Transcriptionally Active HPV and Targetable EGFR Mutations in Sinonasal Inverted Papilloma: An Association Between Low-risk HPV, Condylomatous Morphology, and Cancer Risk?

鼻窦内翻性乳头状瘤中转录活性HPV和靶向EGFR突变: 低危HPV、尖锐湿疣形态与癌症风险之间的关联?

  • 影响因子:6.06
  • DOI:10.1097/PAS.0000000000001411
  • 作者列表:"Mehrad M","Stelow EB","Bishop JA","Wang X","Haynes W","Oliver D","Chernock RD","Lewis JS Jr
  • 发表时间:2020-03-01

:Sinonasal inverted papillomas (IPs) commonly recur, and transform to malignancy in 5% to 10% of patients. It has long been debated whether IPs are caused by high-risk or low-risk (lr) human papillomavirus (HPV) and whether the HPV is transcriptionally active. EGFR mutations have also been recently implicated in the pathogenesis of IP with an unclear relationship to HPV status. IP cases over a 10-year period were tested for p16 by immunohistochemistry and for transcriptionally active hrHPV and lrHPV by reverse-transcriptase real-time polymerase chain reaction and RNA in situ hybridization, respectively. EGFR tyrosine kinase domain Sanger sequencing was performed on all lrHPV RNA positive and 15 randomly selected lrHPV RNA negative IPs. Seven sinonasal nonkeratinizing squamous cell carcinomas (SCCs) without associated IP were included as controls. Of the 44 IPs, 5 (11.4%) were associated with SCC, all keratinizing type. All IPs and associated SCCs were negative for p16 and hrHPV. lrHPV RNA was detected in 5/42 (12%) cases, including 3/5 (60%) with associated SCC (P=0.009). All 5 lrHPV RNA positive IPs involved the nasal cavity, had a distinct, condylomatous morphology, and were EGFR wild-type. In contrast, 11/15 (73.3%) lrHPV RNA negative IPs that were sequenced had EGFR exon 19 or 20 mutations. All control nonkeratinizing SCCs were lrHPV RNA negative, but 5/7 (71.4%) were p16 and high-risk HPV RNA positive. This study shows that a subset of IPs involving the nasal cavity have transcriptionally active lrHPV, condylomatous morphology, and possibly increased risk of malignancy. Furthermore, lrHPV positivity is mutually exclusive with EGFR mutations, which suggests alternate mechanisms of pathogenesis.


: 鼻腔鼻窦内翻性乳头状瘤 (IPs) 通常复发,并在5% 至10% 的患者中转变为恶性。长期以来一直争论IPs是由高风险还是低风险 (lr) 人乳头瘤病毒 (HPV) 引起的,以及HPV是否具有转录活性。EGFR突变最近也涉及IP的发病机制,与HPV状态的关系不清楚。10年期间的IP病例分别通过免疫组织化学检测p16,并通过逆转录酶实时聚合酶链反应和RNA原位杂交检测转录活性hrHPV和lrHPV。对所有lrHPV RNA阳性和15个随机选择的lrHPV RNA阴性IPs进行EGFR酪氨酸激酶结构域Sanger测序。7例无相关IP的鼻腔鼻窦非角化性鳞状细胞癌 (scc) 作为对照。在44个IPs中,5个 (11.4%) 与SCC相关,均为角化型。所有IPs及相关SCC均未见p16和hrHPV表达,5/42例 (12%) 检测到lrHPV RNA,其中3/5例 (60%) 伴有相关SCC (P = 0.009)。所有5个lrHPV RNA阳性IPs均累及鼻腔,具有独特的尖锐湿疣形态,并且是EGFR野生型。相反,测序的11/15 (73.3%) 个lrHPV RNA阴性IPs具有EGFR外显子19或20突变。所有对照非角化scc均为lrHPV RNA阴性,但5/7 (71.4%) 为p16和高危型HPV RNA阳性。该研究表明,涉及鼻腔的IPs的子集具有转录活性的lrHPV,尖锐湿疣形态,并且可能增加恶性肿瘤的风险。此外,lrHPV阳性与EGFR突变相互排斥,这提示了发病机制的替代机制。



来源期刊:The Laryngoscope
作者列表:["Tyler MA","Mohamed ASR","Smith JB","Aymard JM","Fuller CD","Phan J","Frank SJ","Ferrarotto R","Kupferman ME","Hanna EY","Gunn GB","Su SY"]

