Daisuke Kawakita

Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic and molecular study including 2 cases harboring ETV6-X fusion.

Mammary analogue secretory carcinoma (MASC) is a recently described low-grade carcinoma with morphologic and genetic similarity, including ETV6-NTRK3 fusion, to secretory carcinoma of the breast. ETV6 is frequently involved in other epithelial and nonepithelial tumors, and many fusion partners of ETV6 have been reported. In the present study, 14 Japanese MASC cases were clinicopathologically and molecularly analyzed. The median age of the patients was 39 years, and the male:female ratio was 6:8. All cases showed histopathologic findings compatible with those previously described for MASC and harbored an ETV6 split as visualized by fluorescence in situ hybridization. Two cases showed thick fibrous septa and invasive features including vascular or perineural tumor involvement, findings that are rare in MASC. In addition, in these 2 cases, non-NTRK3 genes appeared to fuse with ETV6 (ETV6-X fusion). NTRK1 and NTRK2, both members of the NTRK family, were not involved. Of the 14 MASC cases, the ETV6-NTRK3 fusion transcript was positive in 6 cases, and the relative expression level of the ETV6-NTRK3 fusion transcript was variable, ranging from 1 to 5.8. Results of the present study of MASC suggest that (1) ETV6 occasionally fuses with unknown non-NTRK3 genes, (2) ETV6-X cases might have an invasive histology, (3) for molecular diagnosis of MASC, fluorescence in situ hybridization to detect ETV6 splits is the method of choice, and (4) the expression level of the ETV6-NTRK3 fusion transcript is considerably variable. These findings provide a novel insight into the oncogenesis, histopathology, diagnosis, treatment, and prognosis of this newly recognized carcinoma.

Coffee and green tea consumption is associated with upper aerodigestive tract cancer in Japan.

The impact of coffee and green tea consumption on upper aerodigestive tract (UADT) cancer risk has not been established. Evaluation of the possible anticarcinogenic properties of their ingredients is confounded by the potential increase in risk owing to the high temperatures at which these beverages are generally consumed. We conducted a case–control study to evaluate the association between coffee and tea consumption and the risk of UADT cancer. The study enrolled 961 patients with UADT cancer and 2,883 noncancer outpatients who visited Aichi Cancer Center between 2001 and 2005. Information on coffee and green tea consumption and other lifestyle factors was collected via a self‐administered questionnaire. Consumption of three or more cups of coffee per day had a significant inverse association with UADT cancer [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.55–0.96]. In contrast, consumption of three or more cups of green tea per day had a significant positive association with UADT cancer (OR 1.39, 95% CI 1.13–1.70). These associations were evident for head and neck cancer but not for esophageal cancer. The association of coffee consumption with head and neck cancer was observed only among never smokers and alcohol drinkers. Similarly, the association of green tea consumption was observed among never smokers and never alcohol drinkers. No change in these associations was seen on stratification by each confounding factors. These findings suggest that consumption of coffee might be associated with a decreased risk of UADT cancer, whereas that of green tea might be associated with an increased risk.

Impact of smoking status on clinical outcome in oral cavity cancer patients

The association between smoking status and survival in oral cavity squamous cell carcinoma (OSCC) patients remains unclear. Therefore, we evaluated the association between smoking status before treatment and clinical outcome in OSCC patients. We conducted a retrospective cohort study of 222 OSCC patients who were treated at Aichi Cancer Center in Japan. Of these, 82 patients (36.9%) were non-smokers, 65 (29.3%) were light smokers (pack-years smoking (PY) <30), 54 (24.3%) were moderate smokers (30≤PY<60), and 21 (9.5%) were heavy smokers (60≤PY). The survival impact of pre-treatment smoking status was evaluated using multivariate proportional hazard models. Five-year overall survival for non-, light, moderate, and heavy smokers was 72.9% (95% confidence interval CI): (61.4-81.5), 85.5% (74.0-92.2), 59.9% (44.3-72.4) and 69.0% (42.8-85.0). Adjusted hazard ratios (HRs) for moderate and heavy smokers in comparison with light smokers were 2.44 (1.07-5.57, P=0.034) and 2.66 (0.97-7.33, P=0.058) and the dose-response relationship among smokers was statistically significance (P(trend)=0.024). In addition, adjusted HR for non-smokers relative to light smokers was 2.27 (0.84-6.15, P=0.108). We observed a suggestive heterogeneity in the impact of smoking status by treatment method (P for heterogeneity=0.069). Effect of smoking was evident only among the chemoradiotherapy or radiotherapy group. In this study, we found the significant positive dose-response relationship among smokers on clinical outcome in OSCC patients and that non-smokers were worse prognosis than light smokers. In addition, this effect might differ by treatment method.

