Nasal mucosa narrow band imaging in granulomatosis with polyangiitis (Wegener granulomatosis): A preliminary study Matteo Trimarchi, M.D.,1 Enrica Bozzolo, M.D.,2 Francesco Pilolli, M.D.,1 Giacomo Bertazzoni, M.D.,1 Corrado Campochiaro, M.D.,2 Maria Grazia Sabbadini, M.D.,2,3 and Mario Bussi, M.D.1,3
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ABSTRACT
Background: Narrow band imaging (NBI) endoscopy is a technique that allows for real-time visualization of mucosal and submucosal vascular patterns. Objective: Because granulomatosis with polyangiitis (GPA) (Wegener granulomatosis) is an autoimmune disease defined by vascular inflammation, we examined patients with GPA and with NBI to evaluate whether disease-specific mucosal vascular patterns were present. To the best of our knowledge, the use of NBI endoscopy for assessment of an immune system disease such as GPA has never been previously attempted. Methods: We conducted a prospective observational study by performing an endoscopic evaluation of upper airways with NBI on patients diagnosed with GPA; on patients with symptoms and signs suggestive for GPA, who were scheduled to undergo nasal biopsy to confirm diagnosis; on patients affected by chronic rhinosinusitis with nasal polyps; and on healthy controls. Results: We enrolled 69 patients. NBI vascular patterns in patients with GPA were consistently and recognizably different from healthy mucosal patterns in 53% of our cases. In patients with GPA, biopsy and NBI results were for the most part comparable, except for three cases. Conclusion: Nasal mucosa NBI endoscopy can be considered a promising rapid and noninvasive live imaging technique for nasal mucosa GPA that, based on further study, could become a supplementary diagnostic tool in the complex workup of GPA and vasculitis. (Am J Rhinol Allergy 29, 170 –174, 2015; doi: 10.2500/ajra.2015.29.4169)
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ranulomatosis with polyangiitis (GPA), or Wegener granulomatosis, is an idiopathic, systemic vasculitis characterized by necrotizing granulomatous inflammation and necrotizing vasculitis, which classically affects the ear, nose, and throat region, lower respiratory tract, and kidneys1,2; however, other organs may also be involved.3 A diagnosis of GPA is based on clinical and serologic findings, and, whenever possible, biopsy should be performed.4 However, biopsy results are often inconclusive and not sufficient for the diagnosis,5,6 thus making a complex and lengthy multidisciplinary diagnostic workup necessary to proceed with treatment.7 Narrow band imaging (NBI) endoscopy allows for real-time visualization and identification of mucosal and submucosal vascular patterns, with no need to perform invasive procedures,8 and it is used to distinguish precancerous and cancerous lesions of the head and neck.9 Because GPA is defined by inflammatory vascular involvement,1,2,10 we examined GPA patients with NBI to evaluate whether disease-specific mucosal vascular patterns were present. Our primary aim was to assess the possible role of NBI as a diagnostic tool for GPA, whereas our secondary aim was to indirectly compare NBI and biopsy diagnostic power. To the best of our knowledge, the use of NBI endoscopy for assessment of GPA has never been previously attempted.
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From the 1Department of Otorhinolaryngology, 2Department of Medicine and Clinical Immunology, San Raffaele Scientific Institute, Milan, Italy, and 3Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy Presented at the 2nd European Academy of Otorhinolaryngology, Head and Neck Surgery, and Confederation of European Otorhinolaryngology - Head and Neck Surgery Meeting, April 27–30, 2013, Nice, France Presented at the 25th Congress of the European Rhinologic Society and 32nd International Symposium of Infection & Allergy of the Nose, June 22–26, 2014, Amsterdam, Netherlands The authors have no conflicts of interest pertaining to this article Address correspondence to: Matteo Trimarchi, M.D., Department of Otorhinolaryngology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy E-mail: [email protected] Published online March 23, 2015 Copyright © 2015, OceanSide Publications, Inc., U.S.A.
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MATERIALS AND METHODS Patients
We conducted a prospective observational study between November 2012 and September 2013 at the Department of Otorhinolaryngology, Head and Neck Surgery of San Raffaele Scientific Institute, Milan, Italy. We performed endoscopic evaluation of the upper airways with NBI in four groups of patients: group 1 was composed of patients diagnosed with GPA referred by the Department of Medicine and Clinical Immunology, San Raffaele Scientific Institute, Milan, Italy; group 2 included patients with symptoms and signs suggestive of GPA, who were scheduled to undergo nasal biopsy to confirm diagnosis; group 3 included patients affected by chronic rhinosinusitis with nasal polyps (CRSwNP); and group 4 was composed of healthy controls. The study was conducted with the approval of the local ethics committee (Comitato Etico dell’Istituto Scientifico Ospedale San Raffaele) and complies with the Declaration of Helsinki. All the patients gave informed consent.
Endoscopy All the patients underwent transnasal endoscopy of the upper airways with a flexible video-endoscope (Exera II Cv-180, Olympus Medical Systems Corp, Tokyo, Japan). The examination was performed with both white and NBI lights by using a single switchable light source and one high-definition monitor. We examined nasal fossae, pharynx, larynx, and the upper tracheal segment, and focused our observation on mucosal and submucosal vascular patterns. All the videos were digitally stored. All the examinations were conducted by a senior otolaryngologist (M.T.) who identified NBI vascular alterations. The vascular abnormalities were subsequently classified according to their architectural pattern. Healthy mucosa was identified by the presence of a low-density homogenous vascular network in the absence of noticeable alterations, as similarly described in other studies that focused on the identification of cancerous lesions.11–17 We classified healthy vascular patterns, for the purposes of our study, as NBI negative (NBI–). Abnormal nasal mucosa was defined as nasal mucosa
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presenting evident alterations that substantially differed from a normal NBI pattern, as we had observed during preliminary clinical observations with NBI. Those areas presented increased vessel density, web-like vasculature, and vessels with hypertrophic morphology. We aimed at the identification of a clearly evident pattern during NBI endoscopic evaluation of patients with GPA that could possibly be related to known GPA alterations in histologic sections. Patients who presented such alterations were classified as NBI positive (NBI⫹).