METHODS:OBJECTIVE:To evaluate long-term global and site-specific health-related quality of life (HRQoL) in patients treated for sinonasal and nasopharyngeal malignancies. STUDY DESIGN:Cross-sectional. METHODS:One hundred fourteen patients with sinonasal and nasopharyngeal malignancies received surgery, radiation, systemic chemotherapy, or a combination thereof, with curative intent. Validated global ([EuroQol-5D] Visual Analogue Scale [EQ-5D VAS]) and disease-specific instruments (MD Anderson Symptom Inventory-Head and Neck [MDASI-HN], Anterior Skull Base Questionnaire [ASBQ]) were administered to patients who were both free of disease and had completed treatment at least 12 months previously. Associations between instruments, instrument domains, and specific clinical parameters were analyzed. RESULTS:The median age was 55 years. The mean EQ-5D VAS, MDASI-22 composite score, and ASBQ score were 74 (standard deviation [SD] 21), 48 (SD 36), and 130 (SD 27), respectively. The most frequently reported high-severity items in MDASI-HN were dry mouth and difficulty tasting food. The most frequently reported high-severity items in ASBQ were difficulty with smell and nasal secretions. Advanced Tumor (T) classification was associated with worse overall ASBQ sum score (P = 0.02). ASBQ performance at home and MDASI-HN drowsy symptom items independently predicted worse global HRQoL as measured by the EQ-5D VAS (P < 0.001). CONCLUSION:Global HRQoL for survivors of sinonasal and nasopharyngeal malignancies after multimodality treatment approximates that of the U.S. population for the same age group. ASBQ and MDASI-HN correlate well with global HRQoL outcomes as measured by EQ-5D VAS. MDASI-HN and ASBQ elicited unique symptoms, highlighting the complex symptom burden experienced by these patients. Further studies should identify patients predisposed to reduced long-term QOL. LEVEL OF EVIDENCE:3 Laryngoscope, 130:86-93, 2020.

翻译标题与摘要 下载文献
作者列表:["Todo-Bom A","Braido F","Molinengo G","Loureiro C","Canonica GW","Baiardini I"]

METHODS:BACKGROUND:Allergic rhinitis (AR) and asthma are two common chronic diseases that often coexist. There is a need for a validated tool to evaluate HRQoL of Portuguese speakers with asthma and/or rhinitis patients in clinical practice. OBJECTIVES:To adapt and validate RhinAsthma Patient Perspective (RAPP) in Portuguese. METHODS:The RAPP questionnaire was translated into Portuguese. Asthmatics with comorbidities and rhinitis attending the allergy department of Coimbra University Hospital were asked to complete the Portuguese translation of RAPP, in addition to the SF-12, ACT, and a Symptomatologic VAS twice, with a 4-week interval between visits. During Visit 2, a Global Rating Scale (GRS) was completed to assess any change in health status. Scale dimensions, internal consistency and convergent validity, reliability, discriminant ability and responsiveness to change, as well as Minimal Clinical Difference were assessed. RESULTS:Factor and confirmatory analysis confirm the unidimensional structure of the questionnaire. Internal consistency has been shown to be satisfactory (0.82 visit 1 and 0.86 at visit 2). The tool is able to discriminate between patients on the basis of asthma severity, asthma control level, and rhinitis severity; convergent validity showed a significant correlation with SF-2 Physical component (r=-0.46 and 0.42, p at Visits 1 and 2). An ICC of 0.97 and a CCC=0.94 indicate that the tool is highly reliable. Responsiveness was shown in detecting a significant association with GRS changes (r=0.41, p<0.01) and ACT (r=-0.47, p<0.01) but not with VAS. (r=.14, n.s.). MID value was 2 points. CONCLUSIONS:The Portuguese version of RAPP has been demonstrated to have good measurement properties and sensitivity to health changes, which will provide a valid, reliable and standardized HRQoL measurement in patients with asthma and comorbid allergic rhinitis in clinical practice.

翻译标题与摘要 下载文献
来源期刊:The Laryngoscope
作者列表:["Goel AN","Lee JT","Wang MB","Suh JD"]

METHODS:OBJECTIVE:To characterize treatment delays in sinonasal cancer managed with surgery and adjuvant radiation and determine the associated impact on survival. STUDY DESIGN:Retrospective cohort study. METHODS:We identified adults in the National Cancer Database treated for sinonasal squamous cell carcinoma with definitive surgery followed by adjuvant radiation from 2004 to 2014. We then examined intervals of diagnosis to surgery (DTS), surgery to radiation (SRT), and radiation duration (RTD). Next, we performed recursive partitioning analysis (RPA) to identify thresholds for these treatment intervals that estimated the greatest differences in survival. We determined the association of treatment delay with overall survival using Cox proportional hazards regression. RESULTS:Among 2,267 patients included, median durations of DTS, SRT, and RTD were 32, 49, and 47 days, respectively. Predictors of treatment delay included care transitions, black race, and Medicare insurance. We identified thresholds of 26, 64, and 51 days for DTS, SRT, and RTD, respectively, as estimating the largest survival differences. Delays in SRT (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.03-1.40), and RTD (HR, 1.27; 95% CI, 1.10-1.46) beyond these thresholds independently predicted mortality. Delay in DTS beyond the RPA-derived threshold was not significantly associated with mortality after adjusting for other covariates. CONCLUSION:Delays in SRT and RTD intervals are associated with decreased overall survival. Median durations may serve as national benchmarks. Treatment delays could be considered quality indicators for sinonasal cancer treated with surgery and adjuvant radiation. LEVEL OF EVIDENCE:NA Laryngoscope, 130:2-11, 2020.

翻译标题与摘要 下载文献