Newer technologies/techniques and tools in the diagnosis of melanoma

ARTICLE

Auteur(s) : Jitendrakumar K Patel¹, Sailesh Konda², Oliver A Perez², Sadegh Amini², George Elgart², Brian Berman³

¹Jamaica Hospital Medical Center, Department of Medicine, Jamaica, NY 11375
²University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Avenue, RMSB, Room 2023A (R250), Miami, FL 33136
³University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Avenue, RMSB, Room 2023A (R250), Miami, FL 33136

accepté le 14 Avril 2008

While the development of melanoma may be unpredictable, its prognosis is directly linked to the stage of the disease. Periodic skin examinations have allowed early melanoma detection and improved the prognosis of this disease [1]. However, differentiating early melanoma lesions from other pigmented skin lesions (PSLs) is difficult and diagnosing melanoma by simple visual examination with the ABCD rule is incorrect in almost 1 out of every 3 melanoma diagnoses [2-4]. Dermatologists are now equipped with the dermoscope, the non-invasive handheld microscope for differentiating PSLs from melanocytic lesions (table 1). The dermoscope has a magnifying lens and a light source to illuminate the visual field and a transparent medium of clear oil or gel may be applied on the skin for better visualization. However, the dermoscope is limited in the diagnosis of early melanomas that do not exhibit classic features [5-8]. Binder et al. have suggested the epiluminescence microscope (ELM) technique increases sensitivity in formally trained dermatologists, but noted this may decrease diagnostic ability in dermatologists without training [9].

Melanocytic lesions can also be evaluated with the Woods lamp, which emits ultraviolet light at a wavelength of 360, and even by sniffer dogs on the basis of odor [10-15]. However, all these techniques as described above are dependent on the skill of the examiner and can often lead to the biopsy of benign PSLs and potential disregard of malignant ones [16]. Additionally, biopsies are invasive, cannot be performed in every suspected lesion and may have side effects that hinder follow-up studies. In order to decrease the number of excessive invasive biopsies and the potential for subjective human error, we searched for new and non-invasive morphological techniques and tools to assist in the diagnosis of melanoma in its early stages. Such tools include digital imaging systems and computer analysis instruments like MoleMax™, SIAscope™, SolarScan, MelaFind^TM, tape stripping mRNA, ultrasonography, MRI and PET scan; laser- based technology like Confocal scanning laser microscopy (CSLM), optical coherence tomography (OCT), laser doppler perfusion imaging (LDPI); and electrical bio-impedance. A search of the literature from the period between 1970 and 2007 was performed using PubMed, Medline and Google and relevant articles, as well as pertinent articles from each of their bibliographies which were reviewed without any language restriction. The search criteria were all new non-invasive technologies useful for diagnosing melanoma, availability of sensitivity and specificity of methods, discussion of advantages and disadvantages of each method, and the capability of producing good images. Studies that detected skin cancers other than melanoma or had a paucity of supporting scientific data were excluded.

Digital image capturing and computer processing/analysis

After an image of the PSL is captured, the computer recognizes the pigmented border of the lesion by processing it via segmentation and border extraction [20-23]. The software then measures the degree of asymmetry, border irregularity index, hue, quantity and changes in colors, textures, diameter, perimeter, length, area, internal color distributions, and linear diameter [24-26]. This allows for algorithms to factor the weight of each component in the formulation of a diagnosis and provide an objective analysis of a PSL, which can be compared to previously taken images of the same lesion or the standard software PSL image [27]. The computer software has the ability to provide a diagnosis after evaluating the data, which avoids the potential for subjective human error.

