A mutation at IVS1 + 5 of the von Hippel-Lindau gene resulting in intron retention in transcripts is not pathogenic in a patient with a tongue cancer?: case report.

BACKGROUND: Von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing the patient to a variety of malignant and benign neoplasms, most frequently hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors. VHL is caused by mutations of the VHL tumor suppressor gene on the short arm of chromosome 3, and clinical manifestations develop if both alleles are inactivated according to the two-hit hypothesis. VHL mutations are more frequent in the coding region and occur occasionally in the splicing region of the gene. Previously, we reported that the loss of heterozygosity (LOH) of the VHL gene is common in squamous cell carcinoma tissues of the tongue. CASE PRESENTATION: We describe a case of squamous cell carcinoma in the tongue caused by a point mutation in the splicing region of the VHL gene and discuss its association with VHL disease. Sequence analysis of DNA extracted from the tumor and peripheral blood of the patient with squamous cell carcinoma revealed a heterozygous germline mutation (c. 340 + 5 G > C) in the splice donor sequence in intron 1 of the VHL gene. RT-PCR analysis of the exon1/intron1 junction in RNA from tumor tissue detected an unspliced transcript. Analysis of LOH using a marker with a heterozygous mutation of nucleotides (G or C) revealed a deletion of the mutant C allele in the carcinoma tissues. CONCLUSIONS: The fifth nucleotide G of the splice donor site of the VHL gene is important for the efficiency of splicing at that site. The development of tongue cancer in this patient was not associated with VHL disease because the mutation occurred in only a single allele of the VHL gene and that allele was deleted in tumor cells.

Tongue cancer patients have a high frequency of allelic loss at the von Hippel-Lindau gene and other loci on 3p.

BACKGROUND: Although genetic abnormalities on 3p have been suggested to be linked to the development of squamous cell carcinoma of the head and neck, to the authors' knowledge no study to date has examined such genetic abnormalities in patients with squamous cell carcinoma of the tongue. In the current study, loss of heterozygosity (LOH) was evaluated at several loci within 3p, including the von Hippel-Lindau gene (VHL), in samples of tongue squamous cell carcinoma. In addition, the coding region of the intact VHL allele was screened for sequence mutations. METHODS: DNA was extracted from tumor and nontumor tissues collected from 28 patients with tongue squamous cell carcinoma. LOH was investigated by analysis of single nucleotide polymorphisms within exon 3 of VHL and by microsatellite analysis within another 10 loci. Mutation analysis of the VHL gene was performed by polymerase chain reaction (PCR) amplification and sequencing of the coding region of the gene. RESULTS: LOH within VHL was found at a high frequency (45.5%) within the tumor. However, mutations of the VHL gene were not detected in all tumor samples. LOH of other microsatellite markers on 3p was observed in 27.3% to 50% of tumor samples. Eleven (58%) of 19 samples that were informative at more than 2 loci exhibited LOH of at least 1 locus; 10 of these 11 cases exhibited LOH at multiple loci. CONCLUSIONS: A wide range of deletions in 3p, including at the VHL gene, may play a role in the development of tongue cancer.

Schwannoma of the retropharyngeal space.

We report a rare case of schwannoma arising from the retropharyngeal space. A 24-year-old man presented a 2-month-history of a foreign body sensation in the throat and gradually progressing dysphagia when he swallowed solids and liquids. The patient had no odynophagia, fever, or blood in his saliva. Computed tomographic scans and magnetic resonance images revealed a well-defined and oval mass, measuring about 40 mm x 20 mm in size, in the retropharyngeal space. Because the tumor existed in the retropharyngeal space and was the adequate size, the patient underwent trans-oral resection under the direct laryngoscope without the need for skin incision. On the basis of the histological findings, the tumor was diagnosed as a schwannoma. It was mostly composed of spindle cells arranged in short bundles and fascicles, with focal palisading of the nuclei. The neoplasm arising from the retropharyngeal space is quite rare, because of few anatomical structures in the space. The post-operative course was uneventful, and the patient is currently free from disease 30 months after surgery. Diagnosis, clinical behavior, and treatment of retropharyngeal schwannoma are reviewed from perusal of the literature. When schwannomas are located in the pharynx, they may cause foreign body sensation or dysphagia. Therefore, when a foreign body sensation in the larynx is present, a thorough diagnostic procedure should be performed to evaluate the morphology of the upper aerodigestive tract.

