Lithuanian University of Health Sciences
Final Master Thesis
Electrical Impedance Spectroscopy (EIS)
– An Overview of a New Method in Melanoma Diagnosis –
Faculty: Medicine
Department: Dermatology
Name of the Author: Philipp Wagner
Study Program: Integrated Master (English)
Supervisor: Prof. dr. Skaidra Valiukevičienė, MD, PhD
Places of Writing: Würzburg, Germany / Kaunas, Lithuania / Florence, Italy
Year: 2018-2020
Table of Content
Summary (English) ... ii
Santrauka (Lithuanian) ... iii
Conflict of Interests ... iv
List of Abbreviations ... v
List of Figures ... vi
List of Tables ... vii
Introduction ... 1
1. Methods and Sources ... 2
2. Melanoma Incidence and Mortality ... 3
2.1. Lithuania ... 4
2.2. Germany ... 5
2.3. The United States ... 6
2.4. Analysis of Incidence and Mortality ... 6
3. Definition of Electrical Impedance Spectroscopy and its Technical Details ... 7
4. The Practical Use of EIS ... 9
4.1. Indications and Intended Use of EIS ... 9
4.2. Contraindications ... 12
4.3. The Procedure of an EIS Examination ... 13
4.4. EIS Examination Results and its Analysis ... 14
5. Advantages and Disadvantages of EIS ... 15
5.1. Advantages ... 15
5.2. Disadvantages ... 16
6. Scientific Background of EIS ... 17
6.1. Effectiveness and Safety of EIS ... 17
6.2. EIS as Adjuvant to Dermatoscopy and Clinical History in the UK ... 19
6.3. Effect of EIS as Baseline Diagnostic Tool ... 20
Conclusion and Outlook ... 22
List of References ... 24
Appendix ... 27
Summary (English) Author: Philipp Wagner
The master thesis “Electrical Impedance Spectroscopy (EIS) – An Overview of a New Method in Melanoma Diagnosis –“ is supposed to give an impression over a new technology for the diagnosis of malignant melanoma. The base of this thesis is reviewed literature of various sources, ranging from information provided by the manufacturer to scientific studies and textbooks, written by leading dermatologists of this specific field.
Incidence rates of malignant melanoma are rising worldwide. The percentages are especially high in northern European countries, north America, and Australia. Due to this fact, early detection and diagnosis of premalignant stages are decisive. To be on the safe side, nevi with a malignant appearance are often excised, preferably sooner than later. In most cases, the excision serves diagnostic and therapeutic purposes at the same time. The disadvantage of this invasive procedure is an enormous amount of excisions, of which many might be unnecessary. A new state of the art technology allows now early detection and tissue interpretation with a non-invasive approach.
Electrical impedance spectroscopy (EIS) is able to analyze a nevus by measuring the electrical resistance of the respective tissue, which is dependent on the structural characteristics of a cell. An algorithm calculates a score, showing the level of atypical changes. The result is meant to be a support in the final decision, whether to excise a nevus or not. Negative predictive values and positive predictive values have very high percentages. Furthermore, a sensitivity of 97 % and a specificity of 34 %, are values achieved by EIS, which cannot be reached easily by other methods.[12] The new method in melanoma diagnosis is highly accurate, fast, and non-invasive.
However, the fixed costs and variable costs are relatively high. A recent study from the UK showed that EIS also can be used as diagnostic tool adjuvant to dermatoscopy.[25] In Australia, dermatologists tested EIS as a baseline tool in melanoma diagnosis.[14] The pivotal study gave hints, that EIS is not only a valuable tool in melanoma diagnosis, but may be also used for the
Santrauka (Lithuanian)
Autorius: Philipp Wagner
Magistro darbas „Elektros varžos spektroskopija (EIS) – naujo melanomos diagnostikos metodo apžvalga“ turėtų padėti suprasti naują piktybinės melanomos diagnozavimo technologiją. Šio darbo pagrindas yra įvairių literatūros šaltinių apžvalga, analizuojant tiek gamintojo pateiktą informaciją, tiek mokslinius tyrimus bei vadovėlius, parengtus šios specifinės srities dermatologų.
Sergamumas piktybine melanoma auga visame pasaulyje. Procentai ypač dideli šiaurės Europos šalyse, Šiaurės Amerikoje ir Australijoje. Dėl to lemiamą reikšmę turi ankstyva ikivėžinių stadijų diagnostika. Siekiant užkirsti kelią piktybinės formos apgamų (nevi) atsiradimui dažniausiai atliekamos ankstyvos ekscizijos. Daugeliu atvejų ekscizija tuo pačiu metu naudojama diagnostikos ir gydymo tikslais. Šios invazinės procedūros trūkumas yra platus audinių pašalinimas, o daugelis jų - nereikalingai. Nauja šiuolaikinė technologija leidžia anksti nustatyti ir išaiškinti apgamus neinvaziniu būdu. Elektros varžos spektroskopija (EIS) yra pajėgi išanalizuoti apgamus, išmatuojant atitinkamo audinio elektrinę varžą, kuri priklauso nuo ląstelės struktūrinių savybių.
