Radiol Oncol 2023; 57(4): 411-418. doi: 10.2478/raon-2023-0057 411 review Imaging microvascular changes in nonocular oncological clinical applications by optical coherence tomography angiography: a literature review Rok Hren 1,2,3 , Gregor Sersa 4 , Urban Simoncic 1,5 , Matija Milanic 1,5 1 Faculty of Mathematics and Physics, Ljubljana, Slovenia 2 Institute of Mathematics, Physics, and Mechanics, Ljubljana, Slovenia 3 Syreon Research Institute, Budapest, Hungary 4 Institute of Oncology Ljubljana, Ljubljana, Slovenia 5 Jozef Stefan Institute, Ljubljana, Slovenia Radiol Oncol 2023; 57(4): 411-418. Received 15 September 2023 Accepted 3 October 2023 Correspondence to: Matija Milanic, Ph.D., Faculty of Mathematics and Physics, University of Ljubljana, Jadranska ulica 19, SI-1000 Ljubljana, Slovenia. E-mail: matija.milanic@fmf.uni-lj.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Optical coherence tomography angiography (OCTA) is an emerging imaging modality that enables noninvasive visualization and analysis of tumor vasculature. OCTA has been particularly useful in clinical ocular on- cology, while in this article, we evaluated OCTA in assessing microvascular changes in clinical nonocular oncology through a systematic review of the literature. Method. The inclusion criterion for the literature search in PubMed, Web of Science and Scopus electronic data- bases was the use of OCTA in nonocular clinical oncology, meaning that all ocular clinical studies and all ocular and nonocular animal, phantom, ex vivo, experimental, research and development, and purely methodological studies were excluded. Results. Eleven articles met the inclusion criteria. The anatomic locations of the neoplasms in the selected articles were the gastrointestinal tract (2 articles), head and neck (1 article) and skin (8 articles). Conclusions. While OCTA has shown great advancements in ophthalmology, its translation to the nonocular clinical oncology setting presents several limitations, with a lack of standardized protocols and interpretation guidelines pos- ing the most significant challenge. Key words: optical coherence tomography angiography (OCTA); oncology; endoscopy; skin carcinoma Introduction It was demonstrated that angiogenesis is closely associated with tumor growth, as the develop- ment of vasculature has the capacity to supply oxygen and nutrients to dividing tumor cells. 1 Microvascular alterations are therefore typical sig- natures of early tumor development and progres- sion. Conventional techniques for assessing micro- vascular changes are narrow band imaging (NBI) 23 and confocal laser endomicroscopy (CLE) 45 in en- doscopy and confocal laser microscopy (CLM) 6 and dermoscopy 7 in skin diagnosis. However, NBI has limited resolution, and CLE utilizes exog- enous tracers, while CLM and dermoscopy cannot visualize deeper vascular changes due to a limited Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 412 penetration depth, with blood vessels also often being hidden in pigmented lesions. To address these shortcomings, various emerging imaging techniques have been explored for microvascular imaging. Optical coherence tomography (OCT) is a ma- ture imaging technique that uses low-coherence light to capture high-resolution, cross-sectional images of biological tissues in real time. It has been applied in various fields of medicine 8 due to its noninvasiveness, high resolution, and ability to visualize microstructure and has become the gold standard for diagnosis in ophthalmology. 9 It is thus not surprising that OCT has found its way into oncological applications as well. 10 To enable further functional assessment of tumors, optical coherence tomography angiography (OCTA) is an impending valuable extension of OCT in on- cological research and clinical practice. OCTA is a modification of OCT and works by comparing the light waves that are reflected from stationary tissue with the light waves that are reflected from moving red blood cells (RBCs), and this informa- tion is then used to create a detailed map of the blood vessels (Figure 1). The distinct advantage of OCTA is that it is a noncontact, nonionizing, and noninvasive modality and does not require a con- trast agent. OCTA has proven highly valuable in helping to better understand and manage a range of nononcological ocular pathologies 11,12,13 , while in oncological ocular clinical applications, OCTA has potential for use in the diagnosis and monitoring of chorioretinal pathologies, such as neovasculari- zation and macular edema. 