascularis.

Pathologic correlations of otologic symptoms in acute lymphocytic leukemia

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.

Marrow-middle Ear Connections: A Potential Cause of Otogenic Meningitis

Hypothesis: We hypothesize that the connections between the hematopoietic bone marrow and middle ear is a potential cause of childhood otogenic meningitis. Background: Although it is known that there is a causal relationship between otitis media and bacterial meningitis, the relationship has never been satisfactorily established. Human fetal and infant temporal bones prepared for light microscopic evaluation revealed direct connections between the hematopoietic bone marrow and middle ear. We noted this difference in anatomy between the infant middle ear and the adult middle ear. Methods: We studied 10 temporal bones from 5 infants in each group: meningitis group with otitis media who died of meningitis, control Group 1 without otitis media, and control Group 2 with otitis media who died of diseases other than meningitis. A quantitative analysis of the frequency of connections between the hematopoietic bone marrow and middle ear was performed. The correlation between unabsorbed mesenchyme and otitis media also was investigated. Results: The frequency of connections was significantly higher in order of the meningitis group, control Group 2, and control Group 1. The degree of unabsorbed mesenchyme tended to be more severe in order of the meningitis group, control Group 2, and control Group 1. Conclusion: The prevalence of connections between the hematopoietic bone marrow and middle ear in patients with meningitis and otitis media is high. A higher prevalence of connections in infants with otitis media could increase the risk for otogenic meningitis in them.

Breast carcinoma metastasis to the internal auditory canal

In patterns of involvement of the internal auditory canal in nonsystemic malignant tumors, 3 distinct patterns of involvement have been recognized: hematogenous spread, leptomeningeal carcinomatosis, and direct extension. The cerebellopontine angle including the internal auditory canal is an uncommon site for metastatic tumors. In a report of 1,345 cerebellopontine angle tumors, 3 of them were secondary metastatic tumors, and 1 of 3 was a metastatic adenocarcinoma from the breast (1). In this study, a case of metastatic tumor of the internal auditory canal from breast adenocarcinoma will be reported.

Conventional MRI findings for predicting submandibular pleomorphic adenoma.

Background Although pleomorphic adenomas account for over 90% of all benign submandibular gland tumors, the imaging features of submandibular pleomorphic adenomas have not been reported in a large number of cases. Purpose To assess the conventional magnetic resonance imaging (MRI) findings for predicting the submandibular pleomorphic adenoma. Material and Methods MR studies of 42 pleomorphic adenomas and 28 other types of tumor were reviewed. MR images were assessed for the presence of hyperintense areas on T2-weighted images (first sign), a well-defined margin (second sign), and presence of crescent-shaped compression of the ipsilateral normal submandibular gland (third sign). Results For identifying submandibular pleomorphic adenoma, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 97.6%, 50.0%, 74.5%, 93.3%, and 78.6% for the first sign, 95.2%, 46.4% 72.7%, 86.7%, and 75.7% for the second sign, and 23.8%, 100%, 86.7%, 46.7%, and 54.3% for the third sign, respectively. Combining the first and second findings achieved to 85.7% specificity and 90.9% accuracy. Conclusion Although non-specific, submandibular pleomorphic adenomas usually have hyperintense areas on T2-weighted images and well-defined margins. In addition, crescent-shaped compression of the ipsilateral normal gland seems to represent a highly specific sign.

Cochlear otosclerosis adjacent to round window and oval window: A histopathological temporal bone study

