4.1.

Overview of TPO

TPO, also known in the literature as tracheobronchopathica osteochondroplastica and tracheopathica osteoplastica, is a rare nonmalignant disorder of the large airways characterized by multiple dense nodules localized in the submucosa of the tracheobronchial wall.¹ TPO is a slowly progressive disease of adulthood with a mean time from presentation to diagnosis of approximately four years, but its true incidence is unknown. TPO is usually detected incidentally upon intubation or when tomographic, magnetic resonance or bronchoscopic imaging is performed for airway symptoms or for unrelated conditions.^{2, 3, 4}

Although TPO may involve the larynx, the disease is usually limited to the large central airways and does not involve the lung parenchyma or other organs. Mucosal changes, impaired ciliary clearance of secretions, and enlarged submucosal nodules may lead to recurrent inflammation, infection, and central airway obstruction. Cough, hoarseness, hemoptysis, exertional dyspnea, wheezing, and recurrent lower airway infections are usual symptoms. Stridor and rhonchi are present in advanced obstructive cases, which can lead to respiratory failure.¹

The differential diagnosis for TPO includes nonmalignant processes, such as relapsing polychondritis, ulcerative colitis, amyloidosis, sarcoidosis, papillomatosis, and saber sheath trachea, but airway neoplasms must also be excluded.^{5, 6} The disease is usually distinguishable from other disorders, however, because it does not involve the posterior membranous portion of the trachea. Bronchoscopy is often considered to be pathognomonic when it reveals focal or diffuse raised, firm nodules overlying the cartilaginous rings. Biopsies are often difficult because of the bony nature of the nodules.^{7, 8}

Histopathologic studies suggest that bone morphogenetic protein 2 acts synergistically with transforming growth factor $\beta 1$ , in the promotion of nodule formation within the tracheal submucosa.⁸ Nodules are actually calcifications, chondrifications, or ossifications of the upper layer of the mucous membrane. These abnormalities may have foci of bone marrow with active areas of hemopoiesis. Ossifications are lamellar-type bone covered by normal mucosa or squamous metaplasia that may connect by bone, cartilage, or connective tissue to the perichondrium of the tracheal rings.⁸ Although there is no obvious relationship with malignancy, a large case series from Japan showed that 24 (19%) of 126 patients had associated cancers, especially bronchogenic adenocarcinoma.⁹ For this reason, bronchoscopic biopsies are usually performed even when TPO is the likely diagnosis.

4.2.

Multimodality Imaging Clinical Applications

The future of multimodality bronchoscopic imaging resides on the premise that by combining appropriate resolutions and depth of penetrations of diverse technologies, characterization and diagnosis of benign, premalignant, and neoplastic abnormalities might be enhanced. Conventional white-light bronchoscopy is a sensitive, but usually nonspecific means with which to identify, locate, and biopsy gross airway mucosal abnormalities in up to fifth-generation segmental bronchi. It provides forward and angled surface visualization with a large field of view and depth of focus but does not allow cross-sectional imaging of bronchial and peribronchial tissues. Endobronchial ultrasound, on the other hand, which allows cross-sectional imaging of soft tissues, has been used to accurately measure depth of bronchial tumor invasion beyond the cartilaginous layers and allows identification of structural layers of the airway wall.¹⁰

Ultrasound is, however, limited in spatial resolution to approximately $50–200\mu \mathrm{m}$ due to long acoustic wavelengths. The standard frequency for radial probe endobronchial ultrasound (EBUS) is $20\mathrm{MHz}$ , which allows for a resolution of $<1\mathrm{mm}$ , but with a depth of penetration of approximately $4–5\mathrm{cm}$ , allows for visualization of mediastinal structures, bronchial wall layers, and peribronchial lymphadenopathy or great vessels.^{10, 11} The conventional convex EBUS bronchoscope probe such as that used in this study has a frequency of only $7.5\mathrm{MHz}$ , allows for deeper penetration but with corresponding loss of resolution. Cartilaginous layers may be difficult to visualize but airway wall thickness can be measured in vivo. In fact, EBUS has been used to distinguish central airway wall structural abnormalities in patients with benign airway disorders, such as malacia caused by tuberculosis, relapsing polychondritis, and extrinsic compression by vascular rings,^{12, 13, 14} identify structural differences in the membranous and cartilaginous portions of the central airways in patients with expiratory central airway collapse,¹⁵ and potentially determine depth of endobronchial tumor invasion¹⁶ which might help guide indications for open or bronchoscopic resection.