14 How valuable OCTA could be in quantifying microvascular changes in nonocular clinical on- cology remains unclear, and to that end, we decid- ed to systematically review the literature with the intention of exclusively focusing only on studies in which OCTA was performed on patients in the clinical oncology setting. Materials and methods Two authors (R.H. and M.M.) conducted jointly— to preclude potential bias—a comprehensive litera- ture search on August 3, 2023, through PubMed, Web of Science and Scopus electronic databases using the following search terms: “optical coher- FIGURE 1. Optical coherence angiography (OCTA) scanning protocol. (A) A raster scanning protocol for blood vessel visualization, with the x-axis sampling density determined by A-scans per B-scan sets and the y-axis determined by B scans per volume sets. (B) OCTA B-scans created by four repeated B-scans at one y-location, repeated for varying positions along the y-axis, impacting sampling density; ΔT represents interscan time and T a denotes acquisition time. (C) Maximum intensity projection (MIP) applied to the OCTA B-scan within the depth range of interest (where vessels are located) to generate one line of the en face OCTA image. (D) Illustration depicting the equal distribution of sampling points for smaller and larger imaging areas. Taken from Sampson et al. 12 and reprinted with permission from the publisher by the Creative Commons license. To view a copy of Creative Commons license, visit http://creativecommons.org/licenses/by/4.0/. A B C D Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 413 ence tomography angiography tumors” and “dy- namic optical coherence tomography tumors”. No restrictions on publication date or language were imposed. The inclusion criterion was the nonocu- lar application of OCTA in the oncological clinical setting, meaning that all ocular oncological clini- cal studies and all ocular and nonocular animal and phantom, ex vivo, experimental, research and TABLE 1. Included articles reporting the use of optical coherence tomography angiography (OCTA) to quantify microvascular changes in nonocular clinical applications in oncology Reference Year of publication Number of patients Oncologic setting GI tract Tsai et al. 15 2014 1 Nondysplastic Barrett’s esophagus Lee et al. 16 2017 52 Nondysplastic Barrett’s esophagus surveillance or endoscopic eradication therapies for low-grade/high-grade dysplasia Head and neck Maslennikova et al. 17 2017 25 Radiotherapy of oropharyngeal and nasopharyngeal cancer Skin De Carvalho et al. 18 2016 1 Naevus to melanoma transition Themstrup et al. 19 2017 47 Actinic keratosis, Bowen’s disease and squamous cell carcinoma Themstrup et al. 20 2018 81 Basal cell carcinoma Meiburger et al. 21 2019 7 Basal cell carcinoma Gubarkova et al. 22 2019 27 Basal cell carcinoma De Carvalho et al. 23 2018 127 Melanoma Welzel et al. 24 2021 159 Melanoma Perwein et al. 25 2023 130 Nevi GI = gastrointestinal FIGURE 2. Images obtained through optical coherence tomography angiography (OCTA) for (TOP ROW) nondysplastic Barrett’s esophagus (NDBE) and (BOTTOM ROW) low-grade/high-grade dysplasia (LGD/HGD) (bottom left LGD; bottom center and bottom right HGD). NDBE images show a regular honeycomb microvascular pattern (arrows, top row), while abnormal vascular features, such as abnormal vessel branching (arrows, bottom left), heterogeneous vessel size (arrows, bottom center) or both (bottom right), are observed in LGD/HGD. Motion artifacts are denoted by asterisks. OCTA images can assist in distinguishing the boundary between abnormal microvasculature and neighboring nondysplastic regions (dashed line, bottom left and bottom center). Taken from Lee et al. 16 and reprinted with permission from the publisher. A B C D E F Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 414 development, and purely methodological studies were excluded. Special care was taken that dupli- cations were removed, both across databases and across studies; for example, if the study was first published in proceedings and later in the journal, then proceedings article was considered a nonpri- mary publication and therefore excluded. Studies were categorized with respect to the anatomical location of the tumors. Results In total, 3977 articles were found to be of interest in the PubMed, Web of Science and Scopus data- bases; it is noteworthy that 3855 articles (96.9% of total) were linked to ocular oncological studies. After excluding duplicates and applying the exclu- sion criteria, first considering the title and abstract and then, if necessary, reading the entire article, 11 articles were identified for further analysis. The anatomical locations of tumors in the selected arti- cles were the gastrointestinal (GI) tract (2 articles), head and neck (1 article) and skin (8 articles). GI tract A pioneering effort in assessing microvascula- ture by means of OCTA in clinical