Table 1. Patient demographics
Men Women Mean age, y Age range, y
Group 2: Suspect GPA
Group 3: CRSwNP
Group 4: Healthy subjects
8 6 51.9 31–72
2 7 48.9 31–69
13 8 55.6 41–73
15 10 46.7 20–90
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CRSwNP ⫽ chronic rhinosinusitis with nasal polyps.
Statistical analysis The presence of NBI vascular alterations in patients in group 2 was matched with the final diagnosis in a cross tabulation. Next, we evaluated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NBI alterations in patients in group 2 with GPA, and calculated confidence intervals (CI). Because group 2 patients had undergone biopsy and histopathologic analysis of nasal mucosa, we also considered biopsy results with the final diagnosis of patients in group 2 in a cross tabulation. The diagnostic value of biopsy in group 2 patients with GPA was then evaluated by calculating biopsy sensitivity, specificity, PPV, NPV, and CI. We then performed the same analyses by considering separately NBI and biopsy results from group 1.
Table 2. Groups 1 and 2 clinical findings Group 1 (confirmed GPA)
RESULTS We enrolled 69 patients, 31 women and 38 men, with a mean age of 50.8 years (range, 20–90 years) who were divided among four groups. Key demographic characteristics of the groups are listed in Table 1. All the patients in group 1 had a previously confirmed diagnosis of GPA according to the European Medicines Agency algorithm,18 which includes American College of Rheumatology classification criteria,19 supported by either a positive antineutrophil cytoplasmic antibody (ANCA) assay,20,21 or a diagnostic biopsy. The main clinical features of the group 1 patients are showed in Table 2; no patient reported other significant comorbidities. Biopsy from the head and neck region was performed on nine patients in group 1. Histopathologic analysis of nasal mucosa biopsy was diagnostic for GPA in two of five patients, samples from tracheal stenosis yielded a diagnosis in one of two patients, one biopsy from the oropharynx was negative, and sampling from retro-orbital tissue in one patient was negative for GPA. Four patients reported previous renal biopsy, but only one sample was diagnostic. One patient underwent histopathologic analysis of a skin lesion of the foot, which was diagnostic for GPA. One patient underwent pulmonary lobectomy and histology confirmed GPA. At the time of endoscopy, the mean GPA Birmingham Vasculitis Activity Score22 was 3.9 (range, 1–7). Eleven patients were positive for cANCA, and two were positive for pANCA. Antiproteinase-3 antibodies were present in 10 cases; no patient presented antimyeloperoxidase antibodies. Group 2 patients were referred to our department for clinical signs and symptoms suggestive for GPA and underwent nasal biopsy to confirm the diagnosis as part of the EMEA GPA algorithm.18 The main clinical features of group 2 patients are reported in Table 1. No patient reported other significant comorbidities. Three patients showed cANCA positivity, and two showed pANCA positivity. Antiproteinase-3 and antimyeloperoxidase were elevated in three and one patients, respectively. Nasal biopsy, under local anesthesia, was performed in the operating room; three patients had histologic findings suggestive for GPA, which allowed for a final diagnosis of GPA. Another two patients from group 2 were diagnosed with GPA based on renal and pulmonary biopsy findings. The mean Birmingham Vasculitis Activity Score in this subset of patients was 2.7 (range, 1–9). NBI endoscopy was always performed within two months after nasal biopsy. No patient was evaluated in the immediate postoperative period.
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Group 1: GPA
Sinonasal involvement Saddle nose deformity Chronic otitis Subglottic stenosis Vocal cord palsy Ocular involvement Pulmonary involvement Renal involvement Neurologic symptoms Myalgia Skin lesions
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11 1 4 4 2 1
Group 2 (suspected GPA)
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9 1 1 2 0 0 3 3 0 0 0
Group 3 patients were all scheduled to undergo functional endoscopic sinus surgery for treatment of CRSwNP . Histopathologic analysis of all surgical specimens was then performed to confirm diagnosis. No patient in group 3 had relevant comorbidities or took any long-term systemic medication. Group 4 patients were healthy volunteers, and none was taking long-term medications. NBI endoscopy of the upper airways was well tolerated by all the patients, no adverse events occurred, and no patient needed local anesthesia or reported pain during or after the procedure. Upon NBI examination, the pharyngeal and laryngeal mucosa of all cases examined had an NBI– healthy vascular pattern (Fig. 1a). The same pattern was present when examining subglottic and tracheal stenosis (Fig. 1 b). Nasal mucosa endoscopic evaluation of healthy patients (group 4) was NBI– in all nasal anatomic regions in all 25 patients. Minor alterations of the normal nasal mucosa vascular pattern were present in seven healthy controls (group 4). In fact, we observed some areas with low-density pitting limited to middle or inferior turbinates (Fig. 1 c). These alterations did not appear to be related to those described in cancerous lesions11–17 and were not comparable with the patterns observed in patients with suspected or known GPA (groups 1 and 2). All healthy controls (group 4), therefore, were considered NBI–. We observed 11 NBI⫹ areas with vascular anomalies in nasal and sinonasal mucosa of 10 patients with GPA (Fig. 1 d–h), eight patients from group 1 (with known GPA) (58.3%), and two patients from group 2 (suspected GPA) (28.6%). In particular, the noted patterns were heterogeneous but obviously abnormal when compared with healthy controls. These macroscopic alterations did not involve the entire nasal mucosa but could be detected only in some areas. In addition, the anomalous patterns did not seem to be related and differed substantially from one patient to another. Nonetheless, the patterns were always clearly evident during NBI endoscopic evaluations and were never present in healthy patients (NBI–). We further cataloged the 11 previously identified areas of vascular abnormality in 3 different categories according to their macroscopic
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Table 3. NBI compared with final diagnosis of GPA (group 2)
NBI⫹ NBI⫺ Total
GPAⴙ
GPAⴚ
Total
2 3 5
0 4 4
2 7 9
Sensitivity 0.40, 95% CI (0 – 0.83); specificity 1.00, 95% CI (1); PPV 1.00, 95% CI (1); NPV 0.57, 95% CI (0.2– 0.94).