Algoritmas apskaičiuoja balą, parodydamas netipinių pokyčių lygį. Rezultatai padeda priimti galutinį sprendimą, reikia šalinti apgamą ar ne. Neigiamos numatomosios ir teigiamos numatomosios vertės yra labai aukštos. Be to, EIS pasiektos vertės tai – 97 % jautrumas ir 34%
specifiškumas, kurių negalima lengvai pasiekti kitais metodais [12]. Naujas melanomos diagnozavimo metodas yra labai tikslus, greitas ir neinvazinis. Tačiau pastoviosios ir kintamosios išlaidos yra palyginus aukštos. Neseniai atliktas Jungtinės Karalystės tyrimas parodė, kad EIS taip pat gali būti naudojamas kaip dermatoskopijos diagnostinis įrankis [25]. Australijoje dermatologai išbandė EIS kaip esminę melanomos diagnozavimo priemonę [14]. Esminis tyrimas davė užuominą, kad EIS yra ne tik vertinga melanomos diagnozavimo priemonė, bet netolimoje ateityje gali būti naudojama ir BCC bei SCC diagnozei nustatyti. [12]
Conflict of Interests
Clause for excluding conflicts of interest with SciBase in general and Nevisense® in particular:
Conflicts of interest: none / independent.
The author has no relations with the manufacturer and is not involved in the sale or does not benefit in any other way from the mentioned products. Furthermore, the author does not have any other conflicting interests with any companies in relation to this paper.
Place: Würzburg, Germany / Date: 10.03.2020
Signature
List of Abbreviations
BCC - Basal Cell Carcinoma
CDC - Centers for Disease Control and Prevention e.g. - Latin: exempli gratia (English: for example) EIS - Electrical Impedance Spectroscopy
EMA - European Medicines Agency
etc. - Latin: et cetera (English: and others)
FDA - United States Food and Drug Administration IARC - International Agency for Research on Cancer
KHz - Kilohertz
MHz - Megahertz
mm - Millimeter
NaCl - Sodium chlodirde NHS - National Health Service NNE - Number Needed to Excise NPV - Negative Predictive Value PPV - Positive Predictive Value
® - registered trademark symbol SCC - Squamous Cell Carcinoma
SDDI - Short-term Digital Dermoscopy Imaging
UK - United Kingdom
VAT - Value Added Tax
WHO - World Health Organization
List of Figures
Figure 1: Melanoma of Skin in Lithuania, Age Standardized Incidence Rate, Age (0-85+)…...…...4
Figure 2: Melanoma of Skin in Germany, Age Standardized Incidence Rate, Age (0-85+)…...…5
Figure 3: Observed and Projected Age-adjusted Melanoma Incidence and Mortality……..……….6
Figure 4: Nevisense® Device and Single Use Electrode ……….………….….8
Figure 5: EIS: High and Low Frequencies……….……..…..…8
Figure 6: Standard and Optional Sources of Information Prior to a Decision to Excise………...…12
Figure 7: PPV and NPV for EIS Scores……….……….…….14
Figure 8: Pathological Diagnosis of Excised Lesions………..………..…..……18
Figure 9: Correlation of EIS Score and Melanoma Depth…………..……….………19
Figure 10: EIS Score versus Histopathological Examination………..………20
List of Tables
Table 1: EIS, SDDI, and Histopathological Analysis………...…….………..………21 Table 2: Overview of SDDI and EIS in Combination………...…...…21
Introduction
During the last 50 years, the incidence of melanomas has continuously risen.[1] According to the International Agency for Research on Cancer (IARC), the incidence rate for cutaneous melanoma in Lithuania climbed within the last decades.[2] Also, other countries like Germany and the United States experienced an increasing incidence rate.[3, 4] This trend also holds for most parts of the world. Australia, New Zealand, and northern Europe are primarily known for their exceptionally high melanoma incidence rates.[5]
This increase may not only result from an actual increase in incidence, but also from a higher awareness of skin cancer in all social ranks, especially among the rural population. The survival rate of melanoma depends to a great extent on the availability of early detection, accurate diagnosis, and adequate treatment for the affected individual. Statistics for melanoma incidence and mortality emphasize the rising importance of early and secure melanoma detection in our day and age. To date for suspicious nevi, the following principle was valid: "If in doubt, cut it out." However, this means possibly many excisions may be necessary, and not every nevus, developing optical characteristics of malignancy, is truly malignant. Therefore, it is even more important to broaden the spectrum of diagnosis for this malignant tumor. Recently, a new state of the art diagnostic tool has been designed to take melanoma diagnosis to the next level.
The Swedish company SciBase AB, which was founded in 1998, is a pioneer in the research and development of electrical impedance spectroscopy (EIS) as a diagnostic tool in dermatology.
Research activities at the Karolinska Institute in Stockholm more than 20 years ago paved the way for this unparalleled technology in dermatology and led to the development of the device Nevisense®, which is able to perform EIS in practice.[6] The device Nevisense® is the first and only one for dermatological applied electrical impedance spectroscopy on the market so far. The system is until now licensed for clinical use by the national health agencies of Australia, the European Union, and the United States. Due to the uniqueness of that device, information, and scientific studies of this thesis, principally rely on research and experience of EIS with Nevisense®.
This master thesis is intended to give an overview of the method of electrical impedance spectroscopy as a technique of diagnosis of malignant melanoma. The objective is to show the level of accuracy, examples of practical use, indications, contraindications, as well as advantages and disadvantages over conventional methods based on scientific studies.
1. Methods and Sources
The content of this master thesis is based on reviewed literature. Since electrical impedance spectroscopy in dermatology is a niche topic and the implementation of EIS is a rather new phenomenon, the available literature is limited to a few scientific studies, books, and information provided by the manufacturer of the only device on the market. Furthermore, statistical data from scientific research institutes are used to confirm trends and developments.