Follow-up after intraoperative sentinel node biopsy of N0 neck oral cancer patients

The objective of the study was to evaluate the validity of sentinel node (SN) biopsy in early oral cancer patients focusing on the accuracy of intraoperative diagnoses of SN status, recurrences in follow-up and impact on patient survival. Previously untreated N0 oral cancer patients were candidates for the study. Using a radioisotope method, an intraoperative SN biopsy was performed. Patients with a positive frozen section of SN underwent immediate neck dissection as a single-stage procedure; they were followed in our outpatient clinic. Forty-five cT1-2N0 patients with squamous cell carcinoma were analyzed. There were seven patients with positive SN, five of whom were detected by intraoperative frozen section analysis. The sensitivity, specificity and accuracy of the intraoperative frozen section analysis of SN were 71.4, 100 and 95.6%, respectively. There were 13 recurrences in the course of all patients treated. Those with positive SN showed a tendency toward recurrence. Three patients with negative SN suffered from delayed ipsilateral neck recurrence. These were considered false negatives at a rate of 7.9%. The 5-year overall survival rate of all patients was 91.1%. SN-positive patient survival was significantly poorer than that of SN-negative patients. Positive SN had a negative impact on the survival. SN biopsy was shown to be a valuable method for determining the neck status of early oral cancer patients. The concordance rate of intraoperative multislice frozen section analysis of SN and patient neck status at the time of operation was 95.6%. SN-positive patients exhibited a tendency toward cancer recurrence. There were three cases of false negatives not conforming to the SN concept and their rate was 7.9%. Positive SN had a negative impact on patient survival.

INVERSE ASSOCIATION BETWEEN TOOTHBRUSHING AND UPPER AERODIGESTIVE TRACT CANCER RISK IN A JAPANESE POPULATION

Oral hygiene is attracting increasing attention as a potential risk factor for cancers. To investigate the association between toothbrushing frequency and upper aerodigestive tract (UADT) cancer, the authors conducted a large‐scale case‐control study.

Time to First Cigarette and Upper Aerodigestive Tract Cancer Risk in Japan

Background: Cigarette smoking is the major cause for upper aerodigestive tract (UADT) cancers. The time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, but scanty information is available on its possible relation with UADT cancers (oral, oropharyngeal, hypopharyngeal, laryngeal, nasopharyngeal, and esophageal cancers). Methods: This case–control study includes a total of 1,009 incident UADT cancer cases and 3,027 age- and sex-matched noncancer controls admitted to the Aichi Cancer Center (Nagoya, Japan) between 2001 and 2005. We estimated OR and 95% confidence intervals (CI) for TTFC using logistic regression models after adjustment for several potential confounders. Results: TTFC was inversely related to the risk of UADT cancer, and this association was consistent across subtypes of head and neck cancer and esophageal cancer. For all UADT cancers considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC more than 60 minutes, the adjusted ORs were 1.40 (95% CI: 0.93–2.11) for 31 to 60 minutes, 1.76 (95% CI: 1.20–2.58) for 6 to 30 minutes, and 2.43 (95% CI: 1.64–3.61) for within 5 minutes. No significant heterogeneity was found in strata of sex, age, alcohol consumption, fruit and vegetable intake, and occupation for overall and site-specific analysis. Conclusion: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of UADT cancers and is therefore an independent marker of exposure to smoking. Impact: Our result indicates more detailed risk evaluation of UADT cancers that is enabled by the TTFC. Cancer Epidemiol Biomarkers Prev; 21(11); 1986–92. ©2012 AACR.

Biomarker immunoprofile in salivary duct carcinomas: clinicopathological and prognostic implications with evaluation of the revised classification

Salivary duct carcinoma (SDC) is an uncommon, aggressive malignant neoplasm histologically resembling high-grade mammary ductal carcinoma. SDC can arise de novo or ex pleomorphic adenoma. To clarify the correlation of biomarker immunoprofile with clinicopathological findings and clinical outcome of SDC, we conducted immunohistochemistry for EGFR, HER2, HER3, AR, CK5/6, p53, and Ki-67, along with HER2 fluorescence in situ hybridization in 151 SDCs. SDCs ex pleomorphic adenoma more commonly overexpressed EGFR, HER2, HER3, and Ki-67 than de novo SDCs (P = 0.015, < 0.001, 0.045, and 0.02, respectively). In multivariate analysis, AR− and CK5/6+ were associated with shorter progression-free survival (P = 0.027 and 0.004, respectively). Moreover, patients with p53-extreme negative/positive demonstrated poorer overall survival (P = 0.007). On assessing the revised classification by the combination of biomarker expression, the percentages of each subtype were as follows: ‘apocrine A’ (AR+/HER2−/Ki-67-low) (24%), ‘apocrine B’ (AR+/HER2−/Ki-67-high) (18%), ‘apocrine HER2’ (AR+/HER2+) (35%), ‘HER2-enriched’ (AR−/HER2+) (12%), and ‘double negative’ (AR−/HER2−) (11%). ‘Double negative’ was further subclassified into ‘basal-like’ (EGFR and/or CK5/6+) (7%) and ‘unclassified’ (3%). Consequently, patients with ‘apocrine A’ showed a better progression-free survival than those with any other subtypes. Our revised immunoprofiling classification was valuable for predicting the survival and might be useful in personalized therapy for patients with SDC.