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Table 4. Nasal mucosa histology compared with final diagnosis of GPA (group 2)
Biopsy⫹ Biopsy– Total
GPAⴙ
GPA–
Total
3 2 5
0 4 4
3 6 9
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Sensitivity 0.60, 95% CI (0.17–1); specificity 1.00, 95% CI (1); PPV 1.00, 95% CI (1); NPV 0.67, 95% CI (0.29 –1).
Figure 1. (a) NBI– endoscopic image of left middle turbinate of a healthy patient (group 4). (b) NBI– image of subglottic stenosis from a group 2 patient (suspected for GPA) who was eventually diagnosed with GPA. (c) NBI– endoscopic image of the left inferior turbinate from a healthy patient (group 4). (d) NBI⫹ endoscopic image from a group 2 patient (suspected for GPA), showing a “vascular islands” pattern on the right middle turbinate. (e) NBI⫹ endoscopic image from group 1 (patients with GPA), showing a high-density, nonhomogeneous vascular network (“web pattern”) on the left middle turbinate. (f) NBI endoscopic image from group 1 (patients with GPA), showing a rosary beads vascular network on the left middle turbinate. (g) NBI⫹ endoscopic image from group 1 (patient with GPA), showing hypertrophic vessels on the nasal floor and septum. (h) NBI⫹ endoscopic image from group 1 (patients with GPA), showing tree-like vessels. (i) NBI– endoscopic image of a polyp in the left middle meatus from group 3 (patient with chronic rhinosinusitis with nasal polyps).
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NBI⫹ NBI– Total
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pattern appearance: vascular islands pattern, web pattern, and hypertrophic vessels pattern. The vascular islands pattern was visible in two areas on the anterior surface of middle turbinate and showed a grouped organization (Fig. 1 d). The web pattern could be observed in 4 areas on the anterior surface of the middle turbinates and was characterized by a highdensity nonhomogeneous network (Fig. 1 e). One of the areas that showed a web pattern presented a higher-density vascular network on the middle turbinate that was more homogeneous and organized, with irregular thin vessels, which resembled rosary beads (Fig. 1 f). Grossly hypertrophic vessels whose diameter was, in some cases, wider than 1 mm were identified in five other patients (Fig. 1 g). In one of those patients, the hypertrophic vessels had a tree-like organization (Fig. 1 h). Patients with CRSwNP (group 3) showed a vascular pattern somewhat similar to a normal healthy pattern. The only difference was that nasal polyps had a more sparse vascular pattern due to reduced vascularization (Fig. 1 i). At any rate, we considered group 3 mucosal patterns as NBI–. Histologic examinations of head and neck region biopsy specimens were available for nine patients with a past diagnosis of GPA (group 1) and was diagnostic in only three patients (33.3%). In patients with suspected GPA (group 2), histologic examination was obtained from the nasal mucosa of all patients and was diagnostic for GPA in three patients (33.3%). A final diagnosis of GPA was obtained in two other patients from group 2, despite nonconclusive histology, because they met other EMEA classification criteria.
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Table 5. NBI compared with final diagnosis of GPA (group 1) GPAⴙ
GPA–
Total
8 6 14
0 0 0
8 6 14
Sensitivity 0.57, 95% CI (0.3– 0.75).
Table 6. Head & Neck histology compared with final diagnosis of GPA (group 1)
Biopsy⫹ Biopsy⫺ Total
GPAⴙ
GPAⴚ
Total
3 6 9
0 0 0
3 6 9
95% CI Sensitivity
0.33
(0.17–0.69)
The results of NBI examination and histopathologic analysis in patients with suspected GPA (group 2) are summarized in Tables 3 and 4, respectively, and show the final diagnosis (GPA⫹ or –). Data were organized in a cross tabulation, and we calculated the sensitivity, specificity, PPV, NPV, and CI of both NBI evaluation and histopathologic analysis (Tables 3 and 4). Data from group 1 were similarly analyzed, and we compared results from NBI examination and histopathologic analysis with patients’ final diagnosis. Data cross tabulation, sensitivity, PPV, NPV, and CI are shown in Tables 5 and 6.
