儿童复发性呼吸道乳头状瘤病的联合治疗

目的：探讨儿童复发性呼吸道乳头状瘤病（JO-RRP）的治疗方法。方法：回顾性分析36例JO-RRP患儿的临床资料，针对病情分别采用支撑喉镜下激光切除术（27例）和喉裂开造口激光切除术（9例），对复发≥2次／年或（和）病变范围累及≥2个解剖亚区的28例患儿术后1周给予干扰素治疗。结果：全部患儿术后均无明显误咽，28例（77．8％）已拔除气管套管。并发症包括：声音嘶哑8例，喉狭窄6例，肺部感染3例。结论：支撑喉镜下激光切除术和喉裂开造口激光切除术是治疗JO-RRP的有效术式，术后联合干扰素治疗可抑制复发。     

儿童复发性呼吸道乳头状瘤病肿瘤范围的量化评估

目的:探讨儿童复发性呼吸道乳头状瘤病(JO-RRP)肿瘤范围的量化评估方法的临床应用。方法:根据肿瘤范围大小分为3级分值(1分,2分及3分),评估68例JO-RRP患儿共238次手术,内镜下观察患儿22个呼吸和消化道的解剖亚区的肿瘤范围,计算积分;量化反映JO-RRP的分布特点及病情演变。结果:本组患儿肿瘤范围的积分在2~20分,7~14分占64.3%。全部患儿均有喉部受累,其中声带和室带是最常见的受累部位,鼻、咽、硬腭、气管、支气管、双肺和食管等受累较少见;随着手术治疗次数增多,肿瘤范围积分有下降趋势,与JO-RRP的临床特点相符。结论:以肿瘤范围为依据的量化评估法客观准确地反映了JO-RRP病变程度和临床疗效,是个科学而方便的方法,临床应用价值高,值得推广。     

气管内窥镜在治疗小儿复发性气管内乳头状瘤中的应用

目的 :探讨小儿复发性喉乳头状瘤播散至气管内的治疗方法。方法 :利用气管内窥镜在全麻支撑喉镜下治疗小儿复发性气管内乳头状瘤 12例。结果 :12例中 ,3例随访 1年余未复发 ,已拔除气管套管 ;9例术后复发 ,但复发周期较既往应用气管镜手术明显延长 ,且病灶有逐渐局限、减少的趋势。结论 :应用气管内窥镜治疗气管内乳头状瘤 ,术野清楚 ,肿瘤摘除彻底 ,术后复发周期延长。     

喉显微切割钻在幼年型复发性气管内乳头状瘤治疗中的应用

目的:探讨幼年型复发性呼吸道乳头状瘤(JO-RRP)播散至气管后的治疗方法。方法:14例JO-RRP患儿均在全身麻醉支撑喉镜下应用气管内镜和喉显微切割钻治疗,手术间隔期内均未应用干扰素等药物治疗。结果:14例中,有8例经治疗3~6次后气管内乳头状瘤趋于局限,拔除气管套管,封闭气管造瘘口。随访6个月,气管内黏膜光滑,无乳头状瘤生长。6例尚未拔管,但肿瘤生长有明显减少的趋势。结论:应用喉显微切割钻治疗复发性气管内乳头状瘤,术野清楚,肿瘤切除彻底,并发症少,术后复发周期延长。     

儿童复发性呼吸道乳头状瘤病临床研究

OBJECTIVE: To study the clinical behavior of juvenile-onset recurrent respiratory papillomatosis in order to find some factors correlated to the development of this disease, and to sum up the significance and experience of CO2 laser surgery. METHOD: Sixty patients with juvenile-onset recurrent respiratory papillomatosis from September 1995 to December 1998 were retrospectively analyzed. RESULTS: The age of onset in 50 cases (83.3%) was below 4 years, and the peak-age was 2 years. The rates of recurrence were 72.0% and 45.7% (chi 2 = 4.71, P < 0.05) below and over 2 years, respectively. The rates of aggressive disease were 88.0% and 54.3% (chi 2 = 7.66, P < 0.01) below and over 2 years, respectively. The predominant sites of the disease were the vocal cords, the false vocal cords, the laryngeal ventricle, the laryngeal surface of the epiglottis and the subglottic region. Tracheostomy induced the development of tracheal papilloma, therefore should be avoided as possible. Laryngeal papilloma might be divided into four types on the basis of the growth manner and surface form corresponding to clinical behaviors. Five patients were followed-up for 1.5 years without recurrence, 18 patients had fewer recurrences following treatment, 33 patients were under treatment, and 3 patients died. Nineteen patients lost follow-up. The major complications included laryngeal and tracheal stenosis. CONCLUSION: Clinical behaviors of juvenile-onset recurrent respiratory papillomatosis were relevant to the age, growth form and tracheotomy. CO2 laser was an ideal instrument for ablation of the laryngeal papillomas with the following advantages: simple management, less bleeding, preservation of laryngeal structure and avoidance of tracheostomy.     

