Sohei Endo’s research while affiliated with Nihon University and other places

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. 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. 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.

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. 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. 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. A wide range of deletions in 3p, including at the VHL gene, may play a role in the development of tongue cancer.

In most cases, pendular tonsils are benign. We report a 75-year-old man who presented with a pendular tonsil which was finally diagnosed as a squamous cell carcinoma of the tonsil. The patient was seen with the chief complaint of a foreign body in his throat. On his first visit, a smooth-surfaced pedunculated mass protruding from the lower pole of the right palatine tonsil was observed. Biopsy of the pendular lesion revealed a squamous cell carcinoma. Extended right tonsillectomy was performed. Pathological examination of the lesion revealed squamous cell carcinomas in the pendular tonsil as well as in the palatine tonsil. At present, no recurrence has been observed and his clinical course is favorable. It is necessary to perform a histological examination for every case of pendular tonsil.

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.

Sixteen patients with advanced laryngeal cancer were treated between 1999 and 2004 with intra-arterial infusion of cisplatin at 64-100mg/m2 and intravenous infusion of sodium thiosulfate (P regimen). For the patients who had received the PF regimen, 5-fluorouracil (5-FU) at 700 mg/m2 was given for 3 days following intra-arterial administration of CDDP. With the patients who had underwent the TP regimen, docetaxel at 10-20 mg/m2 was intra-arterially administered following intra-arterial administration of CDDP. All patients received radiation (50-70Gy). Seven patients were at the T3 stage, nine patients at T4, eight patients had glottic cancer and eight patients had supraglottic cancer. The complete response rates of the primary sites that were achieved were 80% for the P regimen, 50% for the PF regimen, and 100% for the TP regimen. The 5-year overall survival rate and disease specific survival rate of all cases was 58% and 81% respectively. The 5-year laryngeal preservation rates were 53% for the P regimen, below 25% for the PF regimen, and 80% with the TP regimen. Side effects of this treatment were tolerable, with the exception of individual cases of cerebral infarction, neck skin necrosis, and laryngeal necrosis.

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). 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. 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. Concurrent chemoradiotherapy is promising as far as improving survival as well as organ preservation.

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.

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.

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.

進行下咽頭癌に対する放射線化学療法の意義について検討した。比較試験の結果からはシスプラチンを主体とした化学療法を加えると根治切除術不能例では生存率延長に寄与すると考えられ, 手術可能例では喉頭温存に寄与すると考えられた。本邦の報告でも放射線化学療法を加えることによって良い生存率が得られていた。われわれの施設で行ったシスプラチンと5FUによる化学療法と放射線の併用療法では手術検体の検索で55%に局所の腫瘍が消失しており, 喉頭温存が図れることが示された。5年死因特異的および粗生存率は, それぞれ56%, 51%であった。