THERMOGRAPHY AS A SCREENING TOOL IN CLINICAL OPHTHALMIC ONCOLOGY
Although intraocular tumors are rare, with an incidence of 5 per million adults, the diagnosis has been biased towards the physical examination, Color Doppler Imaging (CDI), Optical Coherence Tomography (OCT), Indocyanine Green Angiography (ICGA), or Fluorescein Angiography (FA). Literature reviews suggest a definitive diagnosis in approximately 80-85% of cases. Then there is diagnostic uncertainty (e.g., differentiating benign intraocular tumors from malignant ones). Rarely, the diagnosis demands differentiating neoplastic lesions, for example, in the case of intraocular lymphoma.
Thermography has received interest as a contactless, painless, and radiation-free tool for screening various types of cancers. Breast thermography has been researched for about 50 years or more, and in 1982 the US Food and Drug Administration (FDA) approved thermography as an adjunctive tool for diagnosing breast cancer. Numerous studies identified an abnormal thermogram as the important marker for developing breast cancer; even 10x more significant than a family history. A multimodal approach (clinical examination + mammography + infrared thermography) can significantly improve breast cancer screening.
The use of thermography in ophthalmic oncology is recent. Ocular thermography measures the changes in the distribution of ocular surface temperature, which can be linked to dry eye syndrome, glaucoma, certain inflammatory, and non-inflammatory eye disease as well as intraocular tumors.
The Thermography Study
The objective of this study was to evaluate ocular thermography as a means to simplify the differential diagnosis of intraocular tumors, as well as to determine the efficacy of treatment modalities.
All participants gave their written consent. The protocol was in accordance with the declaration of Helsinki. Ethical approval was by the Bioethics Committee of the Medical University (Approval No. KB-0012/141/15).
The study involved 37 patients with suspected intraocular tumors treated at the Ophthalmology Department, Pomeranian Medical University, Szczecin, Poland, from 2016 to 2018.
The study group included 9 uveal melanoma (UM) patients, 8 UM patients after 6-month Iodine-125 brachytherapy (4 with no significant improvement and 4 in remission), 12 patients with focal uveal metastasis (4 with primary breast cancer, 1 with lung cancer, and 7 with cancer of unknown primary), and 8 patients with retinal capillary hemangioblastoma (RCH) with Von Hippel-Lindau (VHL) disease. Exclusion criteria were: Patients with conditions that disturb the measurement of surface temperatures. (e.g., fever, inflammation, age-related macular degeneration, dry eyes, and glaucoma).
The examination was performed in a room with relatively stable temperature and humidity, isolated from external heat, solar radiation, or air conditioning. The infra-red camera (FLIR T640) detects signals over the spectral range of 7.5–14 μm and has an image resolution of 640× 480 pixels. The thermographic and optical images of each patient were captured in three replications: (i) perpendicular to the test area (eyeball), (ii) 3 s after blinking, and (iii) 1m distance after 15 min of no physical activity. To reduce the impact of variability on the external environment, the images were taken every 1 s.
Student’s t-test for paired samples was used to compare the mean values of the temperature parameters (of individual groups) in the normal and affected eyes. A general linear model was used to analyze the effect of age, sex, tumor type, and the presence of an intraocular tumor in affected and normal eyes on the median temperature. Statistica software (v. 13; Dell Inc., Tulsa, OK, USA) was employed for all calculations. A p≤0.05 was considered statistically significant.
MATLAB Image analysis
ImageJ software was used to analyze: the central corneal region in both eyes, left and right eyes (area), and orbital cavities.
Demographic characteristics analysis
The demographic analysis of 37 patients showed that,
- Retinal capillary hemangioblastoma was more frequent in younger patients (mean age = 44.5 years; SD: ±22.05), with prevalence in female subjects.
- Intraocular metastasis and uveal melanoma were more frequent in elderly subjects. The mean age at diagnosis was 67.92 years (SD: ±12.77) and 73.89 years (SD: ±9.78) for metastasis and uveal melanoma, respectively. Intraocular metastasis was more frequent in females.
The thermography analysis showed that the regions of interest of affected eyes had a higher temperature than the normal eyes.
- The mean temperatures at the central point of the cornea of the affected and normal eyes were 33.63 (SD: ±1.07) and 33.54 (SD: ±1.14) respectively.
- The median temperatures at the area of the affected and normal eyes were 34.31 (SD: ±0.90) and 34.27 (SD: ±0.93) respectively.
- The median temperatures of the area of the orbital cavity in the affected and normal eyes were 34.44 (SD: ±0.81) and 34.37 (SD: ±0.82) respectively.
- The median temperature was selected for further clinical study due to insensitivity to outliers and statistical significance with other temperature parameters.