[Concurrent chemoradiotherapy for advanced hypopharyngeal cancer].

INTRODUCTION: Chemotherapy has been shown to be most effective when delivered concurrently with radiation for the patients with advanced stage tumors. We conducted a concurrent chemoradiation using systemic infusion of cisplatin (CDDP) and 5-fluorouracil (5-FU). PATIENTS AND METHODS: Thirty-nine patients with advanced hypopharyngeal cancer received one or two cycles of intravenous administration of CDDP (80-100 mg/m2) followed by 120-hour continuous infusion of 5-FU (800-1000 mg/m2), and concomitant radiotherapy (200 cGy/day x 20-35 fractions) during the period from December, 1993 through December, 2001. Three of them were in stage III, 31 in stage IVA, and 5 in stage IVB. Until 1999 definitive surgery was planed in almost all the patients, however, primary tumors had pathologically disappeared in eleven out of the 20 (55%) of the surgical specimens. Based on the result, definitive surgery was reserved for residual or recurrent tumors afterwards. RESULTS: The complete response (CR) rates according to the T factor were 100% (1/1) for T1, 86% (6/7) for T2, 67% (2/3) for T3, and 50% (14/28) for T4, respectively. Two cycles of chemotherapy yielded a significantly higher CR rate than that of one cycle (P = 0.0371). One patient died of aspiration pneumonia. The rate of grade 3-4 leukocytopenia was 38%. The projected 5-year disease specific and overall survival rates were 57 and 51%, respectively. CONCLUSIONS: Concurrent chemoradiotherapy is promising as far as improving survival as well as organ preservation.

Abducens nerve palsy and Horner syndrome due to metastatic tumor in the cavernous sinus.

A 41-year-old man was diagnosed as having primary parotid carcinoma on the right side. After radical parotidectomy, radiation therapy and systemic chemotherapy, the primary parotid carcinoma was completely remitted. Two years later, right abducens nerve palsy and Horner syndrome appeared. Neuroimaging demonstrated a gadolinium-enhanced lesion in the posterior portion of the right cavernous sinus, and metastasis of parotid carcinoma was suspected. After radiosurgery and systemic chemotherapy, the intracavernous lesion disappeared. This is the first case of combination of abducens nerve palsy and ipsilateral Horner syndrome due to metastasis from parotid carcinoma to the cavernous sinus.

[Intraarterial concomitant chemoradiation for tongue cancer: analysis of 20 patients].

Subjects were 20 patients with tongue cancer treated between April 1996 and December 2002 with intraarterial infusion of cisplatin (60-120 mg/m2) (and docetaxel 10-30 mg/m2) and intravenous infusion of sodium thiosulfate followed by 5-fluorouracil (5-FU) (800-1000 mg/m2) for 3 to 5 days. All patients underwent radiation (50-80 Gy). Ten had stage II, 4 stage III, and 6 stage IV A disease. Complete response at the primary site was achieved in 50% for T2, 67% for T3, and 0% for T4 lesions in those undergoing IA cisplatin followed by systemic 5-FU with concurrent radiation. Complete response at the primary site was achieved in all patients given IA cisplatin and docetaxel followed by systemic 5-FU with concurrent radiation. Disease-specific survival was 75% and overall survival 69% at 5 years. Side effects of treatment were tolerable, except for grade three radiomucositis in 70% of patients and grade three bone marrow depression in one treated with weekly IA chemotherapy.

Squamous papillomatosis of the bilateral nasal cavities.

