Table 2.
CLE studies head and neck region.
| Study | Year | No. of Cases/Samples | Fluorescent Dye | Main Results | |
|---|---|---|---|---|---|
| ex vivo | Clark et al. [55] | 2003 | 17 | none | HNSCC patients; good visualization of tumor morphology as well as adjacent tumor-free tissue |
| Just et al. [56] |
2006 | 26 | none | larynx biopsies (healthy, dysplasia, benign + malignant tumors); good correlation with histology; primary endpoints Se/Sp | |
| Abbaci et al. [57] | 2009 | 27 | AF/F/5-ALA | laryngectomy specimens; tumor, dysplastic and healthy tissue portions of each specimen were examined; description of CLE morphology compared with HE staining | |
| Muldoon et al. [58] | 2012 | 13 | none | HNSCC samples; primary endpoints Se/Sp; good correlation with histology | |
| Vila et al. [59] | 2012 | 38 | P | HNSCC samples; 7 examiners for the evaluation of CLE images after initial training; primary endpoints Se/Sp/IRR/Ac | |
| Linxweiler et al. [60] |
2016 | 185 | AF/none | HNSCC samples (n = 135) + healthy controls (n = 50); visualization and discrimination between neoplastic and non-neoplastic tissue; identification of the tumor border; evaluation of CLE images by ENT surgeons, pathologists and laymen after initial training; primary endpoint: correct identification of tumor border and tumor localization | |
| in vivo (M) | Farahati et al. [61] |
2010 | 60 | none | 10 healthy mice, 50 mice with chemically induced tongue cancer; description of CLE morphology; primary endpoints Se/Sp/IRR |
| in vivo (H) | White et al. [54] | 1999 | 6 | none | healthy controls; description of CLE morphology; good correlation with histology |
| Zheng et al. [62] | 2004 | 5 | 5-ALA | 2 healthy controls; 3 tongue cancer patients; description of morphology, good correlation with histology | |
| Thong et al. [63] | 2007 | not indicated | 5-ALA/F/H | tissue samples + in vivo measurements in humans and mice; good correlation with histology; differentiation between healthy tissue and tumor tissue | |
| Thong et al. [64] | 2007 | 2 | 5-ALA/F | healthy control patient + tongue cancer patient; description of morphology; good correlation with histology | |
| Maitland et al. [65] |
2008 | 8 | none | HNSCC patients; description of CLE morphology; good correlation with histology | |
| Haxel et al. [66] | 2010 | 5 | AF/F | healthy controls; description of CLE morphology; good correlation with histology | |
| Pogorzelski et al. [67] |
2012 | 15 | none | HNSCC patients; development of a diagnostic score; good differentiation between healthy tissue and tumor tissue | |
| Thong et al. [68] | 2012 | 6 | F/H | healthy controls; description of CLE morphology; good correlation with morphology; application of a 3D fluorescence imaging prototype | |
| Pierce et al. [69] | 2012 | 30 | none | moderate to severe dysplasia + HNSCC patients; good correlation with histology; primary endpoints Se/Sp/PPV/NPV | |
| Just & Pau [70] | 2013 | 10 | none | visualization of laryngeal mucosa from healthy controls and patients with premalignant lesions | |
| Contaldo et al. [71] |
2013 | 6 | AF | healthy controls; visualization of different histological structures | |
| Nathan et al. [72] | 2014 | 21 | F i.v. | visualization of premalignant and malignant lesions of the head and neck mucosa (12 dysplasias, 9) | |
| (9 carcinomas); good correlation with histology; primary endpoints Se/Sp/PPV/NPV | |||||
| Dittberner et al. [73] |
2016 | 12 | F i.v. | automated analysis of CLE images from neoplastic and non-neoplastic oral tissue; primary endpoint AUC | |
| Moore et al. [74] | 2016 | 24 | F i.v. | visualization and discrimination between benign, precancerous and malignant lesions of the head and neck; primary endpoint interobserver agreement; good correlation with histology | |
| Volgger et al. [75] |
