A, Intraoperative endoscopic view of the glottis and the corresponding optical coherence tomographic (OCT) cross-section acquired from the midmembranous part of the left vocal fold of a healthy 3-year-old boy. The optical contrast delineates the stratified squamous epithelium (SsE) and the pseudostratified ciliated epithelium (PcE). The demarcation with the underlying lamina propria (Lp) is clearly visible, which highlights the basement membrane (Bm). The Lp is smooth and uniform within the true vocal fold in opposition to the subglottis, where mucous glands (Mg) are found. B, RRP exophytic epithelial lesions on both vocal folds in a 4-year-old boy. The OCT cross-section shows epithelial hyperplasia (EH) and a compressed lamina propria. V indicates ventricle; Vm, vocalis muscle. Scale bar indicates 500 μm.
Endoscopic views of the glottis obtained before (A), during (B), and after (C) laser therapy (arrowheads indicate the papilloma lesion; dashed lines, the optical coherence tomographic [OCT] cross-section). The OCT cross-section showing epithelial hyperplasia thickness before (D), during (E), and after laser therapy (F) (arrowheads indicate the vessel wall lesion; dashed lines, epithelial layer thickened; asterisk, an oval hypolucent shape consistent with the appearance of a blood vessel). Scale bars indicate 500 μm.
The intensity profile was plotted as a logarithm scale of the optical coherence tomographic (OCT) signal for the vessel wall region (arrowheads in Figure 2D-F). Dashed lines show the blood vessel outside diameter wall acquired before (A), during (B), and after therapy (C). After 30 potassium pitanyl phosphate laser (KTPL) pulses, the region representing the vessel wall seemed to expand in diameter, possibly because of a disruption of the vessel wall. The postoperative OCT acquisition profile shows a shift of 861 μm of the region interest.
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Benboujja F, Bowe S, Boudoux C, Hartnick C. Utility of Optical Coherence Tomography for Guiding Laser Therapy Among Patients With Recurrent Respiratory Papillomatosis. JAMA Otolaryngol Head Neck Surg. 2018;144(9):831–837. doi:10.1001/jamaoto.2018.1375
Could optical coherence tomography provide imaging guidance during laser therapy of recurrent respiratory papillomatosis?
In this in vivo study, optical coherence tomography was performed for 10 pediatric patients before, during, and after laser therapy; images revealed clear lesion margins and different degrees of epithelial hyperplasia and subepithelial changes in all patients. Images acquired during therapy indicated coagulation deep in the tissue, and posttherapy images showed the ability to quantify the amount of tissue ablated by the photoangiolytic laser.
Optical coherence tomography guidance of recurrent respiratory papillomatosis treatments may lead to greater debulking with maximum preservation of healthy and functional laryngeal anatomy.
Recurrent respiratory papillomatosis (RRP) is a viral-induced disease caused by human papillomavirus and the second leading cause of dysphonia in children; however, neither a cure nor a definitive surgical treatment is currently available for RRP. Although laser therapy is often used in the treatment of RRP, the lack of real-time laser-tissue interaction feedback undermines the ability of physicians to provide treatments with low morbidity. Therefore, an intraoperative tool to monitor and control laser treatment depth is needed.
To investigate the potential of combining optical coherence tomography (OCT) with laser therapy for patient-tailored laryngeal RRP treatments.
Design, Setting, and Participants
This in vivo study was performed at the Massachusetts Eye and Ear Infirmary from February 1, 2017, to September 1, 2017. Three-dimensional OCT images were acquired before, during, and after photoangiolytic laser therapy in 10 pediatric patients with a history of papilloma growth who presented with lesions and hoarseness.
Main Outcomes and Measures
Whether intraoperative OCT monitoring of changes in optical scattering and absorption provides quantitative information to control thermal damage in tissue.
Among the 10 pediatric patients (age range, 4-11 years; 6 male) included in the study, high-resolution OCT images revealed epithelial hyperplasia with clear RRP lesion margins. Images acquired during therapy indicated coagulation deep in tissue, and posttherapy images showed the ability to quantify the amount of tissue ablated by the photoangiolytic laser.
Conclusions and Relevance
Concurrent use of OCT imaging and laser therapy may improve postoperative outcomes for patients with RRP by delivering an optimal, patient-tailored treatment. Additional studies investigating the correlation between optical properties with vocal outcomes are required.
