Classification two-photon absorption concept first described 1931 by Göppert-Mayer

Classification of nonlinear microscopyBased on coherence property, NLOM is generally classified into two categories. First one is incoherent and second one is coherent. The incoherent modalities create random phase signal and their power is proportional to radiation producing molecules concentration, such as nonlinear versions of fluorescence microscopes. Nonlinear versions of fluorescence microscopes are based on the simultaneous absorption of two or more photons. Examples of incoherent NLOM are TPEF microscopy, MPF microscopy. One the other hand, second category of NLOM produce signals whose phase is rigorously prescribed by a variety of factors, including the excitation light phase and the geometric distribution of the radiating molecules.

Coherent signal power is proportional to the concentration of radiating molecules squared. Nonlinear versions of coherent microscopy are based on the simultaneous scattering of two or more photons. Examples are SHG, THG and CARS microscopy. This review describes recent NLOM advances and applications in the field of cancer imaging.

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Application of incoherent nonlinear microscopyMulti-photon excitation fluorescence (MPEF) In MPEF microscopy, photons are being absorbed concurrently. These include two-photon excited fluorescence and three-photon excited fluorescence microscopy. Here every photon corresponds to the half of the energy.

This two-photon absorption concept first described 1931 by Göppert-Mayer 8. After that, in 1961 Wolfgang Kaiser practically first time observed this two-photon absorption 9. Finally, this two-photon excited microscopy was combined with laser scanner and got patent in 1991 by Denk and Strickler 10.Wang et al.

(2002) 11 demonstrated TPEF microscopy in mammary carcinoma xenografts expressing green fluorescent protein (GFP) and cyan fluorescent protein (CFP) in the breast cancer animal model. They revealed extracellular matrix, cell motility, and chemotaxis behavior differences in mammary carcinoma. MPEF microscopy was also used for oral malignancy.

Wilder-Smith et al. (2004) 12 demonstrated a non-invasive squamous cell carcinoma imaging for oral malignancy diagnosis in a hamster model. Their method was able to image of collagen matrix and fibers, cellular infiltrates, blood vessels, and microtumors.

The same group 12 demonstrated premalignancy and oral malignancy imaging through multiphoton microscopy which was combined with OCT, optical Doppler tomography (ODT). By using autofluorescence phenomenon, multiphoton autofluorescence microscopy (MPAM) applied for hamster oral mucosal neoplasia 13. This group was successfully demonstrated quantitative aspects of oral cancer in a hamster model. Also recently in 2016, there was a development of multiphoton microscopy (MPM) for oral epithelial dysplasia based on MPAM by the same group 13. This method was non-invasive and very important, because this dysplasia could progress to cancer 14.  Sipkins et al. (2005) 15 imaged a metastatic tumor spread in the bone marrow through MPM.

Sahai et al. (2005) 16 reported a simultaneous in-vivo GFP, CFP as well as collagen imaging by MPM in mammary carcinoma. Lin et al. (2006) 17 used multiphoton fluorescence (MF) to distinguish basal cell carcinoma from the normal dermal stroma. This technique could replace the Mohs’ surgery. Kirkpatrick et al. (2007) 18 evaluated ovarian cancer by TPEF. They used multiphoton fluorescence lifetime imaging protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia.

Role of macrophage during mammary tumor intravasation was first described through MPM by Wyckoff et al., (2007) 19. Kedrin et al. (2008) 20 described an intravital two-photon excitation microscopic method imaging of metastatic behavior through a mammary imaging window.

Dermatological imaging demonstrated the efficiency of two-photon excited fluorescence microscopy to differentiate normal human skin from skin cancers. Dimitrow et al. (2009) 21 demonstrated this multiphoton based tomographic dermatological imaging to distinguish cancerous skin from normal skin. De Giorgi et al. (2009) 22 used combined two-photon excitation fluorescence microscopy, fluorescence lifetime imaging microscopy, multispectral MPM for cutaneous tumors imaging. This method was effective to distinguish between healthy skin from basal cell carcinoma and malignant melanoma.

Williams et al. (2010) 23 demonstrated MPM to ovarian Cancer by laparoscopic approach. Heuke et al. (2013) 24 described a similar multimodal imaging system for skin cancer, which composed of CARS, SHG and TPEF imaging.