oncology was the work of Tsai et al. 15 They applied a modality to image subsurface vascular patterns in a patient with nondysplastic Barrett’s esophagus (NDBE) and demonstrated that in this way, the diagnostic capability of endoscopic OCT was enhanced. Lee et al. 16 continued their work and collected 97 data- sets from 52 patients with NDBE and low-grade/ high-grade dysplasia (LGD/HGD). Their goal was to differentiate NDBE patients from LGD/HGD pa- tients; however, due to insufficient image quality, 43 datasets (44%) in 20 patients were not used for analysis; OCTA images were also not generated in real time due to the high computational burden. The findings of the study revealed distinct differ- ences in microvascular OCTA features of abnor- mal vessel branching and heterogeneous vessel size between the NDBE and LGD/HGD groups, as shown in Figure 2. Further research with a larger patient population is required to validate these findings and establish the clinical utility of endo- scopic OCTA in routine practice. Head and neck In the study by Maslennikova et al. 17 , clinicians aimed to investigate the use of OCTA for imag- ing microvascular changes in the oral mucosa of cancer patients undergoing radiotherapy (RT). Authors conducted a longitudinal study involving 25 patients with oropharyngeal and nasopharyn- geal cancer undergoing RT. OCTA was employed to visualize and analyze the microvascular network within the oral mucosa over time, and imaging was performed before the treatment and at regular inter- vals during and after RT. OCTA images were gener- ated in real time by the acquisition system shown in Figure 3. The findings of the study demonstrated significant alterations in the microvascular mor- phology and density in the irradiated oral mucosa over the course of RT, with the microvascular net- work showing an increase in the vascular density and total length of capillary-like vessels compared to the baseline measurements. These changes were found to be more prominent when grade two and three mucositis developed. The study demonstrat- ed the potential of OCTA as a valuable tool for lon- gitudinal monitoring of microvascular changes in radiation-induced oral mucosal damage. However, it is important to note that this study has several limitations, as the sample size was relatively small, and the results may not be generalizable to the broader population; additionally, the prognostic significance of the observed microvascular changes needs further investigation. FIGURE 3. Optical coherence tomography angiography (OCTA) acquisition system. OCTA images were acquired in real time. Taken from Maslennikova et al. 17 and reprinted with permission from the publisher by the Creative Commons license. To view a copy of Creative Commons license, visit http:// creativecommons.org/licenses/by/4.0/. Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 415 Skin De Carvalho et al. 18 published a case report in which they showed an increased vasculature in the mel- anoma region compared to the nevus. Following this, Themstrup et al. 19 conducted a study to dis- tinguish subtypes within the keratinocyte skin cancer spectrum enrolling 18 patients with actinic keratosis (AK), 12 patients with Bowen’s disease (BD) and 24 patients with squamous cell carcino- ma (SCC). In this exploratory clinical study, they identified two vascular features that showed sig- nificant differences across the lesion types. One of these vascular features, referred to as “blobs”, i.e., small, isolated points with a simple round appear- ance, was more frequently present in BD cases but either absent or only slightly present in AK and SCC lesions. The other feature, called “curves” , i.e., narrow, curved, continuous structures of varying length, was predominantly present in AK lesions. These findings are illustrated in Figure 4. FIGURE 4. Illustration of two distinct vascular features observed through dermoscopy and optical coherence tomography angiography (OCTA). The first feature, referred to as “blobs”, is small, isolated points with a simple round appearance; the second feature, called “curves”, is narrow, curved, continuous structures of varying length. Panel (A) displays a dermoscopic image of a Bowen’s disease (BD) lesion, and panel (B) shows the corresponding OCTA image. The asterisk in both panels points to the same vessel. The thin arrows in panel (B) indicate examples of vascular blobs. Similarly, panels (C) and (D) display a dermoscopic image of AK and the corresponding OCTA image, respectively. The thick arrows in panel (D) indicate examples of vascular curves. Taken from Themstrup et al. 19 and reprinted with permission from the publisher. In a subsequent study 20 , the same group contin- ued