Recurrent respiratory papillomatosis (RRP) is a viral-induced disease caused by human papillomavirus types 6 and 111 that affects the coordination of critical physiologic functions, such as speech, deglutition, and respiration. It is the most common benign neoplasm of the larynx and the second cause of hoarseness in children.2 The incidence in the United States is 4.3 cases per 100 000 population, with approximately 10 000 surgical procedures per year.3
Recurrent respiratory papillomatosis lesions are characterized by persistent and recurrent exophytic fibrovascular growth of the upper airway with the potential to spread throughout the respiratory tract. The lesions typically develop at the laryngeal junction of squamous and respiratory epithelium,4 which includes the laryngeal surface of the epiglottis, the upper and lower margins of the ventricle, and the undersurface of the true vocal folds.4 The predilection of papilloma lesions for these sites affects the vibratory function of the vocal fold, restricts the airflow, and can be life-threatening when not treated early. In addition to airway concerns, RRP involvement in the anterior commissure is particularly difficult to eradicate. Because aggressive treatments must be avoided to prevent subsequent scarring and potential anterior glottic web formation, RRP lesions on the anterior commissure often require procedures to be staged, resulting in more frequent trips to the operating room. Therefore, RRP on the true vocal folds is associated with high morbidity regarding voice quality, which drastically interferes with social functioning and academic performance.5
Although RRP can occur in pediatric and adult populations, the pediatric form is the most aggressive subtype. Pediatric patients may undergo multiple operations per month and, in some cases, more than 100 procedures in a lifetime.6 Historically, in the 1980s and 1990s, the primary treatment for juvenile-onset RRP was surgical ablation with a carbon dioxide laser. Carbon dioxide lasers coupled with an operating microscope allow precise vaporization of the papilloma with minimal bleeding.7 The laser’s 10.6-μm wavelength is absorbed by water molecules in biological tissue, which improves coagulation and provides blood-free procedures, a better visualization, less scarring, and faster recovery. Although carbon dioxide lasers offer technical advantages over cold surgical instruments,8-12 they also cause collateral damage to the surrounding healthy laryngeal structures, often leading to clinical complications, such as tissue necrosis, anterior commissure web formation, and scarring of the superficial lamina propria, all of which affect voice preservation.13,14
A recent addition to surgical treatments for RRP is the introduction of angiolytic lasers: a 585-nm pulse dye laser (PDL) and a 532-nm pulsed potassium pitanyl phosphate laser (KTPL). Both lasers are safe and effective for the treatment of benign tumors in adults and children.15-18 The flexibility offered by fiber-based photoangiolytic lasers allows reaching airway lesions more quickly and efficiently. Although KTPLs and PDLs exploit peaks in the absorption spectrum of the oxyhemoglobin, 541 and 571 nm, the KTPL is a better match to the absorbance peak of the oxyhemoglobin, showing stronger absorption by red blood cells. The theory behind the use of such angiolytic lasers is to reduce the progression of the disease by selectively and safely destroying the subepithelial microvasculature, directly affecting the blood supply of RRP lesions while preserving important underlying laryngeal structures for greater functional outcomes. Furthermore, in opposition to the continuous lasers, the pulse delivery of angiolytic lasers (KTPL at 15 milliseconds and PDL at 0.45 milliseconds) allows limiting heat diffusion to surrounding tissue, potentially restricting tissue trauma within a target region.
The main drawback with surgical laser procedures is the lack of quantitative metrics evaluating the tissue response to the energy delivered. There is no real-time laser-tissue interaction feedback, but there are several factors that influence the heat delivery: the laser wavelength, the exposure time, the power density, and the absorption coefficient of the tissue.19 All these factors can play a significant role in the treatment outcome. Even the lesion microvasculature (vessel wall rupture) can be a factor. As such, without a proper assessment of the subepithelial structures, it is impossible to find a balance between treatment efficacy and the amount of thermal damage. Because RRP lesions are often heterogeneous and spatially nonuniform, monitoring and controlling laser therapy depth would ensure that treatments are tailored to each lesion with minimal collateral damage to surrounding tissue. Preserving the underlying normal anatomy, both in the treatment of laryngeal papilloma and, theoretically, with regard to treatment of laryngeal dysplasia and carcinoma, would constitute a critical step forward.
Optical imaging of the larynx, specifically with optical coherence tomography (OCT), has been used to evaluate noninvasively the adult and pediatric laryngeal anatomy.12-18 Although OCT can reliably assess laryngeal microstructures beyond the basement membrane,20 it still remains a screening tool, considerably limiting its use in a surgical setting. The aims of this study were to characterize the optical contrast observed in RRP lesions with OCT and investigate its potential for laser therapy assistance. To our knowledge, this study reflects the first attempt to use OCT to control collateral damages induced by photoangiolytic lasers for a pediatric population with laryngeal RRP.
