使用光學同調斷層掃描術早期偵測口腔上皮變異及口腔鱗狀上皮細胞癌

背景：全世界每年約有640,000例新診斷之口腔癌(oral cancer)患者，這些患者中，超過一半(52%)於確診時已達預後較差之第三或第四期(advanced stages)。不管在全世界或臺灣，口腔癌亦名列前十大常見癌症中之第六位。儘管口腔癌之治療在多年來的發展下，已有顯著之進步，但過晚診斷導致延誤治療，長久以來，仍是使口腔癌患者預後不佳以及五年存活率低落之主要原因。口腔癌的診斷主要依靠肉眼直接口腔檢查(visual oral examination)及手術切片(surgical biopsy)搭配組織病理檢查(histopathological examination)。但往往受限於時間、病人配合度(patient compliance)、侵犯性的術式(invasive surgery of biopsy)、及醫療資源等等，使得口腔癌難以早期偵測。為達早期診斷以增進治療效果、提升患者存活率、改善治療後生活品質之目標，光學同調斷層掃描術（optical coherence tomography)在近數十年來的蓬勃發展與研究中，顯示其為一具高潛力成為早期偵測及診斷口腔上皮變異(oral epithelial dysplasia)及口腔上皮鱗狀細胞癌(oral squamous cell carcinoma)之理想工具。光學同調斷層掃描術為一低侵犯性(minimally invasive)光學功能性成像技術(optical functional imaging technology)，可對生物組織產生近組織等級解析度(near histologic resolution)、即時(real-time)、多角度之切面(longitudinal and cross sectional)、顯微組織構造之成像(structural microscopic images)。此特性使其適於檢測口腔內黏膜組織之癌前病變或惡性病變，亦可將光學同調斷層掃描影像與組織病理影像作對照，達到組織分析及診斷之目的。過去數十年來，已有許多文獻發表研究光學同調斷層掃描術用於臨床場域以檢視口腔正常組織、辨別上皮變異及惡性組織、與組織病理影像對照、以及合併診斷標準(diagnostic criteria)藉以診斷組織惡性程度等等。雖然已有許多研究證明光學同調斷層掃描術可有效且正確辨別口腔上皮病變組織，但距離實際使用於臨床上，進行口腔上皮細胞變異與口腔上皮鱗狀細胞癌之早期診斷仍有許多待克服之挑戰存在，例如:普遍過少的收案數量、光學同調斷層掃描影像之判讀方法、有效可靠之診斷標準、掃描介面、與三維掃描成像蒐集得之大數據分析等。研究目的:探索驗證光學同調斷層掃描術是否可作為早期診斷口腔上皮細胞變異與口腔上皮鱗狀細胞癌之客觀且再現行高之可靠工具。透過與掃描檢體相對應之組織病理切片影像對照，以及藉由合併診斷標準與影像分析演算法，檢視光學同調斷層掃描術對正常組織、口腔癌前病變、與惡性病變之辨別力。材料與方法:使用一客製(customized)高解析(high-resolution)、長波長(long-wavelength)、全視野(full field-of-view)、及多倍率(multiscale)之三維光學同調斷層掃描系統，檢視西元 2019 至 2022 年，來自國立臺灣大學醫學院附設醫院牙科部口腔顎面外科，經開刀房全身麻醉或門診局部麻醉手術切片之 131 位收案患者，共 171 份檢體之光學同調斷層掃描影像與組織病理切片影像。其中共有來自包括頰黏膜(buccal mucosa)、舌(tongue)、齒齦(gingiva)、顎黏膜(palate mucosa)、唇黏膜(labial mucosa)、下顎臼齒後三角區 (retromolar trigone)等不同部位之健康組織，以及輕度 / 中度 / 重度上皮細胞變異、與口腔上皮鱗狀細胞癌組織。各檢體經掃描成像後，藉由影像分析演算法(image analysis algorithm)進行影像處理及不同診斷標準下之影像分析判讀。結果:藉由合併適當診斷標準及影像分析演算法進行口腔黏膜部位之光學同調斷層掃描，於區別正常健康組織與口腔上皮鱗狀細胞癌上，可得到79%之敏感度與73%之特異度。與本研究所使用之光學同調斷層掃描系統之影像具最高配合度與鑑別力之診斷標準為:B-scan下隨深度所吸收之強度分佈圖形所顯現出之顯著波峰所在深度(intensity distribution of depth resolved B-scan)以及 A-scan 所得之指數衰減常數(exponential decay constant of A-scan spatial spectrum)。結論:光學同調斷層掃描術結合適當診斷標準及影像分析演算法進行口腔黏膜部位之分析，不僅可一定程度地快速且早期鑑別診斷口腔上皮變異與口腔鱗狀細胞癌，透過光學同調斷層掃描術所蒐集得之高品質口腔黏膜組織三維影像，亦可用於建立本土口腔上皮變異大數據資料庫，供未來研究相關影像與發展人工智慧判讀分析之用。本研究之方法及系統，提供一臨床上口腔癌早期診斷與偵測之高潛力選擇，期將可裨益於口腔病變患者，增進其早期診斷率與提高其預後。

