The Presence of HPV DNA in Neck Lymph Node Metastasis Correlates with Improved Overall Survival of Patients with Oropharyngeal Cancer Undergoing Surgical Treatment.

BACKGROUND: Few studies have addressed how human papilloma virus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) affects the outcome of surgical therapy; furthermore, the relationship between the presence of HPV DNA and neck lymph node (LN) metastasis has not been well established. METHODS: A total of 65 patients who underwent surgery as a first-line therapy for OPSCC were enrolled in this study. In HPV-positive patients, the presence of HPV DNA in metastatic neck LN lesions was evaluated. RESULTS: The HPV-positive patients had significantly better overall survival than the HPV-negative patients (log-rank test, p = 0.04), whereas HPV infection status did not significantly affect disease-free survival (log-rank test, p = 0.65). In all of the HPV-positive OPSCC patients who developed cervical LN metastasis, the same HPV DNA type was found in both the primary tumour and the metastases. CONCLUSIONS: The present results suggest that HPV infection is a determining factor for good prognosis in patients undergoing first-line surgical therapy for OPSCC.

Primary adenoid cystic carcinoma of the nasolacrimal duct treated with proton beam therapy.

Primary malignant tumors of the lacrimal passage, particularly of the nasolacrimal duct, are rare. We describe a 72-year-old woman who presented with lacrimation 5 years previously. She had pain and bloody and purulent lacrimation, and a mass was identified in the inferior meatus. Accordingly, she was diagnosed with primary adenoid cystic carcinoma of the nasolacrimal duct. She was treated with proton beam therapy and showed a favorable response. Owing to the long-term risks of recurrence and distant metastasis, adenoid cystic carcinoma requires sufficient follow-up.

Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.

BACKGROUND: Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse. METHODS: We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively. RESULTS: UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method. CONCLUSIONS: These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

Distinctive mucositis and feeding-tube dependency in cetuximab plus radiotherapy for head and neck cancer.

OBJECTIVE: Prophylactic percutaneous endoscopic gastrostomy may be considered before chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma, because severe mucositis is a common complication. We evaluated the mucosal findings and necessity of prophylactic percutaneous endoscopic gastrostomy in patients with head and neck squamous cell carcinoma receiving cetuximab and radiotherapy. METHODS: Fourteen consecutive patients with locally advanced head and neck squamous cell carcinoma receiving cetuximab and radiotherapy were analyzed. RESULTS: Patients' backgrounds were as follows: male/female, 8/6; median age, 64.5 years (range, 35-83 years); performance status, 0/1, 9/5. Primary tumor sites included the oropharynx, hypopharynx and larynx in four, seven and three patients, respectively. Patients completed a median of eight cetuximab cycles. All patients received three-dimensional conformal radiotherapy (median dose, 70 Gy). Thirteen patients were treated with elective neck irradiation at the ipsilateral (n = 3) or bilateral (n = 10) nodes. Grade ≥ 3 mucositis/stomatitis (clinical examination) occurred in 85.7% patients (n = 12). The median irradiation dose was 33 Gy at the Grade 3 mucositis onset. Eight patients showed mucositis with distinctive features, a wide range of white-coated lesions with a clear border; hypopharyngeal atresia was observed in two patients. Prophylactic percutaneous endoscopic gastrostomy was performed in 11 patients, and 11 patients (78.6%) actually required nutritional support because of Grade ≥ 3 mucositis/stomatitis (functional/symptomatic). CONCLUSIONS: Prophylactic percutaneous endoscopic gastrostomy is recommended because most patients receiving cetuximab and radiotherapy for locally advanced head and neck squamous cell carcinoma have Grade ≥ 3 mucositis with distinctive features.

MUC expression in adenosquamous carcinoma of the head and neck regions of Japanese patients: immunohistochemical analysis.

Adenosquamous carcinoma (ASC) is a rare malignant neoplasm of the head and neck regions. We elucidated the relationship between ASC and MUC molecule expression. We selected 14 cases of ASC in the head and neck, and examined them immunohistohcmically. Seven cases of tongue, 3 cases of larynx and 4 cases of hypopharynx carcinoma were selected. Nine (64.3%) of 14 cases showed lymph node metastasis at the diagnosis. Laryngeal and hypopharyngeal cases showed a higher stage. Six cases (66.7%), all of which showed lymph node metastases, died of disease. Immunohistochemical examinations showed that ASC was positive for both markers of squamous cell carcinoma and adenocarcinoma. ASC showed positivity for MUC1 (13 cases: 92.3%), MUC1core (12 cases: 85.2%) and MUC4 (12 cases: 85.7%). In rare ASC of the head and neck region, it was revealed that MUC1 and MUC4 expression might be associated with its nodal status.

Squamous cell carcinoma with rhabdoid features of the gingiva: a case report with unusual histology.

Squamous cell carcinoma (SCC) with rhabdoid features (SCCRF) is extremely rare in the oral cavity. We report herein a case of oral SCCRF. The patient was a 69-year-old Japanese woman who had been suffering from a mass in the right lower gingiva. Right hemi-mandibulectomy was performed. The gingival tumor was composed of pleomorphic, non-cohesive ovoid tumor cells with abundant cytoplasm and eccentric nuclei, which were positive for both pan-cytokeratin and vimentin. In another portion, moderately differentiated SCC and carcinoma in situ were also seen. A transition zone existed between the components. Finally, we diagnosed SCCRF. Four months after the operation, multiple bone metastases, lung and skin metastases and marked hypercalcemia were found. SCCRF, therefore, might be more aggressive than the usual type of oral SCC.

Salivary duct carcinoma with rhabdoid features: report of 2 cases with immunohistochemical and ultrastructural analyses.