SciBase, the manufacturer of Nevisense® provides necessary useful information about the device published on its website about the background of EIS technology, principles of use, etc.[6] SciBase also issued instructions and practical knowledge combined with scientific evidence about Nevisense® in its “Clinical Reference Guide”.[7] The “Summary of Nevisense Labeling Information” is a paper specifying knowledge gained from the pivotal study.[8]
Statistical information on melanoma incidence and mortality rates are derived from the International Agency for Research on Cancer (IARC) and their platform Global Cancer Observatory.[2, 3, 5, 9, 10] Both of them belong to the WHO. For statistical data about incidence and mortality concerning the United States, data from the Centers for Disease Control and Prevention (CDC) was used.[4] The CDC is one of the leading national public health institutes of the United States.
An essential book for this thesis is the German title “Nichtinvasive physikalische Diagnostik in der Dermatologie” written by some of the most influencing dermatologists of prestigious University hospitals in Germany.[11] Some of the authors also participated with their dermatological departments in the pivotal study for EIS application with the device Nevisense®.
To emphasis the scientific background of EIS, some analytical studies have been taken into consideration. The most important and pioneering one was the pivotal study, which proves the
effectiveness of EIS, with the title: “Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety." More than 20 dermatological departments in the United States and Europe participated in the accumulation of results. In total, 1961 patients with 2416 lesions were involved.
The results were published in 2014 in the British Journal of Dermatology.[12]
In the year 2017, the University Hospital Southampton published a study to evaluate the position of electrical impedance spectroscopy as an adjuvant in the current process of diagnosis of pigmented lesions. The working paper had the title: “Utilisation of an Electrical Impedance Spectroscopy System in an NHS setting in a pigmented lesion clinic as an adjuvant to dermoscopy and clinical history”.[13]
Another study from 2017, authored by Australian dermatologists, was published in the British Journal of Dermatology. The aim of this study was the “Analysis of an electrical impedance spectroscopy system in short-term digital dermoscopy imaging of melanocytic lesions." The authors wanted to show the outcome of adding an EIS analysis at baseline diagnostics to nevi with features of malignancy, which underwent routine short-term sequential digital dermatoscopy imaging (SDDI).[14]
2. Melanoma Incidence and Mortality
A Melanoma is a malignant, invasive growing tumor of melanocytes, which tends to lead to early metastasis. Mucosae can also be affected by melanoma. A vast majority of more than 90 % of all mortalities due to skin cancer can be associated with melanoma. Therefore, it is the malignant skin tumor with the highest metastasis rate.[15]
The following statistical data should give an overview of current situations in countries, which are either medically essential, or vital concerning this master thesis. Furthermore, the importance of improved and enhanced melanoma diagnostics should be emphasized by this data.
2.1. Lithuania
Statistical data form the International Agency for Research on Cancer regarding the melanoma incidence rate in Lithuania revealed that in time from 1990 to 2011, there was an increase among males from 1,35 in 1990 to 5,56 in 2011 per 100.000 people. Among females, the melanoma incidence has risen from 2,74 in 1990 to 7,46 in 2011 per 100.000 people.[2]
Figure 1: Melanoma of Skin in Lithuania, Age Standardized Incidence Rate, Age (0-85+) [2]
Up to date data from the year 2018 shows that there was a total number of 461 new cases in Lithuania, which corresponds to 2,8 % of all cancers. About 100 individuals died from melanoma in Lithuania, which relates to 1,2 % of all cancer deaths.[9]
2.2. Germany
In Germany, statistical data from a period from 1998 to 2011 showed an incidence rate of males of 8,95 in 1998 and 11,25 in 2011 per 100.000 individuals. Among females, the rate rose from 9,30 in 1998 to 10,74 in 2011 per 100.000 individuals.[3]
Figure 2: Melanoma of Skin Germany, Age Standardized Incidence Rate, Age (0-85+) [3]
Up to date data from the year 2018 shows that there was a total number of 31.432 new cases in Germany, which corresponds to 5,2 % of all cancers. About 3.641 individuals died from melanoma in Germany, which relates to 1,5 % of all cancer deaths.[10]
2.3. The United States
According to the Centers for Disease Control and Prevention, the melanoma incidence rate in the United States was 19,7 per 100.000 in 2011, and the death rate was 2,7 per 100.000. Since the beginning of the recording of these data an increasing trend can be seen.[4]
Figure 3: Observed and Projected Age-adjusted Melanoma Incidence and Mortality [4]
2.4. Analysis of Incidence and Mortality
These figures show that all of the countries mentioned above experience a rise in melanoma incidence. This fact is not only a consequence of a rising incidence rate itself, but also a result of greater awareness of this kind of cancer. Patients go more frequently to screenings, and subsequently, more cases of melanoma are detected.
Early and firm diagnosis of melanoma is essential for a successful treatment. Therefore, the availability of new precise diagnostic tools is crucial. The overall aim is to keep mortality rates at the same level or even decrease it, despite continually increasing incidence rates.
3. Definition of Electrical Impedance Spectroscopy and its Technical Details Electrical impedance is defined as the total resistance that a circuit presents to electrical current.
The resistance is influenced by two factors: on the one hand, by current carrying charged elements and by the internal configuration of the conductor.[16]
In the case of EIS, the human tissue, or more precisely the layers of the skin, represent the circuit.