Some systems can also objectively evaluate pigmented cutaneous lesions by artificial neural networks (ANNs) [6, 28, 29]. ANNs are mathematical networks based on a biologic neural system that may be implemented as a computer software program. ANNs have powerful modalities for the recognition of complex patterns, with the ability to maintain accuracy even when confronted with missing or inaccurate data which are not readily apparent to human analysis [30]. The functioning ANNs knowledge is self-learning and uses its experiences from previous input data (i.e. melanocytic lesions) to analyze new data. Although ANNs have traditionally been used in engineering, researchers are now applying them to medicine to help doctors analyze, model, and make sense of complex clinical data. ANNs do not require any specific criteria for the diagnosis and function independently of the physician’s knowledge, so the inexperienced user can screen PSLs [30, 31]. With the help of these digital imaging and computer analysis techniques, sensitivity and specificity levels can be reached which are near or better than those of expert dermatologists [32-35].

MoleMax™ (Derma Medical Systems, Vienna, Austria) is based on the light polarization technique of dermoscopes [36]. There are two types of MoleMax™ available, with MoleMax I™ containing only one camera and MoleMax II™ having a two camera system, which is particularly helpful for continuous use by different users. The polarized light source is used with the handheld ELM for close-up imaging and does not require any oil immersion or contact fluids between the skin and ELM. ELM images are automatically transferred, allowing for continuous real-time documentation of PSLs with the examination process [36]. The MoleMax I™ software is conducive for follow-up examinations as the transparent overlay feature performs a standardized comparison of images with previous data. Apart from live videoscopy, MoleMax™ has a CD-ROM based technology that allows total body photography to create a digital map of the patient’s skin for patients with high risk factors and large PSLs. Physician use the stored images in the CD-ROM as a baseline comparison when suspicious changes are found and also for follow-up melanoma screening visits.

Spectrophotometric Intracutaneous Analysis (SIAscope™, Astron Clinica, Cambridge, UK) is a fast, non-invasive and safe method for the diagnosis of PSLs up to 2 mm. This high resolution instrument visualizes the skin structure, vascular composition and reticular pigment networks with detail and clarity, attaining up to 96% sensitivity [37, 38]. There are two methods of SIAscopy, contact and non-contact. Contact SIAscopy utilizes a hand held scanner (SIAscanner) that is placed directly on skin surface of interest before scanning it with light. In non-contact SIAscopy the skin is not touched. A digital camera with a special filter is used to produce images of larger areas of skin. Both methods generate SIAgraphs, computer-generated images that show the distribution of major skin components (melanin, collagen and blood) [37]. The SIAscope™ is based on the principle that individual skin components vary in their optical properties. The device emits harmless radiation ranging from 400 to 1,000 nm into an area of skin with dimensions of 24 × 24 mm or 12 × 12 mm and then measures the reflected light quantity for each wavelength [33, 38]. Skin and its components absorb and/or reflect light to various degrees and can interact preferentially with particular wavelengths of light. The SIAscope™ extracts information regarding the location, quantity and distribution of the skin and its chromophores, including melanin, collagen, and hemoglobin (i.e. vascularity) within the epidermis and papillary dermis, producing eight narrow-band spectrally filtered images, and then displays a characteristic SIAscopic image (figure 1). The data are then displayed via SIAgraphs, which are graphical representations of the digital information [38]. These chromophore wavebands may be removed to view only the melanoma diagnostic information on the graph. These simple features were found to be highly specific (up to 87%) and sensitive (up to 96%) for melanoma [38]. Moncrieff et al. studied 348 lesions over a 12 month period with the SIAscope™ and found it to be highly specific (80.1%) and sensitive (82.7%) [33].