with the differentiation of common basal cell carcinoma (BCC) subtypes by scanning 81 patients with 98 BCC lesions, of which 27 were superficial BCC (sBCC), 55 were nodular BCC (nBCC) and 16 were infiltrative BCC (iBCC). In this study, they found various structural and microvascular fea- tures that would aid in identifying nBCC, iBCC and sBCC subtypes. For example, it was shown that the presence of so-called “serpiginous” ves- sels, i.e., wavy structures of varying length, indi- cated an increased risk of nBCC and a reduced risk of sBCC. Meiburger et al. 21 applied OCTA to a patient with nBCC and six patients with sBCC and developed an algorithm for automatically determining skin lesion area using vascular density. While authors were hopeful in their conclusion that proposed method could facilitate diagnosis and treatment of BCC, no further study was published. Gubarkova et al. 22 examined 27 patients with BCC who received photodynamic therapy (PDT). They utilized OCTA imaging before and imme- diately after PDT and during follow-up visits to monitor vascular changes. Analysis of the OCTA images allowed for quantification of parameters such as blood vessel density and uniformity, aid- ing in distinguishing among BCC subtypes. The study demonstrated that OCTA offers real-time information on vascular changes in response to PDT. The researchers observed a decrease in blood vessel density at 24 hours after PDT, with OCTA images having 97% predictive value for differen- tiation between complete and partial responders. De Carvalho et al. 23 conducted a systematic anal- ysis of melanoma lesions in 127 patients and found a significant link between specific microvascular features and Breslow’s thickness. In a more re- cent study, Welzel et al. 24 assessed 159 melanomas from 156 consecutive patients and found that ir- regular vascular shapes, including blobs, curves and serpiginious vessels, were more common in high-risk and metastatic melanomas than in low- risk lesions. Most recently, the same group 25 pro- spectively examined a total of 167 nevi, including dysplastic ones, in 130 participants and compared these microvascular features to those found ear- lier in 159 melanomas. 24 They found that increased blood vessel density and diameter and irregular tissue architecture were associated with melano- mas, while nevi showed more regular structures and lower blood vessel density and diameter, indi- cating their benign nature (Figure 5). Researchers also found excellent predictive diagnostic value of B C D A Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 416 microvascular features (e.g., blobs, serpiginious vessels) for nevi (88.2% to 91%) and melanoma (95.5% to 96.8%) and concluded that OCTA “may be a valuable addition to the current clinical-der- moscopic gold standard”. 25 Discussion Based on this literature review, the inference could be made that OCTA is still finding its place in on- cological clinical applications. It appears that the translation of OCTA from ocular applications to the nonocular clinical oncology setting faces cer- tain limitations that could potentially hinder its widespread adoption. Limited penetration depth One of the obvious limitations of OCTA in nonoc- ular clinical oncology settings is its restricted pen- etration depth. OCTA relies on detecting motion contrast generated by moving RBCs, which limits its applicability to superficial structures. Tumors FIGURE 5. Microvascularization in skin lesions (nevi, dysplastic nevi, and melanomas) through optical coherence tomography angiography (OCTA) scans (denoted as D-OCT). (A) Compound nevus on the scapula, displaying a globular appearance with recent changes. (B) Dysplastic nevus, flat lesion on the scapula, exhibiting a complex appearance, atypical network, irregular pigmentation, and dots/globules. (C) Melanoma, a lesion on the scapula, measuring 3.35 mm in tumor thickness, classified as pT3aN1bM0S2, stage IIIB. Taken from Perwein et al. 25 and reprinted with permission from the publisher by the Creative Commons license. To view a copy of Creative Commons license, visit http://creativecommons.org/licenses/by/4.0/. B C A Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 417 and lesions in deeper anatomical locations, such as within organs or soft tissues, may not be adequate- ly visualized using OCTA due to limited tissue penetration. This constraint hampers its potential for comprehensive evaluation and monitoring of oncological conditions. However, this limitation can be overcome by us- ing endoscopic techniques bringing the instrument closer to the tissue of interest. As demonstrated in the GI tract studies by Tsai et al. 15 and Lee et al. 16 , OCTA can be used endoscopically. Namely, com- mon OCT has been developed as endoscopic probes of different types and used to obtain microscopy images of entire luminal organs, solid tumors, or vessels. 