According to Meer, spectroscopy is defined as “the science concerned with the investigation and measurement of spectra produced when materials interact with or emit electromagnetic radiation."[17] In other words: the measured electrical resistance of the skin provides valuable clues about its structure. As healthy cells differentiate histologically from abnormal cells, their electrical properties, or, more precisely, their electrical resistance, shows different results.
The skin has specific electrical properties, which are dependent on diverse factors, such as volume, shape, alignment, compactness, and arrangement of the cell membrane of the cell.[11] These factors impact the capability of the cell to conduct electricity. In a cell with atypical characteristics, also the electrical characteristics are subject to change. The technology of EIS is able to detect and analyze these changes in electrical properties, which are deviating from those of healthy cells by using harmless electrical rays. This is key for the EIS technology for recognizing malignancies.
For the identification, it is crucial to examine the electrical properties of the respective tissue not only in width but also in depth. The measurement is performed at 35 frequencies ranging from 1.0 KHz – 2.5 MHz.[6] Frequencies are emitted at four different depth levels and at 10 set permutations over the lesion, applied by a single-use electrode.[6]
Figure 4: Nevisense® Device and Single Use Electrode
Each measurement results in 700 variables, which are the background for the Nevisense® classifier.
The classifier analysis deviations by comparing the impedance of the lesion and a reference spot and by evaluating detailed features of the impedance within the lesion itself.[7]
Normal Tissue Abnormal Tissue
Low frequencies
• Primarily reflect the extracellular environment.
High frequencies
• Reflect both the intra- and extracellular environments.
Figure 5: EIS: High and Low Frequencies [7]
The examination and analysis of Nevisense® finally lead to a score, which is based on an algorithm that compares data form the location of a potential lesion and a reference of the same patient. The Nevisense® score can range from 0-10, reflecting the grade of atypia of the respective location and the probability that a lesion is evidently a malignancy and not merely having only its optical characteristics.[7]
The references analyzed electronically by EIS, such as the structure of intra- and extracellular milieus, cell profile and dimension, and cell membrane composition are very similar those used by histopathologists, but with the significant difference, that there is no requirement for an excision.
4. The Practical Use of EIS
4.1. Indications and Intended Use of EIS
According to Welzel & Sattler Nevisense® is designed for the application at cutaneous lesions with one or more clinical features of melanoma.[11] The clinical features of Melanoma are comprised in the ABCDE rule according to Stolz:[18]
• A: Asymmetry in shape
• B: Irregularity of borders, such as notched or scalloped margins
• C: Changes in color, which means an imbalanced scattering of pigments
• D: Diameter growth over time; more than 5-6 mm in diameter is regarded as potentially dangerous
• E: Evolving
Another famous principle for the assessment of malignancy is the so-called 7 point checklist.[19]
This list includes the following criteria:
• Change in size of the lesion
• Irregular pigmentation
• Irregular border
• Inflammation
• Itch or altered sensation
• Lesions larger than others
• Oozing/crusting lesion
In case of any suspicion for malignancy or potential malignant development in the future, a dermatologist usually excises these local nevi. This is, of course, an effective way to minimize risk for patients and to treat developing melanomas successfully. However, not every nevus, which fulfills the optical criteria according to the ABCDE rule or 7 point checklist, is histologically a melanoma. Studies show a comparably low sensitivity percentage. The requirements out of the 7 points checklist with the highest sensitivity rate, is irregular pigmentation with 71,1%.[19]The overall sensitivity of the 7 point checklist is 68,8 %, with a specificity of 86 %.[20] The sensitivity of the ABCDE rule is only 47,3 % with a specificity of 56 %.[20]
In the past, every nevus with the slightest sign of malignancy was advised to be excised, even at unfavorable conditions in terms of location or in terms of aesthetical aspects. The prevailing rule was: "If in doubt, cut it out."
The gained information by EIS, together with clinical and anamnestic evidence, provides additional knowledge about the lesion and supports the physician in the decision whether an excision should be performed or not. In principle, an examination with the system is allowed to be used or ordered only by dermatological experts, who are educated and familiar with the diagnosis of melanomas.
According to Welzel & Sattler the main indication for EIS with Nevisense® is the early detection of malignant melanomas.[11] In particular, Nevisense® is intended for the following application areas:[7]
• Primary skin lesions with a diameter between 2 mm and 20 mm, which are reachable for the Nevisense® sensor.
• Lesions on intact skin that means without ulcers and nonbleeding
• Lesions without scars or fibrosis due to a previous trauma
• Lesions that are not close to psoriasis, eczemas, acute sunburn, or other similar pathologies
• Lesions that are not found in hairy areas
• Lesions without foreign bodies
• Lesions on specific body areas, like limbs, genitals, eyes, mucosae
The method of EIS allows additional complementary information in uncertain cases in addition to the conventional diagnostic methods by the physician. Especially in the case of cutaneous lesions with uncertain clinical or anamnestic conspicuousness, the decision of excision can be made a lot easier.
The intended use of Nevisense® is to support clinical evaluation of suspicious nevi in unclear cases in patients, where one or more clinical or anamnestic features of malignancy apply. The device provides additional information if excision is taken into consideration. The application of this device is aimed for trained dermatological experts, who have the possibility to include the Nevisense® result as one component of their overall clinical analysis, in addition to clinical and anamnestic characteristics of malignancy before the final decision about an excision.[7] Figure 6 below shows how EIS can be embedded in the existing diagnostic scheme on a daily basis.