SolarScan^® is an automated instrument (Polartechnics Ltd, the Sydney Melanoma Unit and CSIRO) for the diagnosis of primary melanoma. It has a three charge-coupled device (CCD) video camera for acquiring digital images of lesions, which can be compared with an empirical database of more than 1800 benign and malignant lesions. Oil is placed on the lesion to eliminate surface reflections and the remote-head camera takes 24-bit, 760 × 570-pixel images with each pixel capturing a 32 × 32 μm area of the skin [39-41]. The fiber optic light source is coupled to a halogen lamp with a color temperature of 3,000 °K. The calibration procedure consists of white balance, black balance, shading correction, dynamic range, and image capture of a reference surface of known reflectivity [39]. In addition to the session-level calibration, the system also has image-level calibration, which is facilitated by 4 gray-scale calibration targets present in each image. The resolution of each of these images is 64 μm per pixel (× 6.2 screen magnification) [39]. Changes in color, pattern and size are recorded along with the position of each monitored lesion on a graphical map of the patient’s body. Images of a lesion from different time points can be viewed simultaneously and the corresponding analysis is displayed on four different graphs. The SolarScan^® software can automatically select a computerized border for each lesion photo or the user can select one of the three border selection methods to assist the computer with lesion analysis (figures 2A-B). The three-chip camera and color calibration ensures accurate detection of up to 14 shades of dermatoscopic colors, as well as the specific color of Blue-White veil, which is extremely useful for invasive melanoma diagnosis, with a specificity of 97% [39]. Preliminary data suggest that its performance is comparable or superior to that of clinician groups [24, 39, 40]. In the multicenter study of SolarScan, SW Menzies et al. studied 2,430 PSLs and found that SolarScan^® has 91% sensitivity and 68% specificity, which is comparable or superior to expert diagnosis [24].

MelaFind^TM (Electro-Optical Sciences Inc., NY) is a multispectral digital dermoscope with a specialized imaging probe and software to assist with differentiation between early melanoma and other PSLs. Filtered white light from a stable source is transmitted to the skin by a fiber optic illuminator controlled by the computer. After the CCD camera has detected 10 different, narrow-spectrum wavelength bands including visible and infrared light, a multi-spectral sequence of digital images 1,280 × 1,000 pixels in size is produced in less than 3 seconds [34]. Afterwards, each sequence of multi-spectral images is analyzed for wavelet maxima, asymmetry, color variation, perimeter changes, and textures changes, the software assists with a differential diagnosis [35]. Images are obtained with the MelaFind^TM digital dermoscope gray-scale with 1024-level intensity resolution and are produced in each of 10 spectral bands ranging from 430 nm to 950 nm controlled by narrow interference filters on a rotating wheel [42]. Each image has more than 1 million pixels within a 2 × 2 cm visual field, and each pixel is approximately 20 μm [34]. The acquired images are stored without loss of resolution and identified with headers that record wavelength and exposure. Initial studies demonstrated that MelaFind^TM can achieve 95% to 100% sensitivity and 70% to 85% specificity [34, 35].

The Fotofinder dermoscope, DermDOC^IM is an example of a video dermoscope attached to a digital camera system [36]. It can provide high quality images, variable magnification, macro and micro application, and analytical capability. However, video dermoscopes are at a disadvantage compared to cameras because they lose image resolution after conversion to images.
Table 1 Dermoscopes and theirs features

Tape stripping mRNA method

DermTech’s (La Jolla, CA) Epidermal Genetic Information Retrieval (EGIR^TM) technology is the commercialized form of this nucleic acid retrieval process and relies on the use of a custom adhesive film to sample the surface layer of skin. The EGIR^TM technique has the advantage of being non-invasive, rapid and easy to perform, painless, and practical for virtually any skin surface. EGIR^TM technology also has the advantage of being able to retest the same lesion, leading to a more accurate diagnosis of melanoma and reducing the need for painful biopsies. In a study by Wachsman and colleagues, suspicious pigmented lesions were tape stripped four times using EGIR^TM and then biopsied as per standard of care. Normal, uninvolved skin was also tape stripped to serve as the negative control. They found a 20-gene classifier that discriminated melanoma from atypical nevi and subsequent testing of this classifier found it to be 100% sensitive, 90.6% specific and 92.4% accurate for detection of both in situ and invasive melanoma [45, 46]. Additional clinical trials are currently underway to finalize candidate gene expression profiles for identifying early stage melanomas.

It is important to note that tape stripping is not expected to substitute for necessary biopsies. Tape stripping is most beneficial as a pre-screen for suspicious pigmented lesions. If an RPA comes back positive for a particular gene expression profile associated with melanoma, the pigmented lesion should be excised and the depth determined.