累及气管的小儿复发性呼吸道乳头状瘤的治疗（17例报告）

目的探讨累及气管的小儿复发性呼吸道乳头状瘤的治疗方法。方法支撑喉镜联合支气管镜下Nd：YAG激光治疗小儿复发性气管内乳头状瘤17例。结果4例随访1年6个月未复发,已拔除气管套管,13例术后复发。结论支撑喉镜联合支气管镜下Nd：YAG激光治疗小儿复发性气管内乳头状瘤是一种有效的方法。     

人乳头瘤病毒型别与儿童复发性呼吸道乳头状瘤临床病程的相关性

目的　研究人乳头瘤状病毒（human papilloma virus,HPV）型别对儿童复发性呼吸道乳头瘤（juvenile onset recurrent respiratory papillomatosis,JORRP）临床病程的影响。方法　收集38例JORRP患儿新鲜瘤体标本,采用流式荧光杂交法检测HPV型别。将患儿分为HPV6阳性组和HPV11阳性组。量化评分其201例手术,对发病年龄、并发症、临床症状、手术次数、乳头瘤侵袭范围程度等方面进行统计学分析。结果　55.2%（21/38）JORRP患儿感染HPV6,36.8%（14/38）感染HPV11,7.9%（3/38）HPV6/11均阴性。两组患儿在发病年龄、术前临床症状评分、乳头瘤解剖亚区数、Derkay、Dikkers评分方面均有统计学差异。结论　感染HPV11发病年龄更小,侵犯范围更广病灶性状更严重,临床症状更严重,致JORRP临床病程更严重。     

The predictive value of serum interleukins in recurrent respiratory papillomatosis: a preliminary study

OBJECTIVE: IL-2 is the primary interleukin responsible for activation of the cell-mediated (Th1) arm of the immune response. Our objective was to determine whether a correlation existed between circulating levels of interleukin-2 as well as its soluble receptor (sIL-2R) and the clinical course of recurrent respiratory papillomatosis. METHODS AND MATERIALS: Fifteen children with a histological diagnosis of RRP were recruited. Age at the time of study, time since first diagnosis, and number of surgical interventions were recorded. The number of surgically treated recurrences per year was then calculated. We obtained serum samples from each of these 15 children and from 10 normal control subjects. We then performed in vitro determination of serum IL-2 and soluble IL-2 receptor levels using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: IL-2 was significantly lower (136.6 vs. 199.9 pg/mL, P =.035) in papilloma patients than in control subjects. IL-2R was also lower in papilloma patients (531.7 vs. 785.8 U/mL, P =.025). There was no statistical age difference between the papilloma and control groups. Among patients with papillomatosis, IL-2 and sIL-2R levels were significantly higher in those with aggressive disease (>4 surgically treated recurrences per year) versus non-aggressive disease (179.2 vs. 99.2 pg/mL, P =.024; and 697 vs. 387 U/mL, P =.022). Age was also significantly lower in the aggressive papilloma group (P =.002). CONCLUSIONS: Levels of interleukin-2 and IL-2 receptor were significantly lower in patients with recurrent respiratory papillomatosis compared with normal children. These data support the presence of an aberrant cell-mediated immune response in children with recurrent respiratory papillomatosis.     

Mucosal swabs detect HPV in laryngeal papillomatosis patients but not family members

Seven patients, aged 2-7 years, with active recurrent respiratory papillomatosis (RRP) attending the University of Michigan Pediatric Otolaryngology Clinic were studied to determine if human papillomavirus (HPV) is harbored in sites of the upper aerodigestive tract other than in the laryngeal papilloma itself. We also determined if close family members had detectable virus in their oral cavities. Noninvasive swabs of buccal mucosa, posterior pharynx, nasal vestibule, and tonsillar pillar of patients, as well as buccal mucosa and posterior pharyngeal swabs of family members were studied. Swabs of the patients' papillomas served as the positive controls. HPV was detected using polymerase chain reaction (PCR) amplification and Southern hybridization techniques. Six of seven patients had detectable HPV in papilloma and endolaryngeal swabs. Four were HPV type 6, and two were HPV type 11. The patient whose swab was negative for HPV was found to be biopsy negative for papilloma 3 weeks after a single laser excision which was performed 6 months prior to the endolaryngeal swab. HPV types 16, 18 and 31 were not found in any of the patients. No swabs from other sites in patients or family members were HPV positive despite the presence of adequate DNA in the swabbed material for successful amplification of beta-actin sequences. The absence of HPV (other than in the papilloma itself) in the upper aerodigestive tract of patients and caregivers is consistent with the absence of reported cases of horizontal transmission to siblings or other family members. The findings are also consistent with the conventional view that juvenile respiratory HPV is transmitted vertically from vaginal condylomas in the mother.     