Figure 6: Standard and Optional Sources of Information Prior to a Decision to Excise [7]
(Standard sources = blue arrow, Optional sources = red arrow)
First of all, the dermatological evaluation starts with the patient anamnesis, which is concerned with personal information about the patient. Facts like age, profession, family history, previous melanomas, leisure time activities, etc. may provide useful indications, whether the development of cutaneous malignancy is possible in that individual case. After that, the patient is inspected visually on a macroscopic level. In case of any suspicion, usually, dermatoscopy is applied.
Typically, a well-trained dermatologist is now able to identify the clear signs of malignancy and evaluates every nevus for a possible excision. However, now, in case of any doubt, the portfolio of diagnostic tools is now broadened. In unclear or doubtful cases, EIS can be added to the diagnostic procedure to deliver a final basis for the decision of excision, without substituting other diagnostic steps before it. If suspicion for malignancy remains after the EIS examination, an excision is mandatory. Nevertheless, the probability is high, that an unnecessary excision can be avoided.
4.2. Contraindications
There are no conditions of patients that contradict the use of Nevisense® or that put patients in danger by a procedure with the device, but there are conditions that lead to a wrong analysis of the measured lesions. These include lesions with a diameter smaller than 2 mm or more prominent than 20 mm. If the diameter is too small, the possibility is very low that there is evidence of malignancy already. Furthermore, it is difficult to place the measuring device over a lesion, smaller than 2 mm.
For lesions bigger than 20 mm, it is very likely to expect a malignancy in the future. A diagnosis with EIS is difficult and not very purposeful, and excision is usually preferred in these cases.
Other contraindications are structures of the skin or nearby other than melanoma, which have a significant influence on the electrical conductivity and resistance of the skin and therefore lead to falsified results of EIS. These abnormal conditions are ulcers, bleedings, scars, but also hairy areas, such as scalp, beards, mustaches, or whiskers. An EIS measurement can also lead to wrong results in areas, which have been biopsied before or regions affected by any surgical intervention or by trauma. The same is valid for lesions or reference areas found on acute sunburn. Mucosal surfaces have been shown to be steep terrain for an EIS analysis and are therefore not recommended for this way of diagnosis. Also, foreign matters in very close proximity can lead to misinforming EIS results, for example, tattoos or splinters. Sometimes it is anatomically challenging to reach the skin surface, and therefore measurement is not possible, e.g., inside ears or under nails. Furthermore, skin diseases such as psoriasis or eczema change the electrical properties of the skin in a way that conducting EIS is not productive.[11, 12]
Electrical impedance spectroscopy is very difficult to perform over palms, soles, genitalia, eyes, and mucosal areas.[21] The mentioned structures have multiple electrical properties which make a significant EIS result impossible. Therefore, a use over these mentioned parts is not recommended.
4.3. The Procedure of an EIS Examination
The examination with EIS is rather simple and may be done according to the following procedure.[11] During the procedure, those lesions are marked, for which more profound information is needed for the final decision in favor of a biopsy. Subsequently, the EIS examination is performed. Therefore both, a reference measurement and a measurement of the actual lesion are needed. The reference measurement is done of presumable healthy tissue in close proximity to the lesion.
According to Kardorff, the concrete procedure is done in 3 steps:[22]
• Step 1: Moistening of the skin. Before the measurement is performed, the chosen reference location is wiped down four to five times by using wet NaCl compresses. After that, the wet
• Step 2: The reference measurement. After the wet compress acted 30 seconds on the reference location, the excess moisture is wiped down with a dry compress, and the reference measurement is performed by impressing the measurement probe on the respecting tissue location. The actual analysis requires 8 seconds.
• Step 3: The lesion measurement. The procedure of step 1 and step 2 is repeated over the location of the lesion, which is to be examined. At this step, it needs to be ensured that all conspicuous areas of the lesion are completely captured by the measurement. In the case of more prominent lesions, accordingly, it is required to perform measurements at several selected points of the lesion until the entire area of the atypical skin changes is examined. Usually, the preparation, respectively, the moisturizing of the reference locations and the lesions can be performed at the same time.
4.4. EIS Examination Results and its Analysis
After the termination of the measurement, the device provides the analysis in a few seconds. The result is expressed by the Nevisense® classificatory on a scale that ranges from 0 to 10. A score of 0 means no atypical tissue changes, and 10 means the most significant atypical tissue changes. A detailed view of the Nevisense® score can be seen in the following figure.
EIS Negative EIS Positive
0 1 2 3 4 5 6 7 8 9 10
98 % 9 % 13 % 18 % 22 % 39 % 51 % 64 %
NPV PPV
Figure 7: PPV and NPV for EIS Scores [7, 12]
A Score from 4 to10 can be interpreted as “EIS positive." The percentage for PPV is 9 % at a score of 4 and continuously increases until a value of 64 % at a score of 10. This means that at a value of 10, 64 % of the examined nevi are malignant. On the contrary, to that, a score from 0 to 3 can be interpreted as “EIS negative." The percentage of NPV is 98 %, which means that if the examination reveals a score between 0 and 3, 98 % of these nevi are benign. The Nevisense® score also allows concluding the level of the severity of the lesion, which is explained in some further sections below.
The score for the examination is displayed immediately. In contrast, additional information like the PPV/NPV ratio can be viewed and taken into consideration for diagnosis at the push of a button.