Ten pediatric patients with a history of papilloma growth who presented with lesions and hoarseness underwent OCT before, during, and after laser therapy. Patients had mild to moderate signs of infection, with lesions mostly on the true and false vocal folds. All patients who underwent imaging in this pilot study had been previously treated with KTPLs and had a confirmed diagnosis of RRP based on a previous histopathologic evaluation with no evidence of malignant lesions. Parents were informed, and written informed consent was obtained before surgery. Patients were discharged the same day. As a comparative baseline, 20 OCT images of healthy pediatric laryngeal tracts obtained from a previous study21 were used. The procedures were performed at the Massachusetts Eye and Ear Infirmary from February 1, 2017, to September 1, 2017, under the approval of the Massachusetts Eye and Ear Infirmary Institutional Review Board.
The OCT system is based on vertical-cavity surface emitting lasers22,23 with a center wavelength of 1300 nm, a tuning range of 110 nm (at full width at half maximum), and an acquisition speed of 100 kHz (ie, the number of OCT lines per second). The intraoperative OCT endoscope used in this study was previously described21,24; it was designed for rapid volumetric imaging of the airway. The rigid probe outer diameter is 3.6 mm and is sufficiently small and ergonomic to allow accurate positioning of its tip on the RRP lesion. A translucent disposable sterile sheath (0.2-mm thickness; Slide-ON Endosheath, Medtronic) encloses the OCT probe before each acquisition. The side-viewing window can be rotated rapidly to image lesions in the anterior commissure. The output power at the tip of the endoscope is 4.6 mW, which provides a sufficient penetration depth to assess lesion margins within the vocal mucosa. The 2 fast galvanometers (6215H, Cambridge Technology) inside the handheld unit allow real-time scanning of the airway. The field of view is 2 mm. Depending on the age group, the field of view is extended between 5 and 10 mm with a lateral sweep (pullback) to capture images of the surrounding aerodigestive tract. The spatial axial and lateral resolutions of the system in tissue are 12 and 25 μm, respectively. A 3-dimensional high-resolution examination of the tissue is accomplished within 18 seconds (2, 2, and 5 mm, 1040 × 1040 × 1040 voxels) and saved to the hard disk for postprocessing analysis (lesion segmentation).
For therapy, a commercial, 532-nm pulsed KTPL (Aura XP, Boston Scientific) was used in this study to treat RRP lesions. The output power of the KTPL is 35 W, with a 15-millisecond pulse train duration at 3 repetitions per second, which delivers approximately 545 mJ of energy per pulse. The number of pulses delivered was proportional to the size of the lesion, ranging from 30 to 75 pulses.25 The Table gives the imaging and treatment technical specifications used in this study.
With spontaneous ventilation and while under general anesthesia, patients underwent suspension with a Lindholm laryngoscope for direct laryngoscopy and bronchoscopy (Karl Storz Endoscopy). The handheld OCT probe tip was precisely positioned on the lesion. The real-time OCT acquisitions of the surrounding tissue also helped identify the region of interest. A full sweep of the aerodigestive tract was acquired by slowly pulling the probe back superiorly from the subglottic region. Three-dimensional acquisitions of the mucosa pathologic state were captured before, during, and after laser therapy. Imaging and therapy were performed sequentially. Each step required repositioning the OCT handheld probe tip for imaging lesions. Clinical images obtained with endoscopy were correlated with OCT images for comparison.
This study evaluated 10 patients (age range, 4-11 years; 6 male) before, during, and after laser therapy using OCT. All patients successfully underwent imaging with the OCT handheld endoscope without any complications. A typical representation of a normal aerodigestive tract of a 3-year-old boy is shown in Figure 1A. The OCT cross-section was acquired along the coronal plane of the midmembranous part of the true vocal fold. With a single OCT sweep (10-mm long and 2.5-mm deep), the subglottic and the glottis mucosal layered microstructures were visible. At the surface, the first thin layer of the cross-section was composed of epithelial cells. On the basis of the thickness of this layer, the nonkeratinized stratified squamous epithelium (65-110 μm) located in the true vocal fold was further distinguished from the pseudostratified ciliated epithelium (85-160 μm) located in the subglottic region of the aerodigestive tract. The basement membrane and the lamina propria were visible beneath the epithelium. Along the aerodigestive tract, the lamina propria was mostly hyperlucent (highly scattering). The superficial part of the lamina propria was water rich and composed of glycoproteins, mucopolysaccharides, and highly spaced collagen fibers,26 which is consistent with an increase in backscattering light in this region. In the subglottic region, hypolucent (weakly scattering) bands were visible, representing seromucinous glands. These salivary glands protect the airway from pathogen invasion while maintaining lubrication for optimal biomechanics conditions.27 In opposition to the subglottic region, the lamina propria of the normal true vocal fold is relatively smooth and homogeneous, devoid of any glands. However, the intensity level varied slightly along the length and depth of the true vocal fold. It is hypothesized that this could be an indicator of the variation of elastin (hypolucent) and collagen (hyperlucent) fibers in the extracellular matrix as reported in previous histologic studies.28,29 Finally, the OCT signal decayed inside the lamina propria until it reached the thyroarytenoid muscle (vocalis muscle).