Ultrasound

Resolution of ultrasound systems can refer to either axial or lateral resolution. The axial resolution is the smallest thickness that can be measured and the lateral resolution refers to the width of the smallest structures that can be resolved [51]. In general, ultrasound systems convert the voltage changes recorded by the transducer and display these signals as images. There are different types of signal processing ranging from A through E [53]. B-scans combine the information from sequential A-scans (Acoustic scan) and display each point according to its relative brightness (hence B-scan). Each point on a B-scan is brighter or darker, corresponding to the intensity of echoes from the corresponding anatomic structure. Therefore, B-scans provide images that resemble anatomic cross sections of scanned tissues [55]. Currently, B-scans are mainly used as ultrasonographic procedures in dermatology using intermediate- or high-frequency ultrasound systems while A-scan ultrasound systems are mainly used in ophthalmology. However, A scans can be used to assess skin thickness and C, D, and E-scans are various forms of B-scan addition also useful in dermatology (figure 4) [53].

With sonography, the preoperative tumor thickness is sometimes overestimated because of an underlying inflammatory infiltrate, which is also visualized as a hypoechoic area and cannot be distinguished from melanoma [51]. The dermatologic applications of B-scan ultrasound with 7.5 to 10.0 MHz transducers include the identification and description of suspicious palpable structures within the subcutaneous (solid, cystic, and complex); exploration of deeper aspects of larger tumors, assessing the relationship to nerves and vessels to provide crucial preoperative information; and follow-up of patients with malignant skin tumors including melanomas [56]. According to various studies, 7.5 to 10 MHz ultrasound transducers have excellent sensitivity (99.2%) and specificity (99.7%) [51, 57-59]. However, in patients with melanoma, ultrasound scanning should be performed every 3 to 12 months according to the thickness of the primary melanoma [57-60]. Despite various frequency transducers examining depths greater than 1.5 cm, melanoma metastasis cannot be separated from that of another tumor. The quality of information depends heavily on the skill and experience of the examiner, clinical setting and history of melanoma. Ultrasound systems available for dermatological examinations are the Dermascan C (Cortex Technology, Hadsund, Denmark) (figures 5A-B), DUB 20 (Taberna pro medicum, Lüneburg, Germany) (figure 6), SSA-340 A (Toshiba Medical Systems, Neuss, Germany), and the Siemens Sonoline Elegra (Siemens, Erlangen, Germany), AU 4 Idea, and AU 5 Idea sonography (Esaote Biomedica, Genoa, Italy) (figures 7A-B).
Table 2 Resolution of high frequency transducers [53]

Laser based technology

Reflectance CSLM depends on the inherent reflective properties of tissue structures and the presence of melanin, which results in a bright-white image signal that illuminates the cytoplasm of melanin-containing cells like pigmented keratinocytes, melanocytes, and melanophages [69]. Free cytoplasmic melanin pigments and cytoplasmic pigmented and nonpigmented melanosomes provide strong contrast for infrared laser light resulting in bright cytoplasm [66, 69-71]. Using near infrared illumination, the maximum depth of imaging is limited by the scattering of the sc surface and the optics of the skin [72]. There are two types of reflectance CSLM, diffuse and polarized.

Diffuse reflectance spectroscopy in the wavelength range of 550 to 1,000 nm has oblique incidence imaging which helps to distinguish between benign and cancer-prone skin lesions [73, 74]. Polarized reflectance spectroscopy provides real-time diagnostically useful information for precancerous lesions which are characterized by increased nuclear size, increased nuclear/cytoplasmic ratio, hyperchromasia and pleomorphism, which are currently assessed by invasive biopsies [75, 76]. Pellacani et al. found the presence of non-edged dermal papillae, atypical cells, and isolated nucleated cells within dermal papilla, pagetoid cells, widespread pagetoid infiltration, and cerebriform clusters to be strongly correlated with MM diagnosis in their reflectance CSLM examination [77, 78].