By this means it is correspondingly possible to involve the patient in the decision in case of a potential biopsy or for a control decision. By taking into consideration both the dermatological- clinical diagnosis and the results of the additional objective EIS information, a final and reliable decision, based on scientific facts, is achievable.
5. Advantages and Disadvantages of EIS
As a tool in melanoma diagnosis, EIS or respectively Nevisense® can deliverrelevant information on tissue characteristics of a lesion. Nevertheless, some advantages and disadvantages accompany the use of EIS in the diagnosis of melanoma.
5.1. Advantages
EIS is a fast and straightforward method to gain additional information on a melanocytic lesion. A diagnostic procedure takes only a few minutes and delivers the result immediately. The process is noninvasive and, therefore, very convenient for the patient.
In the pivotal study of EIS technology for the device Nevisense®, a sensitivity of 97 % was proven.[12] This fact demonstrates a very high accuracy in the detection of melanomas.
Conventional diagnostic methods are far below this value.[20] Precautionary excisions of lesions that fulfill the slightest features of melanoma are daily practice to rule out any potential risk for the patient. With EIS, these excisions can be avoided, as its diagnosis is based on cell characteristics and not on potentially misleading optical appearance.
According to the pivotal study, the specificity is of EIS performed with the device Nevisense® is indicated with 34 %. That means 34 % of all examined nevi were true negative. These nevi show optical characteristics of malignancy but were correctly identified as benign by EIS. If these nevi were only examined with visual methods, they would have been excised to avoid any risk for the
anatomically important structures, where excision is risky or over cosmetically essential structures, where wound healing is challenging, such as the face. With the support of EIS, the integrity of the skin can be maintained at very low risk.
The result of an examination with EIS delivers an objective conclusion. It gives a specific score for each measured spot, without taking other cofactors into consideration, which may lead to a subjective decision of the dermatologist. In the case of optical analysis, the decision is based on the overall impression by recognition of other circumstances like previous melanomas, skin type, family history, etc.
Despite the relatively high costs for an EIS procedure, it is also saving money due to avoided excisions. Excisions with the following pathological examination is probably a higher financial effort than a noninvasive diagnostic EIS procedure. Furthermore, an EIS procedure is very time efficient compared to an excision procedure.
5.2. Disadvantages
The disadvantages of EIS are very few. At the moment, the device is not widely available, which makes it difficult to get an appointment for patients, but this is subject to change as more and more institutions ordered a device.
One of the most significant disadvantages so far is the cost of the device, so far. As of December 2019, the market price for a new Nevisense® 3.0 device was at relatively expensive € 6.460,00 plus VAT.[23] This amount represents a high investment for dermatologic centers. A single-use electrode for one procedure comes at a price of € 35,00 plus VAT.[23] If EIS can be established as an ordinary step in the diagnosis of melanoma, the cost can be easily amortized.
Both the fixed cost for the investment of the device and the variable costs for the single-use electrodes have a significant impact on the final price for every procedure the patient has to pay.
According to dermatologic centers, which already use EIS as a diagnostic tool, a patient has to pay around € 90-120 for each session depending on the individual effort.[24] The cost acquisition by insurances heavily depends on the country and type of insurance contract. However, at the moment, in most countries, a dermatologic EIS evaluation does not belong to the standard procedures, public insurances will pay for.
The contraindications for EIS lead to the circumstance that EIS cannot be performed over hairy areas, as well as ulcerated, bleeding, scar tissue, etc. This may only apply to a minimal amount of locations, but nevertheless could be a disadvantage.
With a sensitivity level of 97 %, EIS is probably one of the most accurate tools in melanoma diagnostic. Still, nevertheless, this device does not provide a 100% certainty with its results, a meager fraction of risk remains.
6. Scientific Background of EIS 6.1. Effectiveness and Safety of EIS
The pivotal study, published in the year 2014, was conducted to finally prove the ability and potential in the diagnosis of melanoma.[12] The setting of the study was a blinded, multicenter study carried out in 22 dermatology departments in Europe and the United States. All skin lesions were considered according to the indication rules already described. They were first analyzed with EIS, photographed, and dermatoscopically evaluated, followed by excision and histopathological examination. Overall, 2416 lesions were examined. The study resulted in a sensitivity, which is the true positive rate or the rate of detection, of 96,6 % by detecting 256 out of 265 melanomas. The study also revealed, EIS did not identify 9 out of 265 melanomas, which is a false negative ratio of 3,5 %. Out of these 9 melanomas, 7 were staged as in situ and 2 as early invasive T1a. More advance stages of melanomas, such as T2, T3, T4, were detected with a sensitivity of 100 %. All of the false negative lesions showed a minimal median diameter of 4 mm and Breslow thicknesses of 0,4 – 0,6 mm, which made the detection by EIS probably relatively difficult.