OCT is analogous to ultrasound B mode imaging, except that instead of using acoustic waves, it uses near-infrared light to measure reflected or backscattered light to produce high-resolution tomographic pictures. Using contact or noncontact probes, high-resolution OCT, such as that used in this study, is capable of up to two orders of magnitude greater resolution $(2–10\mu \mathrm{m})$ than ultrasound at depths of up to $\sim 2\mathrm{mm}$ in optically scattering tissues.¹⁷ The depth range of OCT is therefore sufficient to penetrate through the upper layers of exposed tissues on airway surfaces, where many airway neoplasms or other airway pathology may present, and is equivalent to the tissue sampling depth of conventional endobronchial forceps.¹⁸

Clinical OCT systems consist of an imaging console and a detachable, flexible fiberoptic probe. Endoscopic OCT probes include an optical fiber with a compact scanner and are categorized into two-/three-dimensional imaging, side/front imaging, or outside/inside actuation depending on whether the scanner is outside the human body or located within the distal tip of the probe. To our knowledge, the smallest currently available probes can have a diameter of $\sim 400\mu \mathrm{m}$ (three-dimensional imaging, side imaging, and outside actuation).

In this study, we used a commercially available, compact time-domain OCT system (Niris System, Imalux Corp., Cleveland, Ohio) with a magnetically actuating probe (two-dimensional, front imaging, and inside actuation). The depth resolution is governed by the superluminescent laser diode bandwidth produced, and the $\sim 15\text{-}\mu \mathrm{m}$ resolution is enough to differentiate tissue layers using the endogenous contrast properties of the tissues. The lateral resolution is $25\mu \mathrm{m}$ with an imaging depth of $2.2\mathrm{mm}$ (in air). The probe, although small enough to access the human trachea and main carina, is too large to fit through the $2\text{-}\mathrm{mm}$ working channel of a conventional flexible bronchoscope. Further reduction in probe diameter, however, may result in reduced lateral resolution. Because of the front-imaging feature, the lateral scanning range is, in fact, limited to $2\mathrm{mm}$ in the contact mode (where the focus is optimal and distance can be controlled) and probe positioning is difficult for visualizing the tracheal wall, though very straightforward for the main carina and other large-airway branching areas. The magnetic actuation method is capable of one-dimensional scanning only so that a three-dimensional tomographic image cannot be constructed. Although the magnetic actuation method, quick-connection/release mechanism, and waterproof design of the probe are unique, the Niris System utilizes time-domain technology, which limits A-scan rate capabilities compared to its Fourier-domain counterpart.

The comparison to advanced OCT systems in the literature is given in Table 1 . Unidirectional sweep rates of $370\mathrm{kHz}$ over a $100\text{-}\mathrm{nm}$ range at a center wavelength of $1300\mathrm{nm}$ can be achieved using Fourier-domain mode lock laser,¹⁹ and high-speed, Fourier-domain OCT have demonstrated speeds of up to $370\mathrm{kHz}$ A-scan rate. Spatially encoded Fourier-domain technology using a high-speed camera has been reported.²⁰ This technology utilized a superluminescent diode with an $873\mathrm{nm}$ of center wavelength and a $144\text{-}\mathrm{nm}$ full-width-at-half-maximum bandwidth or a femtosecond titanium sapphire laser. A-scan rate was $100\mathrm{kHz}$ , and depth resolution was $2.5–3.0\mu \mathrm{m}$ in air. A wavelength swept laser with a $115\mathrm{kHz}$ repetition rate was also developed²¹ based on a polygon mirror filter and showing a depth resolution of $13\mu \mathrm{m}$ . The advantage of these Fourier-domain techniques is the ability to perform three-dimensional imaging within a few seconds. Data acquisition and processing speeds, however, are insufficient to use the full capacity of Fourier-domain techniques.

Table 1

Comparison between the Niris and advanced OCT systems.

In conclusion, to our knowledge, this is the first time a commercially available time-domain OCT system is used as part of a multimodality bronchoscopy platform to study diagnostic imaging of a benign disease, such as TPO. Future OCT systems might be further optimized for such airway applications by developing smaller probes capable of insertion into standard 2.0- and $2.8\text{-}\mathrm{mm}$ working channels of flexible bronchoscopes, longer sweep distances, broader wavelength laser sources with higher resolution capabilities, compact three-dimensional scanning, and integrated rapid Fourier-domain technologies.