DISCUSSION NBI⫹ patterns could be recognized in 53% of patients with confirmed GPA from groups 1 and 2, and presented evident macroscopic differences among themselves as described in the Results section. We acknowledge that the presence of hypertrophic vessels in healthy controls could make the identification of an NBI⫹ “hypertrophic vessels pattern” not as clear cut and possibly less predictive than the other patterns. However, we did not have particular difficulties in discriminating a few isolated hypertrophic vessels in healthy subjects from the more diffuse and numerous hypertrophic vessels of patients with GPA (Fig. 1). Also, none of the other pattern features could be seen in the healthy controls. We could not see any clear correlation between NBI⫹ patterns and the known histologic characteristics of GPA; this is why we correlated
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NBI results with the final GPA diagnosis and not only with biopsy results. However, in both groups 1 and 2, nasal biopsy and NBI results were, for the most part, comparable, except for three patients. One patient from group 1 and one from group 2 had a GPA⫹ nasal biopsy but a completely normal vascular pattern on NBI examination. In the first patient, NBI examination was performed five years after biopsy, and, during that period of time, the patient had been administered immunosuppressive treatment. The time elapsed between biopsy and NBI examination, along with the immunosuppressive therapy, could justify the normalization of the vascular architecture. However, this assumption is not valid for the second patient because biopsy and NBI were performed within a short period. Another patient from group 1 had a negative nasal histology but an NBI⫹ pattern, despite eight years under treatment between biopsy and NBI examination. We cannot rule out that patients with NBI⫹ patterns could present with nondiagnostic nasal mucosa biopsies because many definite histopathologic alterations are needed to precisely diagnose GPA.23–27 As a consequence, NBI could highlight evident (NBI⫹) vascular alterations even in the absence of the complete set of GPA histopathologic characteristics. Our observations on NBI patterns in group 1 could be biased because the examiner knew the final diagnosis of GPA of the patients. Nonetheless, group 2 yielded similar NBI examination results, and patients had not yet received a definitive diagnosis. Few researchers have thus far discussed the diagnostic power of nasal biopsy, whose sensitivity ranges between 21% and 70%.23–26 In our cohort of patients tested for suspected GPA (group 2), biopsy sensitivity was 60% and specificity was 100%. Even though we tested a small number of patients, our results were similar to those reported in other studies on nasal biopsy.23–26 However, not all patients with a known diagnosis of GPA (group 1) underwent biopsy sampling from nasal mucosa, but, also, other regions of the head and neck were sampled. We did not exclude these patients because we aimed at evaluating NBI nasal endoscopy in a similar diagnostic setting as the biopsy, which is often performed in different sites from where the disease is clinically evident in the head and neck region. All patients with GPA (from groups 1 and 2) had a clinical diagnosis of GPA according to the EMEA algorithm,18 supported by either a positive ANCA assay20,21 or a diagnostic biopsy. The algorithm was used to identify patients with a positive diagnosis of vasculitis and to classify them as patients with GPA. Even though the EMEA algorithm offers a high degree of interclassifier reliability, it is not 100% reliable.18 As a consequence, sensitivity and specificity of our NBI evaluation calculated in comparison with our GPA diagnosis can potentially be inaccurate. Overall, we noted that, in our prospective cohort, NBI nasal endoscopy and nasal biopsy results, for the most part, were comparable and offered diagnostic sensitivity and specificity similar to histology. Nevertheless, those observations cannot be generalized and need additional validation with a clinical study on a larger population. Further studies on NBI patterns and related biopsies could also help to elucidate possible relationships between histology and NBI patterns. Analysis of our results, however, suggest that NBI⫹ patterns may not be strictly related to a biopsy diagnostic for GPA. NBI is currently used in the endoscopic diagnosis of various oncologic and benign mucosal conditions, and it is primarily used in many European and Japanese ear, nose, and throat departments to identify head and neck cancerous and precancerous lesions.11–17 Contextual use of NBI during endoscopic evaluation of patients with GPA allows real-time evaluation of mucosal and submucosal vascularization, and requires a little extra time to be performed. In conclusion, nasal mucosa NBI endoscopy can be considered a promising rapid and noninvasive technique for the individuation of possibly GPA-related vascular alterations that, based on further prospective blinded studies, could become a supplementary diagnostic tool in the complex workup of GPA.
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Wegener F. On generalised septic vessel diseases. Thorax 42:918–919, 1987. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 116:488–498, 1992. Lehmann H, and Kiefer B. Clinical manifestations of Wegener’s granulomatosis. APMIS Suppl 19:19–20, 1990. Armengot M, García-Llibero´s A, Go´mez MJ, et al. Sinonasal involvement in systemic vasculitides and cocaine-induced midline destructive lesions: Diagnostic controversies. Allergy Rhinol (Providence) 4:e94–e99, 2013. Martinez Del Pero M, Rasmussen N, Chaudhry A, et al. Structured clinical assessment of the ear, nose and throat in patients with granulomatosis with polyangiitis (Wegener’s). Eur Arch Otorhinolaryngol 270:345–354, 2013. Trimarchi M, Sinico RA, Teggi R, et al. Otorhinolaryngological manifestations in granulomatosis with polyangiitis (Wegener’s). Autoimmun Rev 12:501–505, 2013. Matsubara O, Yoshimura N, Doi Y, et al. Nasal biopsy in the early diagnosis of Wegener’s (pathergic) granulomatosis. Significance of palisading granuloma and leukocytoclastic vasculitis. Virchows Arch 428:13–19, 1996. Piazza C, Dessouky O, Peretti G, et al. Narrow-band imaging: A new tool for evaluation of head and neck squamous cell carcinomas. Review of the literature. Acta