Hypothesis: The purpose of this histopathological study is to examine temporal bones of patients with cochlear otosclerosis adjacent to the round window or adjacent to the oval window as compared with healthy controls. Background: It is unclear if the extent and site of otosclerosis affects the extent of damage to cochlear structures and hearing loss. Methods: Twelve temporal bones from 10 patients with cochlear otosclerosis adjacent to the round window, 11 temporal bones from 8 patients with cochlear otosclerosis adjacent to the oval window, and 12 bones of healthy age-matched controls were selected for study. We calculated the number of spiral ganglion cells, changes in cochlear structures, the extent and site of cochlear otosclerosis, and audiometric data. Results: The loss of spiral ganglion cells and the absence of outer hair cells in patients with cochlear otosclerosis adjacent to the round window were significantly higher than those in patients with cochlear otosclerosis adjacent to the oval window and healthy controls. The area of the spiral ligament in patients with cochlear otosclerosis adjacent to the oval window was significantly smaller than that in healthy controls. However, no significant difference was found in the spiral ligament of patients with cochlear otosclerosis adjacent to the round window and healthy controls. There was no significant difference between patients with cochlear otosclerosis and age-matched controls in audiometric data. Conclusion: Cochlear otosclerosis adjacent to the round window caused significantly more damage to spiral ganglion cells and outer hair cells than cochlear otosclerosis adjacent to the oval window without loss of spiral ligament.

Association of Endolymphatic Hydrops and Otosclerosis

Objectives: Study the correlations of endolymphatic hydrops and vestibular symptoms with otosclerotic foci. Methods: Comparative study of human temporal bone histopathology. In addition to areas of the stria vascularis and spiral ligament and the presence of endolymphatic hydrops, locations and degree of endosteal involvement and size of otosclerotic foci were examined in 132 temporal bones from 95 subjects with otosclerosis. The degree of endolymphatic hydrops was classified as mild, moderate and severe. Results: Fifty temporal bones (37.9%) from 39 subjects with otosclerosis had a histopathological finding of endolymphatic hydrops. The most common location of endosteal involvement was the endosteum of the perilymphatic space of the vestibule. In terms of locations and degree of endosteal involvement and size of otosclerotic foci, there was a significant increase in subjects with otosclerosis with endolymphatic hydrops compared with subjects with otosclerosis without endolymphatic hydrops. Twenty five subjects (26.3%) had a documented history of vestibular symptoms in patients with otosclerosis. In addition to the presence of endolymphatic hydrops, locations and degree of endosteal involvement and size of otosclerotic foci were significantly greater in subjects with otosclerosis with vestibular symptoms compared with subjects with otosclerosis without vestibular symptoms. Conclusions: Endolymphatic hydrops is more common than previously realized in patients with otoslerosis. The common association of these 2 otologic conditions encourages researchers. Clinicians should keep in mind the common association of these 2 otologic conditions when encountering a patient with either of these conditions.

R447 – Temporal Bone Histopathology in Acute Lymphocytic Leukemia

Problem There are reports of hearing loss, tinnitus, and/or vertigo in patients with leukemia. However, there is no human temporal bone study of a large number of cases specific to acute lymphocytic leukemia. We studied the correlation between clinical otologic complaints and temporal bone histopathology in patients with this disease. Methods Clinical otologic complaints and histologic findings were evaluated in 13 patients (25 temporal bones) with acute lymphocytic leukemia. Results Nine patients had a history of clinical otologic complaints including: hearing loss in 5 patients; otalgia in 3; otorrhea in 3; and dizziness in 2. Hemorrhage was seen most commonly in the middle ear in 10 patients, but was also evident in the cochlea in 5 and the vestibular labyrinth in 2. Leukemic infiltration was observed in the petrous apex in 12 patients, in the middle ear in 6, the cochlea in 5, the vestibular labyrinth in 2 and the internal auditory canal in 3. Inflammatory cell infiltration was also seen in the cochlear labyrinth in 4 patient, the vestibular labyrinth in 5 and the modiolus in 1. Otitis media with hyperplasia of subepithelial fibrous tissue was seen in 10 patients. Three patients had granulation tissue extending into the middle ear or mastoid. Conclusion Ear involvement is a common finding in patients with acute lymphocytic leukemia. Significance With prolonged survival due to new chemotherapeutics, the diagnosis and treatment of non-hematopoietic system complications such as ear problems due to acute lymphocytic leukemia have become more important. Support International Hearing Foundation, Hubbard Foundation, Starkey Foundation.