Fluorescence CSLM depends on different fluorescent molecules (endogenous or exogenous) emitting florescence at different levels in tissue. Accordingly, a laser light with the appropriate wavelength can be used to excite these fluorescent molecules to emit a long wavelength signal which can be detected and displayed on a grey scale [79]. Anikijenko et al. showed that fluorescent labeled antibodies injected in an animal melanoma model showed a pathological overexpression of protein and also changes in the microvascular structures that enabled in vivo detection of melanoma and surrounding blood vessels in athymic mice [80].

Remarkably, the presence or absence of monomorphic melanocytes as a single diagnostic criterion has been found to have a sensitivity up to 98.2% and a specificity up to 98.9% (table 4). However, in its current state of technological development, CSLM has two major limitations compared with conventional histology. It has a poor resolution of chromatin patterns, nuclear contours and nucleoli and can assess micro-anatomical structures only to a depth of approximately 300 μm [63]. Thus, processes in the reticular dermis cannot be examined for the presence or absence of invasion. Furthermore, melanomas without an intradermal component will most likely escape detection by CSLM in its current state [61]. The main advantage of CSLM is that it permits non-invasive quasi-histological assessment of the skin ‘at the bedside’. Multiple sites and lesions can be examined during the same visit, the same lesion can be evaluated at different time points, and images are available immediately for electronic storage and histopathology consultation [61]. Various CSLMs on the market use the technology described above, including Vivascope^® 1500 and 3000 (Lucid Inc, NY USA), and Optiscan^TM (Optiscan Pvt Ltd, Australia). Lucid, Inc. (www.lucid-tech.com) developed the VivaNet^® telemedicine server and network which is designed to transfer and manage clinical data between dermatology practitioners using VivaScope^® Confocal imagers with pathologists or other medical specialists.

Optical coherence tomography (OCT) was developed in the late 1980s. While this technique was originally used to examine eye structure, it is now used widely in dermatology [81]. OCT is analogous to ultrasound B-mode imaging with the exception that it uses light rather than sound waves [82, 83]. OCT is described as an intermediate imaging device between ultrasound and CSLM that produces high resolution cross-sectional images of the internal microstructure of living tissue resembling an unstained histopathological section of skin [84, 85]. In contrast to the eye, which is naturally a low light scattering transparent medium, the skin is nearly non-transparent due to absorption and scattering; the former is mainly influenced by the concentration of melanin and hemoglobin, while the latter, by differences in the refraction index. In the wavelength range of 700 to 1,300 nm, absorption is relatively low, so that light penetrates deep into the skin and optical inhomogeneities are the main factor influencing the image [81]. When illuminating the skin, most of the photons are scattered more than once, which can lead to artifacts in the image. In the skin and other highly scattering tissues, OCT can image small blood vessels and other structures as deep as 1-2 mm beneath the surface [86, 87].

The OCT technique is based on the wave principles of the Michelson interferometer. The light sources used for OCT are low coherent superluminescent diodes operating at a wavelength of about 810 nm to 1,300 nm. OCT provides in vivo two-dimensional images with a scan length of a few millimeters, a resolution of about 15 μm and a maximum detection depth of 1.5-2 mm [72, 81, 86, 87]. OCT with an 810 nm light source is able to examine skin depths up to 700 μm while a 1,313 nm light source can examine up to 1.2-2 mm with reduced scattering [86, 87]. The reflection of the skin surface can be reduced by application of an ointment or glycerol, which makes the skin more transparent, reduces light scattering and increases detection depth [81, 88]. Alternatively, short coherence length can be achieved by ultrasound femtosecond laser pulses which can travel two paths [83, 89]. The first light path travels through air and is reflected back by a mirror and the second focuses directly into the skin. These two reflected lights combine at the detector. When the optical paths of the two beams are equal, the light from the two beams interferes constructively giving a bright spot, whereas when they are out of phase, they interfere destructively. Images are logarithmic false color or grey scale and are obtained by scanning the mirror at the end of the light path and the incident spot. Even though it is possible to almost achieve real-time imaging, the resolution only enables the visualization of architectural changes and not of single cells [81]. Axial resolution depends on the coherence length of the light source, whereas the lateral resolution is given by the focal spot size and the scan step. A calculation of the thickness of layers, the intensity of the signal and the light attenuation coefficient in different depths can be performed on the averaged A-scan in a region of interest. Melanocytic skin tumors show increased light scattering and more homogenous signal distribution than healthy skin. The disappearance of the second intensity peak, which represents an intact border between the epidermis and dermis, is suggestive for infiltrative malignant melanoma (MM) [81].

