Close correlation between CXCR4 and VEGF expression and their prognostic implications in nasopharyngeal carcinoma.

The CXCL12/CXCR4 pathway, which is involved in biological phenomena such as inflammation, lymphoid homing and regeneration, may play an important role in tumor progression and distant metastasis, especially in organ-selective metastasis. In addition, the CXCL12/CXCR4 pathway has been reported to regulate tumor angiogenesis. In this study, we examined the immunohistochemical expression of CXCR4 and vascular endothelial growth factor (VEGF) in nasopharyngeal carcinoma. CXCR4 and VEGF mRNAs were also assessed by real-time reverse transcription-polymerase chain reaction. Overexpression of CXCR4 and VEGF was observed in 41 (53.9%) and 30 (39.5%) of 76 tumors, respectively. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (p=0.0339). Additionally, immunohistochemical CXCR4 expression was associated with CXCR4 mRNA expression, and immunohistochemical VEGF expression was associated with VEGF mRNA expression (p=0.0040 and p=0.0476, respectively). Furthermore, patients with VEGF-positive tumors had a significantly worse prognosis than patients with VEGF-negative primary tumors (p=0.0044). Our findings suggest that the expression of CXCR4 and VEGF is associated with metastatic progression, and that VEGF expression is a valuable prognostic marker in nasopharyngeal carcinoma.

A case of primary Hodgkin's lymphoma of the parotid gland.

We report an extremely rare case (sixth reported case) of primary Hodgkin's lymphoma (HL) (mixed cellularity type) of the parotid gland. A 14-year-old man was referred to our hospital for evaluation of a parotid mass. Although the initial aspiration cytology was highly suggestive of HL, the confirmatory diagnosis obtained by open biopsy was non-specific lymphadenitis. Consequently, the patient was observed without any additional treatment. Because the mass continued to increase in size, we performed a total parotidectomy which led to the diagnosis of mixed cellularity HL. This case suggests that the specimen taken during open biopsy may have been too small (about 1 cm3) to detect the presence of Reed-Sternberg giant cells, which is essential for the diagnosis of HL. Therefore, although primary HL of the parotid gland is extremely rare, adequate tissue sampling of a clinically suspicious parotid mass will be required for the diagnosis of HL.

[Phase I study of concurrent radiotherapy with TS-1 and vitamin A (TAR Therapy) for head and neck cancer].

The triple combination of 5-fluorouracil (5-FU), vitamin A and radiation (FAR therapy) has been effectively used to treat head and neck cancer. The biological anti-tumor effect of 5-FU depends on the activity of its metabolizing enzyme, dihydropyrimidine dehydrogenase (DPD). TS-1 is a novel oral DPD inhibitory fluoropyrimidine (DIF). To improve the anti-tumor effect of FAR therapy, we have applied TS-1 in place of 5-FU injection in the combination of Vitamin A and radiation (TAR therapy). In this study, we have examined the appropriate duration of TS-1 medication and the clinical efficacy and safety of TAR therapy. TS-1 was administered orally at a dose of 65 mg/m2 twice a day. Vitamin A (Retinol Palmitate: 50,000 U/day) was administered intra-musculary on each day of radiation. Radiation was given (1.5-2 Gy/day: 5 days/week) for 30-40 Gy. The levels were divided according to the length of TS-1 application as follows: level 1, 2 weeks; level 2, 3 weeks; level 4, 4 weeks. Grade 4 toxicity of anorexia was observed in one case of level 3. We decided that level 2 (3 weeks of TS-1 administration) was the appropriate length of TS-1 application. TAR therapy is a useful concurrent chemo-radiotherapy which might improve the response rate and QOL of patients with HNSCC.

H-ras mutation is an additional event of sarcomatous transformation in aerodigestive spindle cell carcinoma.

The conversion from a carcinomatous component to a sarcomatous one in spindle cell carcinoma (SPCC) of the upper aerodigestive tract is thought to occur via a series of molecular alterations; however the detailed mechanism is still unknown. We examined mutations at the H-ras and p53 genes in 16 SPCCs of upper aerodigestive tracts using PCR-RFLP, PCR-SSCP and direct sequencing analysis. The two distinct components, sarcomatous and carcinomatous components in SPCC, were analyzed independently. p53 mutations were detected in both components of SPCC (50.0%, 8/16), and those in the sarcomatous component were completely in accordance with those in the carcinomatous one. In contrast, H-ras mutations were detected only in the sarcomatous component (12.5%, 2/16), and not in the carcinomatous one (0%, 0/16). There was a statistically significant difference in prognosis between the patients with the H-ras mutation (n=2) and those without (n=14); the former had poorer prognosis (P=0.0049). Our results seem to suggest that the H-ras mutation is a relatively uncommon event in SPCC; however, the presence of H-ras mutations may be associated with a more malignant potential in SPCC, while actually occurring during the sarcomatous change itself.

The role of dihydropyrimidine dehydrogenase expression in resistance to 5-fluorouracil in head and neck squamous cell carcinoma cells.

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs to treat cancer patients. However, the presence of drug resistant tumor cells may cause a poor response to 5-FU based chemotherapy. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and is also responsible for the degradation of 5-FU. In this study, we examined whether DPD expression affects the cytotoxic activity of 5-FU against head and neck squamous cell carcinoma (HNSCC) and the role of DPD in the biological regulation of HNSCC. We constitutively expressed the DPD cDNA in a HNSCC cell line. The effect of DPD expression on in vitro cell growth, cell cycle and 5-FU cytotoxicity was examined. In addition, we also evaluated the association between DPD expression and the proliferation of tumor cells in surgical specimens, and prognosis of the patients with HNSCC. DPD overexpression decreases the cytotoxicity of 5-FU. CDHP, a strong DPD inhibitor, enhances the cytotoxic effect of 5-FU in HNSCC cells in vitro. DPD expression level does not effect cell proliferation and does not seem to have prognostic value in HNSCC. The present results strongly indicate that DPD expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy, suggesting the possibility of personalized chemotherapy including the prediction of response and adverse effects.

beta-Catenin nuclear accumulation in head and neck mucoepidermoid carcinoma: its role in cyclin D1 overexpression and tumor progression.

