Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro-inflammation cues

Abstract

Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging methods that can detect chronic inflammatory features to identify pre-cancerous and cancerous angiogenic changes in tissue microenvironments. This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative experimental preclinical and human clinical studies using these imaging methods provide biological and clinical relevance to cutaneous field carcinogenesis in altered tissue microenvironments in the apparently normal epidermis and dermis. Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options.

Keywords: hyperemia; inflammation; optical imaging; skin neoplasms.

Figure 1.. Comparison of microscopic versus mesoscopic imaging views of true cutaneous field cancerization.

Microscopic imaging only captures a fraction of the field cancerization, while mesoscopic imaging offers a broader view.

Figure 2.. Progression of NMSC cancerization and how mesoscopic imaging modalities can detect cutaneous field carcinogenesis.

(A) Example of a focal area of normal vascularization and quantities of epidermal and dermal cells, prior to radiation or damage. (B) Once prolonged irritation to the area occurs due to radiation or other types of damage (chemical irritation and aging), inflammation causes increased hemoglobin extravasation and angiogenesis. (C) Prolonged irritation and inflammation resulting in inflammatory hyperemia and angiogenesis associated with field carcinogenesis. Mesoscopic imaging technology can efficiently detect such pro-inflammatory changes within the dermis.

Figure 3.. Representative imaging setups for hyperspectral imaging, RGB imaging, and spatial frequency domain imaging (SFDI).

(a) Schematics of an imaging setup that simultaneously acquires hyperspectral and RGB image data. For hyperspectral imaging, a liquid crystal tunable filter (LCTF) is placed in front of the xenon lamp, and a mono CCD camera is used. For RGB imaging, LCTF is removed, and a conventional 3-color CCD camera (trichromatic camera) is employed. (b) Schematics and photo of an SFDI system. LEDs are focused into a liquid light guide and directed onto a digital micromirror device (DMD). DMD generates sine wave patterns acquired by an sCMOS camera. Crossed polarized light is implemented to reject specular reflection. Adapted with permission from Refs [48, 78].

Figure 4.. Representative preclinical histology and hemoglobin (Hgb) content images from experimental carcinogenesis studies.

(a) H&E stain (200×) images showing hyperemic foci at 20 weeks after the cessation of UVB irradiation. (b) Hemoglobin content images from the same UVB-treated mouse at biweekly intervals following the cessation of UVB irradiation. These hemoglobin content images can be generated using hyperspectral imaging or a hyperspectral learning algorithm. Adapted with permission from Ref [48].

Figure 5.. Representative clinical images of tissue oxygen saturation (StO₂) and hemoglobin (Hb) content from lesions.

(a) Tissue oxygen saturation and hemoglobin content images generated using SFDI from a patient with BCC. (b) Tissue oxygen saturation and hemoglobin content images generated using SFDI for a patient with SCC. The scale bar corresponds to 2 mm. Adapted with permission from Ref [76].

Figure 6.. Representative clinical images of photodamage using SFDI.

(a) Photos of patients’ arms, labeled P1, P2, P3, showing increasing visible photodamage. (b) Corresponding images of total hemoglobin, oxygenated hemoglobin, and tissue oxygen saturation. Adapted with permission from Ref [78].