Otorhinolaryngol Ital 28:49–54, 2008. Watanabe A, Taniguchi M, Tsujie H, et al. The value of narrow band imaging for early detection of laryngeal cancer. Eur Arch Otorhinolaryngol 266:1017–1023, 2009. Dimitrijevic I, and Edvinsson L. Increased endothelin 1 type B receptors in nasal lesions of patients with granulomatosis with polyangiitis. Am J Rhinol Allergy 27:444–450, 2013. Piazza C, Cocco D, Del Bon F, et al. Narrow band imaging and high definition television in the endoscopic evaluation of upper aerodigestive tract cancer. Acta Otorhinolaryngol Ital 31:70–75, 2011. Kikuchi O, Ezoe Y, Morita S, et al. Narrow-band imaging for the head and neck region and the upper gastrointestinal tract. Jpn J Clin Oncol 43:458–465, 2013. Lin YC, Wang WH, Lee KF, et al. Value of narrow band imaging endoscopy in early mucosal head and neck cancer. Head Neck 34: 1574–1579, 2012. Yang SW, Lee YS, Chang LC, et al. Diagnostic significance of narrow-band imaging for detecting high-grade dysplasia, carcinoma in situ, and carcinoma in oral leukoplakia. Laryngoscope 122:2754–2761, 2012. Piazza C, Cocco D, De Benedetto L, et al. Role of narrow-band imaging and high-definition television in the surveillance of head and neck squamous cell cancer after chemo- and/or radiotherapy. Eur Arch Otorhinolaryngol 267:1423–1428, 2010. Piazza C, Del Bon F, Peretti G, and Nicolai P. Narrow band imaging in endoscopic evaluation of the larynx. Curr Opin Otolaryngol Head Neck Surg 20:472–476, 2012. Watanabe A, Taniguchi M, Tsujie H, et al. The value of narrow band imaging endoscope for early head and neck cancers. Otolaryngol Head Neck Surg 138:446–451, 2008. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 66:222–227, 2007. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 33:1101–1107, 1990. Andrassy K, Koderisch J, Waldherr R, and Rufer M. Diagnostic significance of anticytoplasmatic antibodies (ACPA/ANCA) in detection of Wegener’s granulomatosis and other forms of vasculitis. Nephron 49:257–258, 1988. Finkielman JD, Lee AS, Hummel AM, et al. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med 120:643.e9–.e14, 2007. Stone JH, Hoffman GS, Merkel PA, et al. A disease-specific activity index for Wegener’s granulomatosis: modification of the Birming-
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Delivered by Ingenta to: Economics Dept IP: 185.14.195.64 On: Tue, 28 Jun 2016 18:17:43 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
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ABSTRACT
Background: Narrow band imaging (NBI) endoscopy is a technique that allows for real-time visualization of mucosal and submucosal vascular patterns. Objective: Because granulomatosis with polyangiitis (GPA) (Wegener granulomatosis) is an autoimmune disease defined by vascular inflammation, we examined patients with GPA and with NBI to evaluate whether disease-specific mucosal vascular patterns were present. To the best of our knowledge, the use of NBI endoscopy for assessment of an immune system disease such as GPA has never been previously attempted. Methods: We conducted a prospective observational study by performing an endoscopic evaluation of upper airways with NBI on patients diagnosed with GPA; on patients with symptoms and signs suggestive for GPA, who were scheduled to undergo nasal biopsy to confirm diagnosis; on patients affected by chronic rhinosinusitis with nasal polyps; and on healthy controls. Results: We enrolled 69 patients. NBI vascular patterns in patients with GPA were consistently and recognizably different from healthy mucosal patterns in 53% of our cases. In patients with GPA, biopsy and NBI results were for the most part comparable, except for three cases. Conclusion: Nasal mucosa NBI endoscopy can be considered a promising rapid and noninvasive live imaging technique for nasal mucosa GPA that, based on further study, could become a supplementary diagnostic tool in the complex workup of GPA and vasculitis. (Am J Rhinol Allergy 29, 170 –174, 2015; doi: 10.2500/ajra.2015.29.4169)
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ranulomatosis with polyangiitis (GPA), or Wegener granulomatosis, is an idiopathic, systemic vasculitis characterized by necrotizing granulomatous inflammation and necrotizing vasculitis, which classically affects the ear, nose, and throat region, lower respiratory tract, and kidneys1,2; however, other organs may also be involved.3 A diagnosis of GPA is based on clinical and serologic findings, and, whenever possible, biopsy should be performed.4 However, biopsy results are often inconclusive and not sufficient for the diagnosis,5,6 thus making a complex and lengthy multidisciplinary diagnostic workup necessary to proceed with treatment.7 Narrow band imaging (NBI) endoscopy allows for real-time visualization and identification of mucosal and submucosal vascular patterns, with no need to perform invasive procedures,8 and it is used to distinguish precancerous and cancerous lesions of the head and neck.9 Because GPA is defined by inflammatory vascular involvement,1,2,10 we examined GPA patients with NBI to evaluate whether disease-specific mucosal vascular patterns were present. Our primary aim was to assess the possible role of NBI as a diagnostic tool for GPA, whereas our secondary aim was to indirectly compare NBI and biopsy diagnostic power. To the best of our knowledge, the use of NBI endoscopy for assessment of GPA has never been previously attempted.
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From the 1Department of Otorhinolaryngology, 2Department of Medicine and Clinical Immunology, San Raffaele Scientific Institute, Milan, Italy, and 3Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy Presented at the 2nd European Academy of Otorhinolaryngology, Head and Neck Surgery, and Confederation of European Otorhinolaryngology - Head and Neck Surgery Meeting, April 27–30, 2013, Nice, France Presented at the 25th Congress of the European Rhinologic Society and 32nd International Symposium of Infection & Allergy of the Nose, June 22–26, 2014, Amsterdam, Netherlands The authors have no conflicts of interest pertaining to this article Address correspondence to: Matteo Trimarchi, M.D., Department of Otorhinolaryngology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy E-mail: [email protected] Published online March 23, 2015 Copyright © 2015, OceanSide Publications, Inc., U.S.A.