OCT measurement is unobtrusive, safe, and has no side effects. Because of the fast scanning mode (4 s for 4 mm scan length) and the low output power of the light source (in a range of a few milliwatts), this technique meets the safety standards for irradiation of tissue [81]. Compared to other non-invasive methods, OCT has higher resolution than ultrasound and greater detection depth and image size than CSLM [90]. Newer OCT modalities, such as the Dopppler OCT, spectroscopic (absorption) and wavelength-dependent OCT, and OCT elastography are more precise and accurate with more real-time images [91]. A portable fiber-optic based OCT requires only 1 second to simultaneously provide high-resolution images of skin structure, collagen birefringence and blood flow [92]. With the Doppler and phase-resolved techniques, one can visualize the location of vessels and capillaries as well as determine the flow velocity in PSLs [93, 94]. Newer systems allow the storage of data and images in a digital format that enables quantitative software analysis of images.
Table 3 Key features of pigmented lesions by CSLM [66]

^**Accuracy for melanoma.

Laser Doppler perfusion imaging (LDPI)

The principle behind LDPI is the doppler effect on monochromatic radiation caused by movement of erythrocytes in the microvascular network [105]. The output of the LDPI system consists of two different two-dimensional data sets, perfusion and total backscattered light intensity (TLI), with a point-to-point correspondence. The blood perfusion data set, represented by a color-coded image, is calculated from the backscattered and Doppler-shifted light, defined as the product of the red blood cells mean velocity times their concentration in the sampled tissue volume [103]. The second data set maps the TLI and is coded into a photographic-like grey scale image of the lesion. When the laser beam is reflected by the erythrocytes, the returning signal is recorded in the head of the scanner and translated into an electrical impulse; a scale of six colors demonstrates increasing degrees of perfusion in colors of blue, green, yellow and red [105]. Since laser light is the origin of this type of image, it should not be confused with common optical grey scale images generated by broadband backscattered light. Each recorded image consists of 64 × 64 measurement sites and represents the blood perfusion in a skin area of approximately 13 × 13 mm. LDPI is influenced by the number and the velocity of erythrocytes in the tissue [106]. Several studies showed that LDPI has a sensitivity of almost 100% and a specificity of 85-90% [104, 107]. Stucker et al. examined 189 patients with LDPI and found that perfusion was 3.6 ± 1.5 times higher in MMs and 2.2 ± 1.1 higher in suspicious melanocytic nevi than in healthy skin [104]. MMs were found to have a significantly higher flow than clinically suspicious melanocytic nevi (p < 0.001) and at least 1.8 times higher flow values than normal healthy skin [104]. Cutaneous blood flow measurement can play an important part in the assessment of melanoma and can possibly be used as an adjunct to clinical diagnosis and follow-up, and as a source of valuable preoperative information about tumor vascularization [104, 107, 108].