The specificity, the true negative rate, of Nevisense® was 34,4 %. The PPV and NPV reached values of 21,1 % and 98,2 %. For skin cancers kinds other than melanoma, such as BCCs or SCCs, Nevisense® reached a sensitivity level of 100 %. Out of 2416, there were 48 BCCs and 7 SCCs. In comparison to the ABCDE rule and to the 7 points checklist via dermatoscopy, the detection rate of EIS was at every tumor stage significantly higher.[12, 20]
By comparing the EIS score with the histopathological examination, the authors of the study noted that the higher the score was, the more severe was the skin lesion. Tis melanomas had an EIS score of 5-8, which gradually rose to 5-9 for T1, 7-9 for T2, and an EIS score of 9-10 was a T3 or a T4
Figure 8: EIS Score versus Histopathological Examination[12]
All in all, the scientists of this study came to the conclusion that “Nevisense is an accurate and safe device to support clinicians in the detection of cutaneous melanoma. “ [12]
The pivot study for Nevisense® detected overall 36 adverse events observed in 28 individuals (1,5%) of the participating patients.[12] 33 of 36 findings were mild adverse events. Two events, classified as moderate, were wound infections after removal. Nevertheless, the latter two were evaluated as unlikely linked to the device. Migraine, as a severe adverse event, was seen one time but was assessed as unconnected to the EIS procedure. 14 events in 12 patients (0,6%) were classified as possibly, probably, or definitely related to the device. These comprised:[12]
• bleeding during the procedure (n=6)
• itching at the location of the procedure (n=1)
• pain, soreness, or bruising (n=3)
• slight tingling perception at the location of the procedure (n=2)
• headache (n=2).
Adverse events that could be explicitly connected to the use of Nevisense® were classified as mild.
During the complete study, there were no severe adverse events linked to the device witnessed.[8]
6.2. EIS as Adjuvant to Dermatoscopy and Clinical History in the UK
Many atypical looking nevi are not malignant, but benign. The average UK center has to perform 6 excisions to identify one melanoma with conventional diagnostic methods, such as dermatoscopy and clinical history assessment.[25]
A study conducted by a NHS hospital, which diagnoses over 200 melanomas each year, shows how EIS can be involved in the practice to decrease excision ration and to improve diagnostic outcomes.[13] The study analyzed a total of 51 suspicious lesions, which were all suitable for an EIS application. Lesions with a Nevisense® score of 3 or lower were considered as negative, whereas 4 or higher were excised. The histopathological result of 51 excisions can be seen in the table below.
Figure 9: Pathological Diagnosis of Excised Lesions [13]
With the support of EIS, the ratio of benign moles and detection of melanoma was 2,6:1 which resulted in an NNE of 3,6 versus 6 excisions without EIS.[13, 25]
The study also illustrated the correlation between the EIS score and the depth of the melanoma, according to Breslow, which is a significant parameter for the classification and prognosis of melanoma.[13] The trend line shows that the higher the EIS score, the deeper reached the
0 5 10 15 20 25
Invasive
Melanoma In Situ
Melanoma Dysplastic /
Atypical Severely
Dysplastic Solar
Lentigo Benign
Naevus Lichenoid Keratosis
Lesion Classification (n=51)
Melanoma (Breslow) Depth (mm)
EIS Score
Figure 10: Correlation of EIS Score and Melanoma Depth [13]
After the study, the University Hospital Southampton concluded that “In a pigmented lesion clinic EIS measurements can be used as an adjuvant to macroscopic, dermatoscopic and clinical history, to identify subtle early melanomas, which might otherwise be missed. EIS measurements can also be used to reassure that an otherwise mildly suspicious lesion does not need excision. “[13]
6.3. Effect of EIS as Baseline Diagnostic Tool
A study, conducted by Australian researchers, explored the effect of the addition of EIS to a standard base diagnosis for suspicious melanocytic lesions with enduring short-term digital dermoscopy imaging (SDDI).[14]
Patients with suspicious lesions with no definite characteristics of melanoma, who qualified for SDDI were evaluated with EIS at their first appointment. Usually, an EIS score of 4 or higher is regarded as positive, but in this specific study, the limit in combination with SDDI was set higher.
Lesions with an EIS score < 4 with a NPV of 98 %, had the standard SDDI interval of 3 months.[7, 12] Lesions with an EIS score of 4-6, which had a PPV of 9-18 %, according to the manufacturer.[7]
They were observed by SDDI at 3 months intervals and followed up. The application of SDDI (excluding lentigo maligna, which necessitates longer observation intervals) has a sensitivity of 94
%, and the specificity is 84 %.[26] Lesions with an EIS score ≥ 7 were excised instantaneously, as
they have a PPV of 22-64 % of being a melanoma.[7]
In total, 160 lesions of 112 patients were evaluated. A number of 31 of these received an EIS score of 7 or more and were therefore excised as a consequence. In the histopathological analysis, five out of 31 were classified as melanoma, 22 received the status as dysplastic nevi, and four were categorized as benign nevi. 85 out of 160 lesions scored 4-6, and 44 out of 160 received the score 3 or less.[14]
Group 1
(EIS score ≤ 3)
Group 2
(EIS score 4–6)
Group 3
(EIS score ≥ 7)
SDDI (total):
• Unchanged
• Changed
• Lesions excised after first visit
44
40 3
1
85
61 22
2
31
Histopathological results:
• Benign
• Dysplastic
• Melanoma
3 (1 excised before SDDI)
1 0
6 (1 excised before SDDI)
17 (1 excised before SDDI)
1
4 22
5
Table 1: EIS, SDDI, and Histopathological Analysis[14]
In group 1 there was no melanoma detected. The negative melanoma from group 2 was classified by EIS with a score of 6 and was detected by its morphological changes by SDDI.