The term "papillomatosis" indicates the tendency towards multicentricity and recurrence that these tumors exhibit (Snyder et al. 1972). A typical squamous papilloma arises from the nasal vestibule and is characterized by the epithelial proliferation growing an exophytic manner. We report a rare case of squamous papillomatosis of the bilateral nasal cavities. A 65-year-old man presented with a 2-year-history of bilateral nasal obstruction. Computed tomographic (CT) scans revealed a soft density mass in the bilateral nasal cavities and ethmoid sinuses. Because the tumors were limited to the nasal cavities and anterior ethmoid sinuses, total removal of the tumors was performed endoscopically. On the basis of the clinicopathological findings, the tumors were diagnosed as squamous papillomas. His post-operative course was uneventful, and he is currently free from disease 13 months after surgery. Nasal papillomas usually arise from the unilateral nasal cavity or paranasal sinus. While some cases of inverted (inverting) papillomas arising from the bilateral nasal cavities have been reported, bilateralism of the nasal squamous papillomas is quite rare. Diagnosis, clinical behavior and treatment of squamous papillomatosis of the bilateral nasal cavities are reviewed.

A case of pleomorphic adenoma of the nasal septum.

We report a rare case of pleomorphic adenoma arising from the nasal septum. A 32-year-old woman presented with a 3-week-history of left-sided nasal obstruction. Computed tomographic scans revealed an oval mass, measuring about 30 mm in its greatest dimension, in the left anterior nasal cavity. The tumor arose from the anterior part of the nasal septum, and was removed endoscopically with endonasal approach. The microscopic finding showed a lobular and duct-like structures consisting of a loose chondromyxoid stroma. This lesion had histological characteristics of a pleomorphic adenoma, and this was confirmed by immunohistochemical expression of cytokeratin and S-100 protein. Her post-operative course was uneventful, and she is currently free from the disease 8 months after surgery. Diagnosis, clinical behavior and treatment of pleomorphic adenoma of the nasal septum are reviewed from perusal of the literature.

Double-blind, placebo-controlled trial of zinc picolinate for taste disorders.

A total of 73 patients with an idiopathic zinc-deficiency taste disorder completed a double-blind, placebo-controlled trial of the efficacy of zinc picolinate. Patients in the zinc treatment group (n = 37) received 29 mg of zinc picolinate orally by capsule 3 times a day for 3 months. No significant difference was noted between the treatment and placebo groups in terms of improvement in subjective symptoms or whole-mouth taste sensation. However, assessment of taste using the filter paper disk method showed significantly better improvement for the group given zinc, and the serum zinc level was also significantly higher in this group than in the placebo control group.

Influence of aging on electrogustometry thresholds.

Taste thresholds were measured using electrogustometry by the same researcher at three pairs of sites in the mouth (soft palate, tongue tip and tongue base) in both smokers and non-smokers (n = 461; age range 15-94 years). Comparison of the results by decades showed that the threshold increased significantly with age, starting at age 60 for areas innervated by the chorda tympani and glossopharyngeal nerves and at age 70 for areas innervated by the greater petrosal nerve. For the older teenage subjects, females had significantly lower thresholds than males and thresholds for women tended to be lower than those for men at all sites examined. Thresholds for the two sides of the tongue were within approximately 6 dB of each other. Thresholds on the soft palate were consistently higher than those on the tongue tip and tongue base. Little difference was detected between thresholds on the tongue tip and those on the tongue base except in older teenage subjects, in whom thresholds on the tongue tip were significantly lower than those on the tongue base. Male smokers in their 30s and 40s had significantly lower thresholds on the soft palate than non-smokers in this age group.

A new whole-mouth gustatory test procedure. 1. Thresholds and principal components analysis in healthy men and women.

Gustatory testing using the whole-mouth method was performed in 123 healthy young male and female subjects. The average thresholds for detection and recognition of the four basic tastes were not greatly different from the normal thresholds previously reported in Japan: a 0.0165 M solution of sucrose for sweet taste, a 0.0316 M solution of table salt for salty taste, a 0.000743 M solution of tartaric acid for sour taste and a 0.0000203 M solution of quinine hydrochloride for bitter taste. These results indicate that the whole-mouth gustatory test procedure employed in this study may be useful for evaluating gustatory function clinically. Principal components analysis confirmed that sweet, salty, sour and bitter are indeed the four basic tastes and revealed that the sensation of taste is detected before the specific taste is recognized, regardless of the specific taste tested.

A new whole-mouth gustatory test procedure. II. Effects of aging, gender and smoking.