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MATERIALS AND METHODS Patients
We conducted a prospective observational study between November 2012 and September 2013 at the Department of Otorhinolaryngology, Head and Neck Surgery of San Raffaele Scientific Institute, Milan, Italy. We performed endoscopic evaluation of the upper airways with NBI in four groups of patients: group 1 was composed of patients diagnosed with GPA referred by the Department of Medicine and Clinical Immunology, San Raffaele Scientific Institute, Milan, Italy; group 2 included patients with symptoms and signs suggestive of GPA, who were scheduled to undergo nasal biopsy to confirm diagnosis; group 3 included patients affected by chronic rhinosinusitis with nasal polyps (CRSwNP); and group 4 was composed of healthy controls. The study was conducted with the approval of the local ethics committee (Comitato Etico dell’Istituto Scientifico Ospedale San Raffaele) and complies with the Declaration of Helsinki. All the patients gave informed consent.
Endoscopy All the patients underwent transnasal endoscopy of the upper airways with a flexible video-endoscope (Exera II Cv-180, Olympus Medical Systems Corp, Tokyo, Japan). The examination was performed with both white and NBI lights by using a single switchable light source and one high-definition monitor. We examined nasal fossae, pharynx, larynx, and the upper tracheal segment, and focused our observation on mucosal and submucosal vascular patterns. All the videos were digitally stored. All the examinations were conducted by a senior otolaryngologist (M.T.) who identified NBI vascular alterations. The vascular abnormalities were subsequently classified according to their architectural pattern. Healthy mucosa was identified by the presence of a low-density homogenous vascular network in the absence of noticeable alterations, as similarly described in other studies that focused on the identification of cancerous lesions.11–17 We classified healthy vascular patterns, for the purposes of our study, as NBI negative (NBI–). Abnormal nasal mucosa was defined as nasal mucosa
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presenting evident alterations that substantially differed from a normal NBI pattern, as we had observed during preliminary clinical observations with NBI. Those areas presented increased vessel density, web-like vasculature, and vessels with hypertrophic morphology. We aimed at the identification of a clearly evident pattern during NBI endoscopic evaluation of patients with GPA that could possibly be related to known GPA alterations in histologic sections. Patients who presented such alterations were classified as NBI positive (NBI⫹).
Table 1. Patient demographics
Men Women Mean age, y Age range, y
Group 2: Suspect GPA
Group 3: CRSwNP
Group 4: Healthy subjects
8 6 51.9 31–72
2 7 48.9 31–69
13 8 55.6 41–73
15 10 46.7 20–90
Y P
CRSwNP ⫽ chronic rhinosinusitis with nasal polyps.
Statistical analysis The presence of NBI vascular alterations in patients in group 2 was matched with the final diagnosis in a cross tabulation. Next, we evaluated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NBI alterations in patients in group 2 with GPA, and calculated confidence intervals (CI). Because group 2 patients had undergone biopsy and histopathologic analysis of nasal mucosa, we also considered biopsy results with the final diagnosis of patients in group 2 in a cross tabulation. The diagnostic value of biopsy in group 2 patients with GPA was then evaluated by calculating biopsy sensitivity, specificity, PPV, NPV, and CI. We then performed the same analyses by considering separately NBI and biopsy results from group 1.
Table 2. Groups 1 and 2 clinical findings Group 1 (confirmed GPA)
RESULTS We enrolled 69 patients, 31 women and 38 men, with a mean age of 50.8 years (range, 20–90 years) who were divided among four groups. Key demographic characteristics of the groups are listed in Table 1. All the patients in group 1 had a previously confirmed diagnosis of GPA according to the European Medicines Agency algorithm,18 which includes American College of Rheumatology classification criteria,19 supported by either a positive antineutrophil cytoplasmic antibody (ANCA) assay,20,21 or a diagnostic biopsy. The main clinical features of the group 1 patients are showed in Table 2; no patient reported other significant comorbidities. Biopsy from the head and neck region was performed on nine patients in group 1. Histopathologic analysis of nasal mucosa biopsy was diagnostic for GPA in two of five patients, samples from tracheal stenosis yielded a diagnosis in one of two patients, one biopsy from the oropharynx was negative, and sampling from retro-orbital tissue in one patient was negative for GPA. Four patients reported previous renal biopsy, but only one sample was diagnostic. One patient underwent histopathologic analysis of a skin lesion of the foot, which was diagnostic for GPA. One patient underwent pulmonary lobectomy and histology confirmed GPA. At the time of endoscopy, the mean GPA Birmingham Vasculitis Activity Score22 was 3.9 (range, 1–7). Eleven patients were positive for cANCA, and two were positive for pANCA. Antiproteinase-3 antibodies were present in 10 cases; no patient presented antimyeloperoxidase antibodies. Group 2 patients were referred to our department for clinical signs and symptoms suggestive for GPA and underwent nasal biopsy to confirm the diagnosis as part of the EMEA GPA algorithm.18 The main clinical features of group 2 patients are reported in Table 1. No patient reported other significant comorbidities. Three patients showed cANCA positivity, and two showed pANCA positivity. Antiproteinase-3 and antimyeloperoxidase were elevated in three and one patients, respectively. Nasal biopsy, under local anesthesia, was performed in the operating room; three patients had histologic findings suggestive for GPA, which allowed for a final diagnosis of GPA. Another two patients from group 2 were diagnosed with GPA based on renal and pulmonary biopsy findings. The mean Birmingham Vasculitis Activity Score in this subset of patients was 2.7 (range, 1–9). NBI endoscopy was always performed within two months after nasal biopsy. No patient was evaluated in the immediate postoperative period.