Figure 1B shows the intraoperative view of a 4-year-old boy with recurrent respiratory papillomatosis. The vocal folds were infected with papilloma growth appearing as a pink- and white-colored lesion. The corresponding OCT cross-section acquired before KTPL therapy revealed a different microstructure compared with normal tissue (Figure 1A). For instance, there was a significant irregular increase in epithelial thickness up to 500-μm thicker than in a normal aerodigestive tract. This finding is consistent with epithelial hyperplasia seen in papilloma lesions. Furthermore, the lamina propria seemed heterogeneous and compressed with some invaginations. Although the contrast between structures was evident, blood vessels and collagen density at the lesion site reduced the overall backscattering signal. However, the basement membrane, which is the transition between the epithelial and lamina propria layer, was distinguishable and had morphologic features along the aerodigestive tract. All patients seen in this study had a basement membrane boundary. This feature is a critical landmark because previous studies20,30 have found evidence that basement membrane disruption could be a sign of early microinvasive squamous cell carcinoma.
Figure 2 shows intraoperative endoscopic views of the glottis of a 5-year-old girl infected with laryngeal human papillomavirus. The preoperative endoscopic acquisition (Figure 2A) showed exophytic epithelial lesions characterized by multiple red dots (superficial blood vessels) in the anterior commissure. The laser directed on the lesion induced thermal damage to the tissue. Structural alterations were visible halfway (Figure 2B) and after therapy (Figure 2C). These white blanching marks on the lesion showed the coagulation of the microvascularization. The burning scars (darker regions) were partially visible halfway during the procedure after 30 KTPL pulses (Figure 2B) and clearly discernable after 75 KTPL pulses (Figure 2C) at the end of therapy.
These endoscopic images highlight the critical problem of laser therapy without depth guidance. Even when a lesion is spatially confined (Figure 2A), it is challenging with endoscopy and current KTPLs to restrict thermal damages to the lesion site only. As shown in Figure 2C, the tissue scars are not uniformly and solely distributed across the lesion. Furthermore, with endoscopic images alone, assessing how much of the lesion was ablated is a difficult task.
The OCT cross-sections acquired for the 5-year-old girl allow evaluation of the thickness of the epithelium and morphologic features of the subepithelial structures. The preoperative OCT acquisition (Figure 2D) revealed an oval hypolucent shape. This structural feature is consistent with the OCT appearance of a blood vessel, an observation confirmed in other cases by histopathologic analysis.20,31 The denaturation of the surrounding structural proteins and the disruption of the vessel wall could explain the wider appearance of the blood vessel after laser exposition (Figure 2E and F). The OCTs obtained during and after laser therapy showed the epithelial hyperplasia thickness (Figure 2E and F). As the laser exposition increased, the epithelial layer thickness decreased. However, more than 30 KTPL pulses were necessary to see a significant reduction of the epithelial hyperplasia thickening.
Figure 3 shows the OCT intensity profile as a function of depth in the region of interest at each stage of the procedure. The intensity profile provided by averaging lateral adjacent A-lines (20 × 20, 125 × 125 μm) under the region of interest highlights quantitative changes generated by therapy.
Coagulation is visible and highlighted by an increase in the backscattering light. The normalized profile in Figure 3B shows a 20% intensity increase in the superficial region of the tissue after 30 KTPL pulses. Compared with prior laser therapy, the change in the signature profile (Figure 3B) suggests that coagulation occurred deeper inside the tissue up to 800 μm. Furthermore, the center of the region of interest (Figure 3C), which was consistent with a blood vessel description, was shifted by 860 μm toward the surface, confirming the ablation of approximately 700 μm of hyperplastic epithelial cells. Finally, the more energy deposited into the tissue, the higher the rate at which the signal decayed. This apparent change in the slope of the intensity profile (ie, relative coefficient of attenuation) suggests that the biological tissue properties changed.