Taste detection and recognition thresholds for the 4 basic tastes were measured in 670 healthy subjects using a new whole-mouth method in which test solutions of the 4 basic tastes were diluted 1:1 with distilled water successively in 13 steps. The taste thresholds were measured by spraying a 1 ml aliquot of solution into the mouth, starting with the lowest concentration, and asking the subject to swallow and note if a taste was detected and, if so, which one. The mouth was rinsed with distilled water only between different taste test solutions. Multiple comparison analysis showed a clear age-related increase in thresholds for salty, sour and bitter tastes for subjects in their eighth decade of life. From the third decade onwards, female subjects had significantly lower thresholds compared to males for sour taste in about half of the age groups and for salty and bitter tastes in some age groups. In contrast, for 18- and 19-year-old subjects, the gustatory thresholds of male subjects were lower than those of female subjects. Regarding smoking, male smokers in their third decade had significantly higher thresholds for bitter taste compared to male non-smokers in this age group.

Characteristics of 2278 patients visiting the Nihon University Hospital Taste Clinic over a 10-year period with special reference to age and sex distributions.

We investigated the incidence of taste disorders in 2278 patients (871 men, 1407 women) who visited our Taste and Smell Clinic during the 10-year period between 1981 and 1990. Although a higher proportion of our patients were women, there was a significant gender difference only in the proportion of women with mild symptoms; the proportions of men and women with moderate or severe taste disorders were not significantly different. We propose that the incidence of taste disorders is the same among men and women but that women with milder symptoms are more likely to seek treatment. The time from onset of symptoms to the first clinic visit lengthened with increasing patient age. The efficacy of treatment decreased with increasing patient age, regardless of the severity of taste disorder at the initial visit.

Sensitivity of three loci on the tongue and soft palate to four basic tastes in smokers and non-smokers.

The filter paper disk method was used to determine the map of the 4 tastes (sweet, salty, sour and bitter) on the tongue and soft palate in 69 healthy individuals. The equipment used for testing included filter paper disks 8 mm in diameter and taste solutions, which were sequentially diluted (in 13 stages from 80% sucrose, 12 stages from 20% NaCl, 12 stages from 8% tartaric acid and 14 stages from 4% quinine hydrochloride). The threshold at which each taste was recognized in three locations (center of the tongue tip, foliate papillae on the left side and center of the soft palate) was determined by testing increasing concentrations of each solution. We found no difference by sex for sweet taste but women were more sensitive to sour taste on the tongue tip and to salty and bitter tastes on the soft palate. No difference in taste threshold was noted at the different locations for sweet, salty or bitter tastes, but both sexes were less sensitive to sour taste on the soft palate than on the tongue tip, and in men the soft palate was even less sensitive to sour taste than the tongue root. Smoking was associated with increased (worse) taste thresholds for all four tastes, for both men and women.

Taste disturbance in two patients after dental anesthesia by inferior alveolar nerve block.

We report two cases of temporary taste disturbance after inferior alveolar nerve block. The first patient to present with this rare complication of anesthesia for dental surgery was a 41-year-old woman. She lost the sense of taste on the left side of her tongue after local anesthesia for treatment of a left mandibular molar and first visited our outpatient clinic complaining of taste disorder 3 months later. Electrogustometry (EGM) and filter paper disk (FPD) testing revealed a taste disturbance in the innervation area of the left chorda tympani nerve and atrophy of the fungiform papillae on the left side of the tongue was observed. Eleven months after the dental treatment, the fungiform papillae and the results of EGM were normal. The second patient, a 22-year-old woman, received local anesthetic for extraction of a right mandibular molar and subsequently developed loss of taste on the right side of the tongue. When she visited our outpatient clinic 3 months later, atrophy of the fungiform papillae on the right side was observed. Her gustatory sense began to improve 4 months after the dental surgery and was normal at 13 months. From these findings we conclude that taste disturbance on the same side as the inferior alveolar nerve block in each case was due to direct injury to the chorda tympani and lingual nerves during administration of the local anesthetic. The results of EGM and FPD testing were diagnostic: atrophy of the fungiform papillae on the same side and disappearance of taste on the same side in the intravenous taste test provided complementary diagnostic information. The outcome was satisfactory in both cases.