Immunocompetency in children with recurrent respiratory papillomatosis: prospective study

OBJECTIVES: We sought to investigate the immunologic status of children with recurrent respiratory papillomatosis and to evaluate possible correlations between the patients' immunocompetency and the clinical course of the disease. METHODS: Twenty children with recurrent respiratory papillomatosis underwent immunologic evaluation every 6 months for determination of complete blood count, serum immunoglobulin levels, lymphocyte subpopulations, lymphocyte response to mitogen stimulation, and natural killer cell function. The patients were observed prospectively (42 to 56 months), and their clinical course was recorded. The findings were compared with those in healthy age-matched controls. RESULTS: The CD4/CD8 ratio and the lymphocyte response to mitogen stimulation were significantly reduced in the study children compared to normal controls. A reduction in lymphocyte response to mitogen stimulation was significantly correlated to a high number of papilloma sites and more frequent recurrences. Abnormal natural killer cell function was significantly correlated to more frequent recurrences. CONCLUSIONS: A compromised cell-mediated immune response may be associated with repeated or persistent human papillomavirus infections, leading to the development of recurrent respiratory papillomatosis. Patients with an aggressive clinical course may have underlying cell-mediated immunodeficiency. Long-term prospective investigations are needed to establish the role of the host immune system in the pathogenesis of recurrent respiratory papillomatosis in children.     

小儿复发性呼吸道乳头状瘤治疗进展

小儿复发性呼吸道乳头状瘤是指发生在呼吸道上下的乳头状瘤病,是一种高度复发性和侵袭性的疾病。患儿可出现声音嘶哑症状,严重时有呼吸困难表现。乳头状瘤疾病常为HPV6和HPV11感染,可由于分娩时患儿经母亲产道感染乳头状瘤病毒所致。手术是治疗的主要的方法,但不能根治,往往因为多次手术给患儿和家属带来巨大的痛苦,故需要其他药物来辅助治疗。本文综述概括了目前各种治疗小儿乳头状瘤的方法。     

喉乳头状瘤临床行为与细胞增殖活性关系的研究

利用ISH方法以及免疫病理手段对不同型的LP组织的标本进行PCNA、P53检测，探讨不同型HPV与LP的发生发展的相关机制，以寻求有效的检测方法帮助临床对LP的预后进行评估。标本选自1994年1月～1995年12月间我院收治的LP共36例。ISH法HPV6b／11阳性率为75％，明显高于HPV16和／或HPV18的表达。10例喉鳞癌各有1例HPV16、18阳性，无HPV6b／11阳性。ABC法行P53检测，36例LP标本中仅1例恶变组织阳性表达Ⅱ级（2．8％）；10例喉鳞癌中9例阳性表达（90．0％），其中Ⅱ级以上阳性表达6例（60．0％）。PCNA阳性表达27／36例（75％）；其中JOP组与AOP组阳性率有显著差异（P＜0．05）。本研究表明LP与HPV感染有极为密切的关系，认为HPV分型的检测在判断LP转归中有意义。PCNA阳性表达程度在预测LP肿瘤的活跃程度方面是一个很有意义的指标。P53蛋白表达在喉鳞癌与LP中有显著差异。     

Prevalence and clinical implications of low-risk human papillomavirus among patients with recurrent respiratory papillomatosis in Rio de Janeiro,Brazil