BACKGROUND: Nuclear/cytoplasmic accumulation of beta-catenin is mainly regulated by its degradation, which is initiated by interaction with adenomatous polyposis coli (APC) protein. Accumulation of beta-catenin activates the transcription of 1 of the target oncogenic genes, cyclin D1, in the Wnt/Wingless pathway. The role of beta-catenin and cyclin D1 in this pathway has not been previously studied in head and neck mucoepidermoid carcinoma (MEC). This study investigates abnormalities of beta-catenin and the APC gene in MEC and correlates the patterns of cyclin D1 overexpression and nuclear/cytoplasmic accumulation of beta-catenin with the clinical outcome. METHODS: Mutations of the beta-catenin and APC genes, as well as overexpression of cyclin D1, were investigated by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) in tissue samples from 44 cases of MEC. In addition, we employed differential PCR method to detect amplification of the cyclin D1 gene. Furthermore, the overexpression of cyclin D1 and nuclear/cytoplasmic accumulation of beta-catenin was examined by immunohistochemistry, and any correlation with clinicopathologic parameters was evaluated. RESULTS: Nuclear/cytoplasmic accumulation of beta-catenin was observed in 6 of 44 MEC cases (13.6%), 5 of which were high-grade MEC, while the other 1 case was intermediate-grade tumor. Mutational analysis of exon 3 of the beta-catenin gene revealed that 4 of 26 cases (15.4%) contained point mutations (3 in codon 32, GAC [Asp] to GGC [Gly]; 1 in codon 42, ACA [Thr] to ATA [Ile]), and all these 4 cases showed beta-catenin accumulation immunohistochemically. The nuclear/cytoplasmic accumulation of beta-catenin was significantly correlated with the adverse outcome of patients (p = .011). Two APC gene alterations were detected in 2 cases of low-grade MEC, where there was no beta-catenin nuclear accumulation. Amplification of the cyclin D1 gene was observed in 10 of 26 cases (38.5%). Cyclin D1 overexpression was recognized in 19 of 44 cases (43.2%) and was significantly correlated with beta-catenin accumulation (p = .003). CONCLUSIONS: These findings suggest that beta-catenin, which, in cooperation with cyclin D1, plays crucial role in the Wnt-signaling pathway, may also contribute to the adverse outcome and high-grade tumor staging of MEC.

Clinical value of serum squamous cell carcinoma antigen in the management of sinonasal inverted papilloma.

BACKGROUND: Although sinonasal inverted papilloma (IP) is a rare benign tumor, it has a tendency to recur and is sometimes associated with squamous cell carcinoma (SCC). Therefore, postoperative long-term follow-up of these patients is recommended. We previously reported that serum SCC antigen might be a useful tumor marker for sinonasal IP. In this study, we investigated whether serum SCC antigen level has a correlation with disease status and is useful in the early detection of recurrent disease. METHODS: Blood samples for the analysis of serum SCC antigen were taken from 28 IP patients before and after surgical treatment. RESULTS: Twenty-five (89%) of 28 cases showed evaluated serum SCC antigen levels above the upper limit. This marker level decreased in all cases after surgical resection. Four of these patients had a recurrence. None of the patients with recurrent tumor showed symptoms at the time of detection of their recurrent tumor, and recurrence was discovered from elevated levels of SCC antigen. CONCLUSIONS: Serum SCC antigen level has a correlation with disease status of IP and has a potential to serve as a useful tool for monitoring the course of disease. SCC antigen is a reliable tumor marker in the management of sinonasal IPs.

Serum squamous cell carcinoma antigen is a useful biologic marker in patients with inverted papillomas of the sinonasal tract.

BACKGROUND: Inverted papilloma (IP) is a frequent benign sinonasal tumor that is characterized histologically by squamous metaplasia, epithelial acanthosis, and hyperplasia of the nasal epithelium. Because of its high recurrence rate and malignant transformation potential, careful long-term follow up is necessary. METHODS: The purpose of the current report was to study the expression of squamous cell carcinoma (SCC) antigen in sinonasal IPs and to evaluate the usefulness of SCC antigen as a biologic marker for the follow-up of patients with sinonasal IP. The expression of SCCA1 in three sinonasal IP cases, three sinonasal SCC cases, and cases of normal nasal epithelium were examined by Western blot analysis, and the SCCA1 expression pattern in 31 IP specimens and 4 carcinoma in IP specimens were evaluated immunohistochemically. The serum levels of SCC antigen in 11 patients with sinonasal IP also were analyzed. RESULTS: SCCA1 was overexpressed in all three sinonasal IP tissues compared with sinonasal SCC tissues or normal nasal epithelium. SCCA1 cytoplasmic immunoreactivity was detected in the suprabasal epidermal keratinocytes of all 31 sinonasal IP cases. In the four carcinoma in IP specimens, SCCA1 expression in the papillomatous lesion was more intense than in the cancerous lesion. The serum SCC antigen level was high in 10 of 11 patients with IP (91%) and significantly decreased after surgical resection of the tumors. CONCLUSIONS: The results of the current study indicate that SCCA1 frequently is overexpressed and may play a biologic role in the development of sinonasal IPs. Serum SCC antigen may be a useful biologic marker in patients with sinonasal IP.