Zhuo et al. (2011) 25 described a label-free colonic cancer monitoring modality of TPEF microscopy. Xiong et al. (2011) 26 described TPEF imaging of human basal cell carcinoma and squamous cell carcinoma. Leupold et al. (2011) 27 used TPEF microscopy for optical detection of malignant transformation in melanocytes. Piletic et al.

(2010) 28 demonstrated use of two-photon microscopy (TPM) for human melanoma diagnosis by combining it with pump-probe imaging in. Later in 2014, a nonlinear spectral imaging modality was introduced by Thomas et al. 29 for murine cutaneous squamous cell carcinoma model. This method was combination of both TPEF and SHG. Adur et al.

(2011) 30 used TPEF microscopy for human serous ovarian tumor diagnosis. Cicchi et al. (2013) 31 used MPM for morphological and functional imaging of adenomatous polyp and adenocarcinoma. Yan et al.

(2010) 32 demonstrated MPM to diagnose gastric cancer. The two-photon imaging system also used for bladder carcinoma diagnosis 33, 34. Cicchi et al. (2010) 35 developed a combined two-photon and SGH imaging system for bladder carcinoma.

Tewari et al. (2011) 36 used MPM for human prostate and periprostatic cancer imaging. Also Durand et al. (2015) 37 demonstrated a real-time MPM for periprostatic nerve tracking.

This method does not require biopsy. Meyer et al. (2012) 38 used TPEF microscopic imaging for advanced carcinoma of the hypopharynx, larynx, and left tonsil. Chen et al. (2013) 39 demonstrated lung cancer imaging by multiphoton imaging modality. This is considered as real-time non-invasive ‘optical biopsy’.Currently, breast cancer is one of most common cancer in women and ranks second as a cause of cancer death in women. Multiphoton imaging could lead early diagnosis of this fatal cancer type.

Wu et al. (2013) 40 applied a label-free breast cancer imaging method. In the same year, Patsialou et al. (2013) 41 described an intravital multiphoton imaging of human breast tumor. Xu et al. (2013) 42 used Two-Photon Excited Auto Fluorescence (TPEAF) microscopy for quantitative label-free lung cancer imaging.

MPM could also play a tremendous role in ovarian cancer diagnosis as it is also fatal and widespread types of cancer. More than 100000 death incidence happens per year worldwide according to a report of 2011 43. Watson et al. (2013) 44 used MPM for ovarian tumorigenesis imaging in model mice. The same group also used MPM for endogenous contrast imaging in ovarian cancer of mouse model 45.

Chen et al. (2013) 46 used TPEF microscopy for cancerous esophagus tissue imaging. Makino et al. (2012) 47 developed multiphoton tomographic imaging modality for colon cancer. They used their multiple photon microscopy based endoscope prototype. Also recently Xu et al.

(2017) 48 demonstrated further about MPM based esophageal cancer detection, which strongly suggest the potential of MPM for development of a multiphoton endoscope system for in vivo imaging in future.  Zhuo et al. (2012) 49 demonstrated label-free two-photon microscopy of goblet cells for colon cancer. Yan et al. (2013) 50 developed low rectal cancer imaging moadlity in real time through MPM, which led to the feasibility of using MPM to make real-time multiphoton colonoscopy.

Also recently Xu et al. (2017) 51 applied MPM for pancreatic ductal adenocarcinoma detection. It showed that MPM could provide in vivo real-time information of pancreatic neck resection margins (RM) status during surgery. Galli et al. (2013) 52 used two-photon excited fluorescence microscopy for kidney tumor imaging.

Recently in 2016, there was a real-time multiphoton imaging method for gastric cancer demonstrated by Yan et al. (2016) 53. This method suggests laparoscopic imaging of T4 gastric cancer which consists of serosal invasion. In association with nanoparticles, TPEF microscopy was also used recently in vitro imaging of breast cancer cell line 54. Recently a combined MPM was demonstrated by Xu et al. (2017) 55. They combined two-photon excited fluorescence (TPEF), SHG microscopy for label-free diagnosis of human esophageal squamous cell carcinoma. Also recently Bower et al.

(2017) 56 made MPM and applied in rat mammary tumor imaging. In the future, it is expected that MPM can be used in clinical research in the future with the development of a new MPM endoscope system.