ObjectiveThe aim of this study was to investigate the presence of human papillomavirus (HPV) in biopsy specimens from juvenile and adult patients with histopathological diagnosis of recurrent respiratory papillomatosis (RRP) treated in two public hospitals in Rio de Janeiro, Brazil.MethodsWe performed the detection and genotyping of HPV by PCR technique for the types 6, 11, 16, and 18 in biopsy specimens from 41 RRP patients.ResultsThe juvenile onset RRP (JoRRP) corresponded to 61% and the adult onset RRP (AoRRP) corresponded to 39% of the study group. Prevalence of males was observed in both the adult (81.3%) and the juvenile (56%) groups. Lesions in the larynx were more frequent in the glottis (46%). Genotyping analysis only revealed patients with HPV-6 (34.1%), HPV-11(17.1%), and co-infection HPV-6 and -11 (48.8%). RRP severity was significantly associated with the JoRRP (p < 0.001), with extralaryngeal disease and more surgeries. However, no significant association between RRP severity and HPV types was found. One co-infected patient in the JoRRP died due to the evolution of the disease with lung involvement.ConclusionThese results show the strong association of HPV-6 and/or HPV-11 types with RRP and could complement the diagnosis, prognosis, and therapies for these patients. In addition, the HPV vaccination should be encouraged to prevent the disease.     

A scheduled protocol for the treatment of juvenile recurrent respiratory papillomatosis with intralesional cidofovir

OBJECTIVE: To assess the efficacy of treating juvenile recurrent respiratory papillomas with intralesional cidofovir using a scheduled treatment protocol. DESIGN: Prospective case series. SETTING: Tertiary care academic medical center. PATIENTS: Of 5 pediatric patients with recurrent respiratory papillomas, 2 had severe recurrent papillomatosis requiring long-term therapy of laser ablations every 2 weeks prior to cidofovir treatments. The 3 other patients were newly diagnosed or had milder disease. INTERVENTION: Intralesional cidofovir (1 mg/kg) was administered during each scheduled visit. The first 4 treatments were at 2-week intervals (week 0, 2, 4, and 6). Subsequent treatment intervals were each increased by 1 week (treatments took place at week 9, 13, 18, 24, etc). Concomitant laser ablation was used only for bulky lesions. MAIN OUTCOME MEASURES: Papilloma stage and need for laser ablation at each scheduled visit. RESULTS: The mean follow-up time was 66 weeks. The mean (SD) papilloma stage decreased from 9.2 (5.5) at initial presentation to 3.4 (2.6) within 2 weeks of the first injection (P<.05), and continued to decrease for the remaining of the follow-up period. Papilloma stage 0 was achieved in 4 of the 5 patients. The need for laser ablation of papillomas also decreased within 4 weeks of treatment initiation (P<.05). At 9 weeks, no patient required laser therapy. One patient was removed from the protocol after 58 weeks. CONCLUSION: An intralesional treatment protocol with cidofovir and increasing intervals between scheduled treatment was successful the long-term management of juvenile respiratory papillomatosis.     

Serial office-based intralesional injection of cidofovir in adult-onset recurrent respiratory papillomatosis

Intralesional injection of cidofovir is used in the treatment of recurrent respiratory papillomatosis as an adjuvant therapy after microsurgical excision and CO2 laser therapy. This is conventionally done in the operating room with the patient under general anesthesia. We report our experience with 5 patients with adult-onset recurrent respiratory papillomatosis who were treated with intralesional injections of cidofovir after recurrence of their papillomatosis. These injections were given monthly in the office without the use of general anesthesia. Before cidofovir injection, all patients required repeated CO2 laser treatments at intervals of less than 5 months. We injected 7.5 mg/mL of cidofovir transorally into the papillomas under office telescopic control. These injections were given monthly for 3 consecutive months. The patients were then followed up for 2 to 10 months after therapy to monitor the size of the papillomas. In all 5 patients, partial remission of the laryngeal papillomatosis was noted during the follow-up period. Their need for repeat microsurgery was delayed, and their vocal function improved. Intralesional injection of cidofovir in an office setting appears to be safe and effective. It might be more convenient and cost-effective than performing the same procedure in the operating room with the patient under general anesthesia.     

幼年型复发性呼吸道乳头状瘤病患儿外周血T细胞初探

目的分析幼年型复发性呼吸道乳头状瘤病(juvenile-onset recurrent respiratory papillomatosis,Jo-RRP)外周血T淋巴细胞免疫状态及其与病情间的相关性,探讨更合适的治疗方案。方法采用流式细胞仪检测19例Jo-RRP患儿外周血T淋巴细胞亚群,按照《复发性呼吸道乳头状瘤病病情严重度评分表》对其病情进行严重度评分,分析外周血T淋巴细胞亚群功能及与病情的相关性。结果Jo-RRP患儿CD3~ 、CD4~ 、CD4~ / CD8~ T细胞以及Th1FFh2均低于正常儿童(P<0.05)。除Th1细胞(P<0.05)外,其余免疫指标与Jo-RRP患儿临床严重度评分间均无明显相关性。结论Jo-RRP患儿可能存在T细胞介导的免疫功能障碍,其紊乱的免疫功能与疾病的发生、发展可能存在相互促进作用,需进一步完善手术切除肿瘤之外的免疫调节等辅助治疗手段。     