2016 | 19 | F i.v. | visualization and discrimination between healthy tissue and various grades of dysplasia up to squamous cell carcinomas of the laryngeal mucosa; primary endpoints Se/Sp; CLE helpful for the discrimination between noninvasive laryngeal lesions | |
| Goncalves et al. [76] |
2017 | 7 | F i.v. | visualization and differentiation between severe dysplasia to invasive carcinoma (n = 3) and benign tumors (n = 4) of the vocal cords; primary endpoints Se/Sp/PPV/NPV/IRR | |
| Aubreville et al. [77] |
2017 | 12 | F i.v. | automated analysis of CLE images of the cancerous and tumor-free oral mucosa from 12 HNSCC patients using a deep learning approach; primary endpoints Se/Sp/AUC | |
| Englhard et al. [78] |
2017 | 11 | FITC-labeled Ab | visualization and differentiation between HNSCC and tumor-free tissue using CLE in combination with FITC-labeled EpCAM and EGF-R-antibodies; in vitro (cell lines) + in vivo (HNSCC samples, n = 11; healthy mucosa samples, n = 5); primary endpoint antigen specificity of the Abs | |
| Goncalves et al. [79] |
2019 | 7 | F i.v. | visualization and differentiation between squamous cell carcinomas (n = 3) and benign tumors (n = 4) of the vocal folds; primary endpoints Se/Sp/PPV/NPV/IRR | |
| Shinohara et al. [86] |
2020 | 10 | AF Food Red No. 106 |
visualization of and differentiation between HNSCC and adjacent healthy tissue using autofluorescence, topical AF, or AF + Food Red No. 106; best results with AF only | |
| Sievert et al. [84] | 2021 | 5 | F i.v. | visualization and differentiation between oropharyngeal squamous cell carcinomas and adjacent healthy tissue; assessment of free resection margins; primary endpoints Se/Sp/PPV/NPV/Ac | |
| Wenda et al. [85] | 2021 | 2 | F i.v. | Visualization of tumor tissue in one patient with sinonasal inverted papilloma and one patient with sinonasal squamous cell carcinoma | |
| Dittberner et al. [87] |
2021 | 13 | F i.v. | visualization of and differentiation between HNSCC and adjacent healthy tissue; primary endpoints Se/Sp/Ac/; concordance between CLE imaging and histology | |
| Sievert et al. [82] | 2021 | 13 | F i.v. | generation and evaluation of an eight-point score for correct assessment of malignancy in laryngeal and pharyngeal squamous cell carcinoma; primary endpoints Se/Sp/Ac/NPV/PPV/AUC | |
| Sievert et al. [83] | 2021 | 5 | F i.v. | CLE-based assessment of safe surgical margins in laryngeal cancer patients; primary endpoints Se/Sp/NPV/PPV/Ac | |
| Sievert et al. [81] | 2022 | 13 | F i.v. | generation and evaluation of a larynx and pharynx confocal imaging score for correct assessment of malignancy in laryngeal and pharyngeal squamous cell carcinomas; comparison between CLE experts and CLE nonexperts; primary endpoints Se/Sp/Ac | |
| Abbaci et al. [88] | 2022 | 44 | patent blue V | visualization of and differentiation between HNSCC tumor core and its margins; primary endpoints Se/Sp | |
| Sievert et al. [89] | 2022 | 5 | F i.v. | visualization of and differentiation between tumor and adjacent healthy tissue in 5 laryngectomy patients; primary endpoints Se/Sp, ROI of tumor and healthy tissue | |
| Sievert et al. [90] | 2022 | 10 | F i.v. | visualization and evaluation of diagnostic value of intraepithelial capillary loops and atypical vessels in 10 laryngectomy patients; comparison between tumor vs. healthy tissue; primary endpoints Se/Sp/NPV/PPV/Ac | |
| Sievert et al. [91] | 2022 | 12 | F i.v. | generation and evaluation of a confocal imaging score for correct assessment of malignancy in oral cavity squamous cell carcinomas; primary endpoints Se/Sp/Ac/NPV/PPV/AUC |
H—Hypericin; AF—Acriflavine; F—Fluorescein; 5-ALA—5 aminolevulinic acid; P—Proflavine; Ab—Antibodies; FITC—Fluorescein isothiocyanate; Se—Sensitivity; Sp—Specificity; PPV—Positive predictive value; NPV—Negative predictive value; Ac—Accuracy; IRR—Inter-rater reliability; AUC—Area under the curve.