O D
Group 1: GPA
Sinonasal involvement Saddle nose deformity Chronic otitis Subglottic stenosis Vocal cord palsy Ocular involvement Pulmonary involvement Renal involvement Neurologic symptoms Myalgia Skin lesions
O N
T
11 1 4 4 2 1
Group 2 (suspected GPA)
O C 8 8 3 2 1
9 1 1 2 0 0 3 3 0 0 0
Group 3 patients were all scheduled to undergo functional endoscopic sinus surgery for treatment of CRSwNP . Histopathologic analysis of all surgical specimens was then performed to confirm diagnosis. No patient in group 3 had relevant comorbidities or took any long-term systemic medication. Group 4 patients were healthy volunteers, and none was taking long-term medications. NBI endoscopy of the upper airways was well tolerated by all the patients, no adverse events occurred, and no patient needed local anesthesia or reported pain during or after the procedure. Upon NBI examination, the pharyngeal and laryngeal mucosa of all cases examined had an NBI– healthy vascular pattern (Fig. 1a). The same pattern was present when examining subglottic and tracheal stenosis (Fig. 1 b). Nasal mucosa endoscopic evaluation of healthy patients (group 4) was NBI– in all nasal anatomic regions in all 25 patients. Minor alterations of the normal nasal mucosa vascular pattern were present in seven healthy controls (group 4). In fact, we observed some areas with low-density pitting limited to middle or inferior turbinates (Fig. 1 c). These alterations did not appear to be related to those described in cancerous lesions11–17 and were not comparable with the patterns observed in patients with suspected or known GPA (groups 1 and 2). All healthy controls (group 4), therefore, were considered NBI–. We observed 11 NBI⫹ areas with vascular anomalies in nasal and sinonasal mucosa of 10 patients with GPA (Fig. 1 d–h), eight patients from group 1 (with known GPA) (58.3%), and two patients from group 2 (suspected GPA) (28.6%). In particular, the noted patterns were heterogeneous but obviously abnormal when compared with healthy controls. These macroscopic alterations did not involve the entire nasal mucosa but could be detected only in some areas. In addition, the anomalous patterns did not seem to be related and differed substantially from one patient to another. Nonetheless, the patterns were always clearly evident during NBI endoscopic evaluations and were never present in healthy patients (NBI–). We further cataloged the 11 previously identified areas of vascular abnormality in 3 different categories according to their macroscopic
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171
Table 3. NBI compared with final diagnosis of GPA (group 2)
NBI⫹ NBI⫺ Total
GPAⴙ
GPAⴚ
Total
2 3 5
0 4 4
2 7 9
Sensitivity 0.40, 95% CI (0 – 0.83); specificity 1.00, 95% CI (1); PPV 1.00, 95% CI (1); NPV 0.57, 95% CI (0.2– 0.94).
Y P
Table 4. Nasal mucosa histology compared with final diagnosis of GPA (group 2)
Biopsy⫹ Biopsy– Total
GPAⴙ
GPA–
Total
3 2 5
0 4 4
3 6 9
O C
Sensitivity 0.60, 95% CI (0.17–1); specificity 1.00, 95% CI (1); PPV 1.00, 95% CI (1); NPV 0.67, 95% CI (0.29 –1).
Figure 1. (a) NBI– endoscopic image of left middle turbinate of a healthy patient (group 4). (b) NBI– image of subglottic stenosis from a group 2 patient (suspected for GPA) who was eventually diagnosed with GPA. (c) NBI– endoscopic image of the left inferior turbinate from a healthy patient (group 4). (d) NBI⫹ endoscopic image from a group 2 patient (suspected for GPA), showing a “vascular islands” pattern on the right middle turbinate. (e) NBI⫹ endoscopic image from group 1 (patients with GPA), showing a high-density, nonhomogeneous vascular network (“web pattern”) on the left middle turbinate. (f) NBI endoscopic image from group 1 (patients with GPA), showing a rosary beads vascular network on the left middle turbinate. (g) NBI⫹ endoscopic image from group 1 (patient with GPA), showing hypertrophic vessels on the nasal floor and septum. (h) NBI⫹ endoscopic image from group 1 (patients with GPA), showing tree-like vessels. (i) NBI– endoscopic image of a polyp in the left middle meatus from group 3 (patient with chronic rhinosinusitis with nasal polyps).
172
NBI⫹ NBI– Total
T
O N
pattern appearance: vascular islands pattern, web pattern, and hypertrophic vessels pattern. The vascular islands pattern was visible in two areas on the anterior surface of middle turbinate and showed a grouped organization (Fig. 1 d). The web pattern could be observed in 4 areas on the anterior surface of the middle turbinates and was characterized by a highdensity nonhomogeneous network (Fig. 1 e). One of the areas that showed a web pattern presented a higher-density vascular network on the middle turbinate that was more homogeneous and organized, with irregular thin vessels, which resembled rosary beads (Fig. 1 f). Grossly hypertrophic vessels whose diameter was, in some cases, wider than 1 mm were identified in five other patients (Fig. 1 g). In one of those patients, the hypertrophic vessels had a tree-like organization (Fig. 1 h). Patients with CRSwNP (group 3) showed a vascular pattern somewhat similar to a normal healthy pattern. The only difference was that nasal polyps had a more sparse vascular pattern due to reduced vascularization (Fig. 1 i). At any rate, we considered group 3 mucosal patterns as NBI–. Histologic examinations of head and neck region biopsy specimens were available for nine patients with a past diagnosis of GPA (group 1) and was diagnostic in only three patients (33.3%). In patients with suspected GPA (group 2), histologic examination was obtained from the nasal mucosa of all patients and was diagnostic for GPA in three patients (33.3%). A final diagnosis of GPA was obtained in two other patients from group 2, despite nonconclusive histology, because they met other EMEA classification criteria.