BACKGROUND: Salivary duct carcinoma with rhabdoid features is extremely rare. METHODS: We report 2 cases of salivary duct carcinoma with rhabdoid features treated at our institution. RESULTS: Case 1 was a 44-year-old Japanese man who had swelling in the left parotid region. This tumor consisted of residual pleomorphic adenoma and widely invasive carcinoma, which showed a diffuse growth pattern by atypical rhabdoid cells. Case 2 was a 66-year-old Japanese man who had swelling of the right cervical region. This submandibular tumor was also composed of both residual pleomorphic adenoma region and invasive adenocarcinoma components, whereas some metastatic lesions were purely composed of rhabdoid cells. Such cells were strongly and diffusely positive for cytokeratins (CKs), gross cystic disease fluid protein-15 (GCDFP), and androgen receptor (AR). Case 1 was also positive for Her-2 and p53. CONCLUSION: Both patients were diagnosed with carcinoma ex pleomorphic adenoma and their carcinomatous components were composed of salivary duct carcinoma with rhabdoid features, which is a highly aggressive tumor, similar to salivary duct carcinoma.

Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma.

BACKGROUND: Tobacco and alcohol consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Recently, whole-exome sequencing clarified that smoking increased TP53 and other mutations in HNSCC; however, the effects of alcohol consumption on these genetic alterations remain unknown. We explored the association between alcohol consumption and somatic copy-number alterations (SCNAs) across the whole genome in human papillomavirus (HPV)-negative HNSCCs, and compared with the effects of smoking on genetic alterations. METHODS: SCNA and TP53 mutations in tumor samples were examined by high-resolution comparative genomic hybridization microarray 180K and by direct sequencing, respectively, and statistically analyzed for associations with alcohol consumption and smoking during the 20 years preceding diagnosis of HNSCC. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.2 or less than -1.2 were considered statistically significant. RESULTS: A total of 248 patients with HNSCC were enrolled. In the HPV-negative patients (n=221), heavy alcohol consumption was significantly associated with SCNAs of oncogenes/oncosuppressors that were previously reported to occur frequently in HNSCCs: CDKN2A (q=0.005), FHIT (q=0.005), 11q13 region including CCND1, FADD and CTTN (q=0.005), ERBB2 (HER2) (q=0.009), 3q25-qter including CCNL1, TP63, DCUN1D1 and PIK3CA (q=0.014), and CSMD1 (q=0.019). But, TP53 mutations were not affected. In contrast, smoking was associated with increased risk of TP53 mutations, but did not induce any significant SCNAs of oncogenes/oncosuppressors. CONCLUSION: These results suggest that both alcohol consumption and smoking had distinct effects on genetic alterations in HNSCCs. Heavy alcohol consumption may trigger previously known and unknown SCNAs, but may not induce TP53 mutation. In contrast, smoking may induce TP53 mutation, but may not trigger any SCNAs.

Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma.

BACKGROUND: Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC). METHODS: We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients.We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis. RESULTS: We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was found in 37 cases (32.2%) for PIK3CA, 10 cases (8.7%) for K-RAS and 2 cases (1.7%) for BRAF. Kaplan-Meier survival analysis revealed that copy-number amplification of PIK3CA was markedly associated with cancer relapse in patients without lymph node metastasis. (Log-rank test, p = 0.026) CONCLUSIONS: Copy number amplification of the PIK3CA gene is associated with poor prognosis in HNSCC patients without lymph node metastasis. The PIK3CA copy number status will serve as a marker of poor prognosis in patients with HNSCC.

Functional mutation analysis of EGFR family genes and corresponding lymph node metastases in head and neck squamous cell carcinoma.

Tumors with certain mutations in the epidermal growth factor receptor (EGFR) family genes dramatically respond to EGFR inhibitors. Therefore, these mutations are important factors that influence disease progression and patient survival. We previously studied the mutation status of EGFR in patients with head and neck squamous cell carcinoma (HNSCC). However, the mutation status of lymph node metastases and the frequency of mutations in EGFR family genes have not been extensively studied. In this study, we sequenced the catalytic domains of the three other members of the EGFR family, HER2, HER3, and HER4 in 92 clinical samples of HNSCC. We identified a HER2 mutation (K716E) in one sample but no mutations were found in HER3 or HER4. Next to investigate the relationship between EGFR mutations and tumor metastasis, we compared the DNA sequences of the EGFR gene between the primary tumor and the lymph node metastasis in 31 clinical samples. Only one of the patients with an EGFR mutation in the primary HNSCC carried the same mutation (L858R) in the lymph node metastasis. Finally, we explored the tumorigenic potential of the EGFR mutations that we had previously identified and their sensitivity to two different EGFR tyrosine kinase inhibitors (CL-387785, OSI-420). Ba/F3 cells transformed with mutant EGFR genes were sensitive to treatment with lower concentrations of CL-387785 than of OSI-420. These results contribute to our understanding of the genetic basis of drug sensitivity and will help design drugs that specifically target different subtypes of HNSCC.

[Cardiac metastasis by hypopharyngeal carcinoma. Case report].

The patient was a 63-year-old Japanese male who came to the hospital with a chief complaint of a sore throat. Hypopharyngeal carcinoma (T4N2bM0, stage IVA) was diagnosed, and at the strong request of the patient he was treated by chemoradiotherapy. The tumor markedly decreased in size, but atrial fibrillation was detected when an ECG was performed in preparation for planned a scheduled re-biopsy of the hypopharynx. The echocardiography findings and result of a myocardial biopsy led to a diagnosis of cardiac metastasis by the hypopharyngeal carcinoma. Metastasis by head and neck malignancies is rare, and it is extremely rare for a confirmed diagnosis to be made while the patient is still alive. The case is described together with some discussion of the published literature.