No cure or current criterion standard treatment is available for RRP. This viral-induced neoplasm recurs despite all current therapies. Therefore, treatments focus on preserving the normal anatomy and debulk to the greatest extent possible for a safe airway with no to minimal postoperative complications. Surgical procedures to treat benign tumors on the true vocal folds and on the anterior commissure need special care because of respiration and phonation. Recently, photoangiolytic lasers, such as the PDL and the KTPL, have been reported to effectively target the microvasculature of the layered laryngeal mucosa, destroying blood supply to RRP lesions while preserving the laryngeal structures.15-18 Despite the benefits of laser surgery, without the ability to visualize subepithelial tissue-laser interactions, it becomes challenging to predict functional and oncologic outcomes. Therefore, we investigated the potential of OCT as a perioperative noninvasive imaging modality to assist RRP lesion treatments.
Optical coherence tomography is a noninvasive optical imaging technique that has been used in vivo in adults and children to evaluate vocal disease.12,13,15,18-20 Other forms of noninvasive imaging have been used to demonstrate the translaryngeal spread of RRP that may not be easily discernible by the naked eye,21 but currently no modality accurately and noninvasively measures the invasion depth in an instrument that might then be coupled with a therapeutic modality. Optical coherence tomography is most often encountered as a diagnostic imaging tool in the operative setting for anesthetized patients not a therapeutic modality.
This article reports the ability of OCT to monitor accurately RRP depth invasion and laser-tissue interaction. Among the 10 patients who underwent imaging, a subset of typical observations was presented. All patients had similar features with different degrees of epithelial hyperplasia and subepithelial changes. After a few KTPL pulses, all lesions responded with a reduction of the epithelial hyperplasia thickening and an increase in the backscattering signal, which highlight tissue ablation efficiency.
Although this study illustrates the feasibility and the relevance of using OCT to decrease the morbidity associated with current RRP treatments, several significant weaknesses remain. The probe size restrains access to small lesions on the anterior commissure, suggesting that a smaller probe may be more suitable. Furthermore, the lesion size and its location affect the image contrast. The 90°-angled rigid handheld scope allows for optimal viewing of the glottis and infraglottic space because the probe tip can be easily aligned with the leading edge of the vocal fold. However, some lesions on the lower margins of the ventricle and on the anterior commissure are difficult to image. A forward-viewing probe with a piezoelectric scan pattern would alleviate this difficulty.
Although OCT can reliably assess lesion invasion beyond the basement membrane, it remains a screening tool currently uncoupled with a therapeutic laser. Without concurrent imaging, the OCT endoscope has to be removed before using the therapeutic laser so that an educated guess is performed without exploiting imaging results to refine the treatment. The use of double-clad fiber could be a solution for multiplexing both light sources in a single fiber. This configuration would provide robust coregistration and minimize the size of the setup. Because both modalities would be combined into a single fiber, coregistration is intrinsic and insensitive to potential misalignment of optical components. Therefore, such a system would shorten the procedure, provide real-time feedback, and allow further studies to investigate vocal outcomes with OCT guidance.
Another weakness of the OCT system is the rigid contact probe not being compatible with transnasal office-based procedures. Our next challenge consists of developing a flexible probe, such as the ones used for cardiology32 and gastroenterology,33 with a double-clad fiber to allow therapy for office-based procedures. Another limitation is the relatively shallow penetration depth (2.5 mm) of OCT. However, RRP lesions occur within the 2 mm inside the mucosa, which is sufficient to expose important pathologic morphologic features.
Our findings suggest that real-time in vivo OCT guidance of RRP treatments may lead to greater debulking with maximum preservation of healthy and functional laryngeal anatomy. A quantitative approach to current laser therapies may further enable effective and repetitive results. However, additional studies are required to correlate optical properties with vocal outcomes, such as acoustic and aerodynamic properties.
Accepted for Publication: May 1, 2018.
Corresponding Author: Christopher Hartnick, MD, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles St, Boston, MA 02114 (firstname.lastname@example.org).
Published Online: August 9, 2018. doi:10.1001/jamaoto.2018.1375
Author Contributions: Drs Benboujja and Hartnick had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Benboujja, Boudoux, Hartnick.
Acquisition, analysis, or interpretation of data: Benboujja, Bowe, Boudoux.
Drafting of the manuscript: Benboujja.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Benboujja, Hartnick.
Administrative, technical, or material support: Bowe, Boudoux.
Supervision: Boudoux, Hartnick.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
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