O D
Table 5. NBI compared with final diagnosis of GPA (group 1) GPAⴙ
GPA–
Total
8 6 14
0 0 0
8 6 14
Sensitivity 0.57, 95% CI (0.3– 0.75).
Table 6. Head & Neck histology compared with final diagnosis of GPA (group 1)
Biopsy⫹ Biopsy⫺ Total
GPAⴙ
GPAⴚ
Total
3 6 9
0 0 0
3 6 9
95% CI Sensitivity
0.33
(0.17–0.69)
The results of NBI examination and histopathologic analysis in patients with suspected GPA (group 2) are summarized in Tables 3 and 4, respectively, and show the final diagnosis (GPA⫹ or –). Data were organized in a cross tabulation, and we calculated the sensitivity, specificity, PPV, NPV, and CI of both NBI evaluation and histopathologic analysis (Tables 3 and 4). Data from group 1 were similarly analyzed, and we compared results from NBI examination and histopathologic analysis with patients’ final diagnosis. Data cross tabulation, sensitivity, PPV, NPV, and CI are shown in Tables 5 and 6.
DISCUSSION NBI⫹ patterns could be recognized in 53% of patients with confirmed GPA from groups 1 and 2, and presented evident macroscopic differences among themselves as described in the Results section. We acknowledge that the presence of hypertrophic vessels in healthy controls could make the identification of an NBI⫹ “hypertrophic vessels pattern” not as clear cut and possibly less predictive than the other patterns. However, we did not have particular difficulties in discriminating a few isolated hypertrophic vessels in healthy subjects from the more diffuse and numerous hypertrophic vessels of patients with GPA (Fig. 1). Also, none of the other pattern features could be seen in the healthy controls. We could not see any clear correlation between NBI⫹ patterns and the known histologic characteristics of GPA; this is why we correlated
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NBI results with the final GPA diagnosis and not only with biopsy results. However, in both groups 1 and 2, nasal biopsy and NBI results were, for the most part, comparable, except for three patients. One patient from group 1 and one from group 2 had a GPA⫹ nasal biopsy but a completely normal vascular pattern on NBI examination. In the first patient, NBI examination was performed five years after biopsy, and, during that period of time, the patient had been administered immunosuppressive treatment. The time elapsed between biopsy and NBI examination, along with the immunosuppressive therapy, could justify the normalization of the vascular architecture. However, this assumption is not valid for the second patient because biopsy and NBI were performed within a short period. Another patient from group 1 had a negative nasal histology but an NBI⫹ pattern, despite eight years under treatment between biopsy and NBI examination. We cannot rule out that patients with NBI⫹ patterns could present with nondiagnostic nasal mucosa biopsies because many definite histopathologic alterations are needed to precisely diagnose GPA.23–27 As a consequence, NBI could highlight evident (NBI⫹) vascular alterations even in the absence of the complete set of GPA histopathologic characteristics. Our observations on NBI patterns in group 1 could be biased because the examiner knew the final diagnosis of GPA of the patients. Nonetheless, group 2 yielded similar NBI examination results, and patients had not yet received a definitive diagnosis. Few researchers have thus far discussed the diagnostic power of nasal biopsy, whose sensitivity ranges between 21% and 70%.23–26 In our cohort of patients tested for suspected GPA (group 2), biopsy sensitivity was 60% and specificity was 100%. Even though we tested a small number of patients, our results were similar to those reported in other studies on nasal biopsy.23–26 However, not all patients with a known diagnosis of GPA (group 1) underwent biopsy sampling from nasal mucosa, but, also, other regions of the head and neck were sampled. We did not exclude these patients because we aimed at evaluating NBI nasal endoscopy in a similar diagnostic setting as the biopsy, which is often performed in different sites from where the disease is clinically evident in the head and neck region. All patients with GPA (from groups 1 and 2) had a clinical diagnosis of GPA according to the EMEA algorithm,18 supported by either a positive ANCA assay20,21 or a diagnostic biopsy. The algorithm was used to identify patients with a positive diagnosis of vasculitis and to classify them as patients with GPA. Even though the EMEA algorithm offers a high degree of interclassifier reliability, it is not 100% reliable.18 As a consequence, sensitivity and specificity of our NBI evaluation calculated in comparison with our GPA diagnosis can potentially be inaccurate. Overall, we noted that, in our prospective cohort, NBI nasal endoscopy and nasal biopsy results, for the most part, were comparable and offered diagnostic sensitivity and specificity similar to histology. Nevertheless, those observations cannot be generalized and need additional validation with a clinical study on a larger population. Further studies on NBI patterns and related biopsies could also help to elucidate possible relationships between histology and NBI patterns. Analysis of our results, however, suggest that NBI⫹ patterns may not be strictly related to a biopsy diagnostic for GPA. NBI is currently used in the endoscopic diagnosis of various oncologic and benign mucosal conditions, and it is primarily used in many European and Japanese ear, nose, and throat departments to identify head and neck cancerous and precancerous lesions.11–17 Contextual use of NBI during endoscopic evaluation of patients with GPA allows real-time evaluation of mucosal and submucosal vascularization, and requires a little extra time to be performed. In conclusion, nasal mucosa NBI endoscopy can be considered a promising rapid and noninvasive technique for the individuation of possibly GPA-related vascular alterations that, based on further prospective blinded studies, could become a supplementary diagnostic tool in the complex workup of GPA.
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