26 Since OCTA is an extension of OCT, the same already developed technology can be used to bring the system closer to the tissue of interest. Another possibility to increase the OCTA pen- etration depth is to use OCTA systems with longer wavelengths. In the studies presented in this ar- ticle, the OCTA systems utilized 1.3 µm wave- lengths, which is a typical wavelength also used for skin imaging; in ophthalmology, a shorter wavelength of 0.8 µm is typically used, result- ing in an approximately 60% lower penetration depth. In a recent publication by Nishizawa and Yamanaka 27 , it was shown that by using a 1.7 µm wavelength, the penetration depth increases by approximately 40% compared to a 1.3 µm wave- length. Therefore, by developing OCTA systems with even longer wavelengths, larger penetration depths could be obtained. Inability to differentiate vessel types OCTA provides detailed structural information about blood vessels but lacks the ability to differ- entiate between different vessel types. In the field of oncology, the distinction between arterial and venous vasculatures is crucial, as tumor angio- genesis is primarily associated with the growth of new abnormal blood vessels. Accurate differentia- tion between these types of vessels aids in assess- ing tumor progression and treatment response. Unfortunately, OCTA’s current capabilities fail to provide this level of vessel characterization, limit- ing its effectiveness in nonocular oncological set- tings. In ophthalmology, recent articles report the possibility of differentiating between arteries and veins utilizing various OCTA image parameters, including vascular diameters and shape and per- fusion intensity density. 28 However, the current methods for artery-vein classification in OCTA employ complex algorithms, thereby making it dif- ficult for clinical applications. To alleviate this hin- drance, deep learning algorithms were developed to reduce the complexity and automate artery-vein classification. 29 Similar algorithms should also be developed for other OCTA modalities. Motion artifacts Movement, including patient motion during OCTA acquisition, can introduce motion artifacts, leading to image distortions and reduced image quality. Unlike ophthalmology, where patients can fixate on a target, patients in nonocular oncology settings often have limited control over motion, making motion artifacts more challenging to miti- gate. This limitation can compromise the accuracy and reliability of OCTA in nonocular clinical on- cology, demanding the need for advanced post- processing algorithms to improve image quality. Since motion artifacts are well-known sources of artifacts in OCT imaging, they have been ex- tensively researched. One possibility is to detect and compensate for the axial motion artifacts pixelwise by comparing the topology of different layers in tissue, and the motion artifacts are then compensated by shifting the pixel numbers with the value detected. 29 Another possibility is to re- move the affected scans in the software and to use only the nonaffected scans for vasculature image reconstruction. 30 However, this approach may in- crease the duration of imaging sessions; therefore, it would be better to use an approach without the need for rescanning. As a solution, it was demon- strated that the motion contribution to the OCT signal can be reasonably estimated by consider- ing statistics of the measured flow signal across all voxels. 30 By implementing motion artifact compen- sation strategies, the translation of OCTA to clini- cal workflow would become more feasible. Lack of standardized protocols and interpretation The lack of standardized protocols and interpreta- tion guidelines is a significant limitation of OCTA in nonocular clinical oncology. Unlike ophthal- mology, where standardized imaging protocols and interpretation criteria exist, the application of OCTA in oncology lacks such standardization. As a result, different centers may use varying ac- quisition settings, image processing algorithms, or interpretation approaches, leading to inconsistent and noncomparable results. Establishing stand- Radiol Oncol 2023; 57(4): 411-418. Hren R et al. / Optical coherence tomography angiography in nonocular oncology 418 ardized protocols and guidelines specific to non- ocular oncology would enhance the accuracy and reproducibility of OCTA findings. While OCTA has shown great promise in oph- thalmology, its translation to the nonocular clini- cal oncology setting faces limitations. 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