關鍵字

光學同調斷層掃描；早期偵測；口腔上皮細胞變異；口腔鱗狀細胞癌；診斷指標；影像分析演算法

並列摘要

Background: There are approximately 640,000 new cases of oral cancer diagnosed worldwide annually. More than half of the patients (52%) are diagnosed at advanced stages that result in poor prognosis. Oral cancer has also been the sixth most prevalent cancer in Taiwan and the world for more than a decade. Despite the advancement in treatment methods, the poor treatment outcome and low survival rate of oral cancer patients mostly result from late detection and diagnosis. Current diagnosis methods mainly rely on visual oral examination of suspected lesions, followed by surgical biopsy and histopathological analysis, which are invasive, yet they detect malignant changes too late. Since early detection has been consented to be the best way to ensure treatment outcome of oral cancer, increase patient survival rate, and improve quality of life, optical coherence tomography (OCT) technology has been actively developed as a potential approach for early detection of oral dysplatic lesions and oral squamous cell carcinoma (OSCC). OCT is an optical functional imaging technology that can generate near histologic resolution, real-time, cross sectional, and structural microscopic images of biological tissues with minimally invasion. These features make the technology an ideal option for identifying premalignant and malignant changes in the oral mucosa, as well as correlating the results with histopathological analysis. Over the past decades, there have been several studies developed to evaluate the usefulness of OCT in examining normal intraoral soft tissues, diagnosing dysplatic and malignant lesions, comparing OCT with histopathological images, and identifying diagnostic indicators so as to improve OCT applications in the clinical setting. Although the systemic literature review suggests that OCT technology offers an attractive diagnosing and monitoring prospects for pathological conditions in the oral cavity, there are still several challenges for this technology to be resolved before being applied to early detection and diagnosis of precancerous lesions and OSCC, such as limited sample size, definitive diagnostic indicator development, objective image interpretation, scanning interface, and big data analysis. Purpose: The object of this study is to validate the use of OCT technology as an objective and reproducible approach for early detection of oral epithelial dysplasia and oral squamous cell carcinoma by comparing the corresponding histopathological diagnosis, and further develop the diagnostic indicators, in combination of the image analysis algorithm for distinguishing normal, dysplasia, and malignant tissues. Materials and methods: In this study, a customized high-resolution, long-wavelength, extended-field-of-view, and multiscale OCT three-dimensional imaging system was designed, developed, and built. The system was utilized to examine 171 ex-vivo specimens acquired from surgical biopsy in operation rooms and the outpatient clinics of National Taiwan University Hospital from 2019 to 2022. Thirty-three patients with OSCC, thirty-five with oral dysplatic lesions, and thirty-one healthy subjects were enrolled in this study. Three-dimensional and multiscale OCT volumetric imaging data was acquired after surgical biopsy, following by histopathological analysis. More than 150,000 B-scan (longitudinal section) OCT images from different intraoral sites were collected from the 103 patients and compared with the clinical and histopathological diagnosis for evaluation and correlation in an imaging processing and analyzing algorithm by utilizing diagnostic indicators. Results: The result revealed that the OCT system in combination with the selected diagnosis indicators and image analysis algorithm is capable to differentiate OSCC and healthy intraoral tissues with sensitivity and specificity of 79% and 73%, respectively. The reliable diagnostic indicators include intensity distribution of depth resolved B-scan signal profile and exponential decay constant of A-scan spatial frequency spectrum. Conclusion: Not only has combining OCT system with appropriate diagnostic indicators and image analysis algorithm the potential to distinguish malignant and healthy tissues, but also the high-quality imaging data collected from the system could establish an oral tissue information databank based on the volumetric architecture datasets from the OCT scan for further research. The approach in this study shows considerable impact in increasing accuracy of early detection and improving oral cancer outcomes through advanced detection and diagnosis.

並列關鍵字

optical coherence tomography ； early detection ； oral epithelial dysplasia ； oral squamous cell carcinoma ； diagnostic indicator ； image analysis algorithm

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