Group 1 subjects with uveal melanoma showed significant differences in the mean values (p≤0.05) for the temperature at the three regions of interest of affected and normal eyes. A significant effect of the investigated parameters on the median temperature was observed only in subgroups distinguished depending upon the presence of the intraocular tumor and the type of tumor.
Significant differences in the median surface temperature of the orbital cavity were observed between Group 1 (uveal melanoma without treatment) and Group 3 (melanoma after treatment – regression), as well as between Group 2 (melanoma after treatment – relapse), Group 3 (melanoma after treatment – regression), and Group 5 (Retinal capillary hemangioblastoma) (p≤0.05).
Klamann et al. investigated and measured the ocular surface temperature in healthy individuals using a novel ocular thermography device; the reported mean ocular surface temperature was 34.02°C ± 0.22. However, there were no significant temperature differences between the right and left eyes, or between the male and female subjects. Some studies suggested that the physical characteristics of patients (e.g., body hair, body fat, and lesions) may influence the acquired thermograms.
In the ophthalmoscopic examinations, Modrzejewska A, et al. recorded melanoma to be a dark brown tumor whereas metastases had a bright, off-white color. In the case of retinal hemangioblastoma, it appeared as a reddish-orange tumor with a diameter of 1-1.5 dd, occasionally accompanied by exudative retinal detachment and dilated tortuous retinal veins.
Thermography has been explored for imaging intraocular tumors since the 1970s. A 1971 work by Kruszewski suggested that uveal melanoma can be visualized as hot lesions in thermograms. A 1992 study by Wittig et al. found supportive evidence; the investigators observed high corneal surface temperature in uveal and conjunctival melanoma compared with the normal eyes. Other researchers reported that the thermal response of benign lesions, as opposed to malignancies, is somewhat similar to that of healthy tissue. Consequently, there are reports on the increased metabolic activity of melanomas that can be detected by thermography. An increased pulsatile ocular blood flow and total choroidal blood flow in patients with uveal melanoma was reported in a study by Yang et al.
Olbryt et al. in their study emphasized the role of the immune system and the microenvironment in the progression of melanoma. The levels of pro-inflammatory cytokines, such as IL-6, IL-8, interferon-gamma-γ (IFN-γ), monocyte chemoattractant protein-1, and vascular endothelial growth factor are higher in the eyes of patients with uveal melanoma. Some studies demonstrated that chemokines such as growth-regulated oncogene α (GROα)/CXCL1, GROβ/ CXCL2, GROγ/CXCL3, and interleukin-8 (IL-8)/CXCL8 can control cancer cell proliferation.
This study by Modrzejewska A, et al. supported the above observations. The investigators found the higher temperature in the regions of interest in Group 1 patients compared with the normal patients. The significant differences in the mean temperatures at the central point of the cornea, median, and mode temperature of the eye area and mean, maximum, median, and mode temperature at the orbital cavity area are also observed. This is more likely related to the increased microvascular density observed in melanoma.
Interestingly, in Group 2 patients, the mean temperature at the central point of the cornea, mean, maximum, median, and mode temperature in the area of the eye and orbital cavity was higher. On the other hand, the temperature was lower in eyes with diagnosed melanoma.
In Group 3, all measured parameters were lower in the affected eye. This could be attributed to the ischemia caused by radiation.
The role of the vasculature in tumor metastasis is less well known, but recent evidence shows that the blood vessels at the target site are a key component of the local microenvironment for the tumor cells. This may explain the similar temperature ranges measured near the ocular area.
This study showed lower temperatures for all tested parameters and areas in eyes with choroidal metastases. One possible explanation could be the low-metabolic nature of ocular metastases. That means they do not necessarily increase eyeball metabolism but could be influenced by the activity from the choroid.
Retinal capillary hemangioblastoma
Retinal capillary hemangioblastoma is a benign vascular proliferative tumor characterized by increased blood flow, resulting in greater thermal emission. Strumila et al. measured the surface temperature of Infantile hemangiomas (IHs); the reported median initial temperature for stable hemangiomas, slightly growing group, and growing group were 36.7°C, 37°C, and 37.4°C respectively.
In the current study, Group 5 with retinal capillary hemangioblastoma showed higher parameters for all three regions of interest.
The great merit of ocular thermography is that it can generate real-time assessments of ocular surface temperature. According to numerous literature reviews including this study, thermography can help to screen intraocular tumors, like uveal melanoma, as well as in treatment planning and measuring treatment efficacy. Another perk is that the evaluation of thermograms is not dependent on the experience of the investigator because the camera software independently determines the thermal emissions. Plus, it is fast, non-invasive, and cost-effective.
Potential limitations of thermography include measurement error, errors arising during image acquisition due to environmental factors or contact angle. Failure to exclude other ocular diseases (e.g., dry eye syndrome) that may raise ocular temperature may also negatively affect the result.
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