复发性呼吸道乳头状瘤病

本文结合一组63例复发性乳头状瘤的基础及临床研究资料进行分析，其中16例的瘤组织以Slotblot和Southernblot杂交技术检测HPV－DNA，其阳性率：HPV6b为87.5％，HPV11为93．7％，HPV16为81．2％。本文就病因学、感染途径、复发部位与上皮组织特性及治疗选择进行讨论。     

An epigenetically derived monoclonal origin for recurrent respiratory papillomatosis

OBJECTIVE: To investigate the contribution of promoter methylation-mediated epigenetic events in recurrent respiratory papillomatosis tumorigenesis. DESIGN: Archival tissue DNA, extracted from microdissected papilloma lesions, was interrogated for methylation status by means of the novel, multigene methylation-specific multiplex ligation-dependent probe amplification assay. SUBJECTS: Fifteen subjects with recurrent respiratory papillomatosis, 3 females and 12 males, all with adult onset of illness (age range, 23-73 years) except for 1 female patient with juvenile onset (1 year old). RESULTS: Promoter hypermethylation was recorded in 14 of 15 cases, and 19 of 22 unique methylation-prone cancer genes in the multigene panel had altered DNA methylation in at least 1 laryngeal papilloma biopsy specimen. Identical abnormally methylated genes were found in 5 of 15 recurrent cases, of which the CDKN2B gene was hypermethylated in all 5 cases. Dissimilar epigenetic events were noted in the remaining cases. CONCLUSIONS: A clonal origin was derived for 5 of 15 recurrent respiratory papillomatosis biopsy specimens based on identical epigenetic events. The high frequency of epigenetic events, characterized by consistent promoter hypermethylation of multiple tumor suppressor genes, points to the use of gene silencing mechanisms in the pathogenesis of recurrent respiratory papillomatosis.     

A simple measurement of parotid salivary flow using material quick absorber.

We applied Material Quick Absorber (Inami Co Ltd, Tokyo, Japan), a small triangular paper strip made mainly from viscose and used for fluid absorption during surgery, to collect right resting parotid saliva directly from Stensen's orifice and estimated nonstimulated parotid salivary flow by weighing the saliva absorbed in a given period of time. We assayed this method in 53 patients with dry mouth and/or throat and in 115 healthy young and elderly control subjects. The median salivary flow rates in male and female patients were 18 mg/min (almost equal to 0.018 mL/min) and 11 mg/min, respectively, significantly lower (P less than .05 for men, P less than .01 for women) than those obtained from young male (36 mg/min) and female (34 mg/min) controls and consistent with previously reported physiologic flow rates obtained by means of the "cup method." Although the median flow rate for elderly male controls (35 mg/min) was rather close to that of young male or female controls, there was no significant difference in flow rates between elderly male controls and male patients. On the other hand, in female control subjects, a significant decrease (P less than .05) in salivary flow was shown with aging. Repeated 3-minute measurements (eight times at 5- to 6-minute intervals) with this method in 10 healthy younger male volunteers showed that the coefficient of variance in the same subject ranged from 14.1% to 57.2% and that the larger the mean flow rate the smaller the coefficient of variance (P less than .05 by simple regression analysis).(ABSTRACT TRUNCATED AT 250 WORDS)     

Recurrent respiratory papillomatosis: Juvenile versus adult forms

Recurrent respiratory papillomatosis (RRP) has been described to have a juvenile or aggressive form and an adult or less aggressive form. However, the aggressive form may occur in an adult and vice versa. Some authors have reported a quiescence in the juvenile form with the onset of puberty. In order to further characterize these two forms of RRP and to analyze the effects of puberty, we reviewed the records of 32 patients treated for RRP at our institution over a 10-year period. We found that the aggressive form typically occurs in the very youngest of patients (average of 2 years old as compared to an average of 17 years old in the less aggressive form). Although subglottic involvement universally occurred in our group with aggressive disease, approximately 40% developed subglottic disease very early as compared with 20% of patients with less aggressive disease. Additionally, our data do not support the theory of spontaneous regression with the onset of puberty. These and other findings will be discussed in detail. We also propose a new classification for RRP to eliminate confusion.