## 1 Introduction  
Colon cancer is the second most common cause of cancer death in Europe both for women and men, and the third most common cancer worldwide [1]. About 1.8 million new cases of colorectal cancer were recorded globally in 2018 [2], being the third most common cancer in men and second in women. The five-year survival rate is 90 percent for colorectal cancers diagnosed at an early stage, but unfortunately only 4 out of 10 cases are found this early [3]. Clinicians demand new non-invasive technologies for early diagnosis of colon polyps, especially to distinguish between benign and malignant or potentially malignant lesions that must be resected immediately. New methods should also proportionate information for safety margin resection and remaining tissue inspection after resection to decrease the possibility of tumor recurrence and improve patient prognosis. The current gold-standard imaging technique during patient examination is colonoscopy with narrow band red-flag technology for improved lesion visualization. During the procedure, lesions can be classified with Paris (morphology) [4] and Nice (vessel and surface) [5] classification patterns based on the physician experience. As this superficial information is not enough, the final diagnosis of the lesion is determined by the histopathological analysis after biopsy, meaning that all the suspicious polyps are resected. Bleeding related problems usually occur after biopsies are performed, with the risks that this entails for the patient. In fact, most problems occur when the biopsy is performed on a blood vessel and the incidence is higher when it is performed on patients with an abnormal blood coagulation function [6]. In relation to the latter, the rate of perforation associated to colonoscopies with polypectomy is 0.8/1000 (95% confidence interval (CI) 0.6-1.0) and the rate of bleeding related to polypectomies is 9.8/1000 (95% confidence interval (CI) 7.7-12.1) [7]. However, it is demonstrated that hyperplastic polyps are of a benign nature and can be left untouched, avoiding the underlying bleeding risk of resection, saving diagnosis time, costs, and patient trauma during that period [8]. On the other side, pre-malignant lesions and adenomatous polyps cannot be distinguished from neoplastic lesions as adenocarcinoma with the current diagnosis methods. In this sense, new imaging techniques and interpretation methods could allow real-time diagnosis and would facilitate better in-situ treatment of lesions, improving patient prognosis, especially if the diagnosis is made at early stages of the disease. In recent years, different advanced imaging technologies that allow sub-surface microscopical inspection of tissue in an \"optical-biopsy\" manner have been under study for colonic polyps [9], such as: reflectance confocal microscopy (RCM) [10], multi-photon microscopy (MPM) [11], and optical coherence tomography (OCT) [12], among others. Of the mentioned techniques, a device called Cellvizio based on confocal laser endomicroscopy (CLE) is the only one commercially available. Using confocal mini-probes inserted in the working channel of flexible endoscopes, the system is used for studying the cellular and vascular microarchitecture of tissue. Colorectal lesions diagnosis [13; 14; 15] is one of the targeted applications and the corresponding probe reports a field-of-view (FOV) of 240 \(\upmu\)m, 1 \(\upmu\)m resolution and 55 to 65 \(\upmu\)m confocal depth, with 20 maximum uses. The inconvenience of this system is that the successful usage by clinicians depends on specific training on image interpretation. Moreover, the main limitation is that this technology requires the use of an exogenous fluorophore which results in a more invasive procedure for the patient. In the case of MPM [16; 17], which relies on the absorption of an external or endogen (as collagen) tissue fluorophore, high resolution images at sub-cellular level can also be obtained to study structural information, including also functional information.