Other imaging

Electrical bio-impedance

Measurements of suspicious PSLs are made with an electrical impedance spectrometer both over the center of the lesion as well as an ipsilateral reference skin site. Prior to measurements, the site and lesion are soaked with 0.9% normal saline solution (pH 6) for 1 min to reduce the naturally high impedance of the SC and increase the contact between the tissue and probe. Magnitudes between 1 and 10 kHz and phases between 0.1 and 1 MHz are used to differentiate melanoma from benign nevi [109]. Impedance spectra of the lesions and the reference skin are measured at five depth levels, approximately 0.1-2 mm into the tissue [109, 116]. Newer models of electrical impedance have a digital camera along with an automated software analysis. The induced electric current is detected at each sensor element and measured using a trans-impedance technique, while the other electrodes remain at ground potential [117]. The typical amplitude applied between the source electrode and the measuring probe is in the range of 2.5 V with a frequency range of 100 Hz-100 kHz. After the probe is applied to the lesion, the measured trans-impedance signals are converted to digital signals and transferred to the computer for further analysis [116]. A digital picture of the lesion and its surroundings is recorded followed by a close-up frame of the lesion. The borders and axes of the lesion are displayed on the computer and an automatic algorithm provides five parameters to describe the lesion. The first parameter is asymmetry (A1 and A2) which is defined as the ratio between the non overlapping area of the lesion when folded over either of the two perpendicular axes, and the total area. The ratio between the squared perimeter of the lesion and a factor of the area inside the border is defined as the second border parameter (B). The color parameter (C) is defined as the standard deviation of the red-gray levels inside the border. Finally, the surface (S) is defined as the area of the lesion in square millimeters [116]. The combined examination of electrical impedance scanning and image analysis lasts approximately 7 minutes [116].

Electrical impedance has a high sensitivity of almost 100 percent for in situ and thin melanomas [116]. Therefore, electrical impedance can differentiate melanoma from benign nevi with studies demonstrating ranges of 92-100% sensitivity and 67-75% specificity [109, 117]. However, electrical impedance properties of human skin vary significantly with the body location, age, gender, and season [118-121]. Aberg et al. studied the bio-electrical impedance spectra from skin cancer and other lesions by using both regular non-invasive probes and a novel micro-invasive electrode system with a surface furnished with tiny spikes that penetrate the SC [122]. Even though the spiked electrode is invasive by definition, Aberg et al. considered it micro-invasive because the spikes penetrate the SC and epidermis but do not reach the depths of blood vessels or sensory nerves in dermis [122]. Thus, the information from micro-invasive impedance is better suited for detecting subtle skin alterations that manifest beneath the SC, such as melanoma. Aberg et al. found that the spiked micro-invasive electrodes are better for melanoma detection (92% sensitivity and 80% specificity) than the regular non-invasive probes [122]. Commonly used instruments in electrical impedance studies include the SciBase II impedance spectrometer (SciBase AB, Huddinge, Sweden), and the TS2000M (Mirabel Medical System Ltd., Migdal Ha’Emek, Israel).

Magnetic Resonance Imaging (MRI)

Positron emission computed tomography (PET)

PET using 18F-FDG has been studied extensively since 1991 and shows great promise in the detection of metastatic cutaneous melanoma and may also prove useful in the secondary prevention of primary melanoma in those individuals at high risk or with a familial disposition [136]. Although rare, primary melanomas have also been found in ocular, gastrointestinal, anorectal, genitourinary, mucosal, leptomeningeal, sinonasal, pulmonary, mediastinal, ovarian, vaginal, and vulvar sites and can represent diagnostic challenges [137-148]. PET may be valuable in detecting these primary melanocytic lesions in non-skin sites as a dermatologist’s trained eye and the other diagnostic techniques described above can only detect those primary melanomas localized to skin.

When 18F-FDG is used, it emits a positron which is directed onto negatively charged electrons. When the two particles collide and exterminate each other at 180°, two photons are formed, with each having an energy of 511 KeV [149]. PET scan has the ability to detect these photons, localize their source of origin, and produce an image based on the photon activity. The entire body can be analyzed either in qualitative or quantitative measurements, which may be helpful in differentiating between benign and malignant cells and determining the treatment response [150-155]. Table 5 displays the overall sensitivity and specificity of PET in different studies. When compared to ultrasound, PET scan is more costly and time consuming. However, ultrasound examination of lymph node metastasis requires more time due to the sequential examination of individual lymph nodes. Additionally, whole-body PET scanning is cheaper than whole-body MRI scanning [156, 157]. The sensitivity of PET is also decreased when tumor size is small (table 6).
Table 5 Detection of melanoma using FDG-PET

Table 6 Comparison of technologies

Conclusion

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