Heterogeneous impact of alcohol consumption according to treatment method on survival in head and neck cancer: A prospective study

Alcohol consumption is an established risk factor, and also a potential prognostic factor, for squamous cell carcinoma of the head and neck (HNSCC). However, little is known about whether the prognostic impact of alcohol consumption differs by treatment method. We evaluated the association between alcohol drinking and survival by treatment method to the primary site in 427 patients with HNSCC treated between 2005 and 2013 at Aichi Cancer Center Central Hospital (Nagoya, Japan). The impact of alcohol on prognosis was measured by multivariable Cox regression analysis adjusted for established prognostic factors. Among all HNSCC patients, the overall survival rate was significantly poorer with increased levels of alcohol consumption in multivariable analysis (trend P = 0.038). Stratification by treatment method and primary site revealed that the impact of drinking was heterogeneous. Among laryngopharyngeal cancer (laryngeal, oropharyngeal, and hypopharyngeal cancer) patients receiving radiotherapy (n = 141), a significant dose–response relationship was observed (trend P = 0.034). In contrast, among laryngopharyngeal cancer patients treated with surgery (n = 80), no obvious impact of alcohol was observed. This heterogeneity in the impact of alcohol between surgery and radiotherapy was significant (for interaction, P = 0.048). Furthermore, among patients with oral cavity cancer treated by surgery, a significant impact of drinking on survival was seen with tongue cancer, but not with non‐tongue oral cancer. We observed a significant inverse association between alcohol drinking and prognosis among HNSCC patients, and its impact was heterogeneous by treatment method and primary site.

Prognostic Value of Drinking Status and Aldehyde Dehydrogenase 2 Polymorphism in Patients With Head and Neck Squamous Cell Carcinoma

Background The association between alcohol drinking, aldehyde dehydrogenase 2 (ALDH2) polymorphism, and survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods We performed a retrospective cohort study of 267 HNSCC patients at Aichi Cancer Center. Of these, 65 patients (24%) were non-drinkers, 104 (39%) were light drinkers (ethanol <46 g or <5 days/week), 46 (17%) were moderate drinkers (ethanol intake 46–68 g/day and ≥5 days/week), and 52 (20%) were heavy drinkers (ethanol intake ≥69 g and ≥5 days/week). The prognostic value of pre-treatment drinking status and ALDH2 polymorphism was investigated using multivariate proportional hazard models. Results Drinking status was associated with disease-free survival (DFS) in HNSCC patients, with marginal statistical significance (5-year DFS: 67.9% [95% confidence interval {CI}, 53.8–78.4%] for non-drinkers, 57.6% [95% CI, 47.4–66.6%] for light drinkers, 46.1% [95% CI, 30.8–60.1%] for moderate drinkers, and 43.5% [95% CI, 29.3–56.9%] for heavy drinkers; P = 0.088). However, this association lost significance when multivariate analyses were adjusted for established prognostic factors. ALDH2 genotype was not significantly associated with DFS in HNSCC patients (5-year DFS: 85.7% [95% CI, 53.9–96.2%] for Lys/Lys, 56.2% [95% CI, 47.4–64.1%] for Glu/Lys, and 50.5% [95% CI, 40.3–59.7%] for Glu/Glu; P = 0.154). After stratification by ALDH2 genotype, we observed a significant positive dose-response relationship between drinking status and DFS in HNSCC patients with ALDH2 Glu/Glu (P trend = 0.029). Conclusions In this study, we identified a significant positive dose-response relationship between pre-treatment drinking status and DFS in HNSCC patients with ALDH2 Glu/Glu. To confirm this association, further study is warranted.

Inverse association between yoghurt intake and upper aerodigestive tract cancer risk in a Japanese population.

Although the combination of tobacco smoking and alcohol drinking account for approximately 80% of upper aerodigestive tract (UADT) cancer risk, the role of dietary factors, including dairy products, in the risk of these cancers remains controversial. We aimed to evaluate the association between dairy product intake and UADT cancer risk in a Japanese population. We conducted a case–control study in 959 patients with UADT cancer and 2877 sex- and age-matched noncancer control subjects who visited the Aichi Cancer Center in Nagoya, Japan. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Associations were assessed by multivariate logistic regression models that considered potential confounders. We found a significant inverse association between yoghurt intake and UADT cancer risk with multivariate-adjusted odds ratios and 95% confidence intervals for <1 time/week, ≥1 time/week and <1 time/day, and ≥1 time/day consumption of yoghurt of 0.70 (95% confidence interval: 0.54–0.91), 0.67 (0.54–0.84), and 0.73 (0.55–0.95) relative to nonconsumers (Ptrend=0.005). When stratified by primary tumor site, this association was significant among patients with hypopharyngeal, laryngeal, and esophageal cancer. However, we saw no significant association between milk or butter intake and UADT cancer risk. In this study, we found that a high intake of yoghurt may lower the risk of developing UADT cancer in a Japanese population. Further investigation of this association is warranted.