Nevisense Scores
Clinical Actions
Melanoma
Found Study Conclusion
160 lesions in SDDI measured
with EIS were included in the
study
EIS Score 0-3:
44
3 month
SDDI 0 EIS 0-3:
Benign and no need for SDDI The protocol reduced the
need for SDDI by 47% using
EIS EIS Score 4-6:
85
3 month
SDDI 1
EIS 4-6:
SDDI required and excised after 3 months if changed
EIS Score 7-10:
31
Excised
immediately 5
EIS 7-10:
Excised due to high risk of melanoma, no need for
After the study, the researchers conducted a protocol for the combined use of EIS and SDDI at baseline diagnosis, which made the conclusion, that the need to use SDDI can be reduced by around 47 % in favor of EIS, by excluding EIS scores of 7 and higher and EIS scores of 3 or lower.[14]
The advantage of this protocol is an immediate excision of nevi with a high PPV without the delay of an usual SDDI. Furthermore, scores with a very high NPV and are considered as benign, and time-consuming procedures at a given interval can be avoided as there is no need for an SDDI at this stage.
To draw a final conclusion, the number of cases is too small in this study. Nevertheless, there are clear hints that this protocol can lead to more efficient processes in the diagnosis of malignant melanomas.[14] The indicated use of EIS and SDDI has the potential to save time, money, and make melanoma diagnosis more accurate.
Conclusion and Outlook
The results of the pivotal study of EIS show an unprecedented level of accuracy for a non-invasive diagnostic method in detecting melanomas. The EIS method is an easily applicable technique, which is very convenient for patients as well in practice. The system for the early detection of melanomas is scientifically proven, automated, and can be simply delegated. It gives profound additional information about the degree of atypical tissue of a lesion within a short period of time.
With a sensitivity of 97 %, the device has a very high detection rate. The specificity of 34 % helps to reduce the number of unnecessary excisions significantly.[12]
Although nothing is more accurate than a biopsy, EIS supports the dermatologist in reducing excisions. Other studies also proved, how EIS can be used in a practical environment successfully with other methods. In future, the algorithm behind the impedance spectroscopy may be further advanced to make results even more accurate and to shift the role of EIS from a supportive diagnostic tool to a substitutional technique of current methods that are less accurate, in order to reduce excision to an absolute minimum.
According to the general principle of EIS, there is no requirement of pigments in order to make an analysis of the tissue. There are indications that Nevisense® may be used for the suspected diagnosis of non-melanocytic cutaneous malignancies in the near future.[11] In the context of the pivotal
study, 55 non-melanocytic skin lesions were analyzed. Among these were BCCs and SCCs.[12]
The Nevisense® detected all 55 lesions without exception. Therefore, the sensitivity was 100 %.
However, the number of cases of non-melanocytic cutaneous lesions is too low for a definite judgment. Furthermore, more research, testing and targeted studies are required to finally authorize and evaluate the system as a diagnostic method for cutaneous cancer other than melanoma.
At the moment, costs for one procedure are relatively expensive. The assumption of costs strongly depends on the country and the individual insurance company. Nevertheless, insurance companies need to be convinced that paying for an EIS procedure can be much more cost-effective than paying for excisions and its histopathologic examination, or even worse for a treatment of advanced melanoma and its metastasis, which have a very high probability to develop. Potentially other suppliers may find a solution to produce more cost-efficient single-use electrodes or even multiple- use electrodes which can be cleaned after each patient.
The long-lasting principle, "if in doubt, cut it out" for secure melanoma prevention, could be transformed into "if in doubt, use EIS." The device has the potential to contribute to a high degree to patients' wellbeing and to relieve doctors' workload at the same time.
List of References
1. Matthews NH, Li W-Q, Qureshi AA, Weinstock MA, Cho E. Epidemiology of Melanoma [Internet]. Cutaneous Melanoma: Etiology and Therapy [Internet]. U.S. National Library of Medicine; 2017 [cited 2019Nov5]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK481862/
2. IARC. Melanoma of Skin Statistics [Internet]. Redirect CI5. [cited 2019Oct17]. Available from:
http://ci5.iarc.fr/CI5plus/old/Graph4p.asp?cancer[]=130&male=1&female=2&country[]=
44000000&sYear=1950&eYear=2012&stat=3&age_from=1&age_to=18&orientation=1
&window=1&grid=1&line=2&moving=1&scale=0&submit= Execute
3. IARC. Melanoma of Skin Statistics [Internet]. Redirect CI5. [cited 2019Nov5]. Available from:
http://ci5.iarc.fr/CI5plus/old/Graph4p.asp?cancer[]=130&male=1&female=2&country[]=
27600000&sYear=1950&eYear=2012&stat=3&age_from=1&age_to=18&orientation=1
&window=1&trend=1&line=2&moving=1&scale=0&submit= Execute
4. Vital Signs: Melanoma Incidence and Mortality Trends and Projections - United States, 1982–2030 [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2015 [cited 2019Oct17]. Available from:
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6421a6.htm
5. Globocan. Global Cancer Observatory Melanoma of Skin Worldwide [Internet]. Global Cancer Observatory. 2012 [cited 2019Oct17]. Available from:
https://gco.iarc.fr/today/data/factsheets/populations/276-world-fact-sheets.pdf
6. Scibase. THE EIS TECHNOLOGY [Internet]. Scibase. [cited 2019May28]. Available from: https://scibase.com/the-eis-technology/
7. SciBase. Nevisense Clinical Reference Guide [Internet]. 2014 [cited 2019Oct24].
Available from: https://scibase.com/wp-content/uploads/2017/11/Clinical-Reference- Guide-1.pdf
8. SciBase. SUMMARY OF NEVISENSE LABELING INFORMATION [Internet]. [cited 2019Oct30]. Available from: https://scibase.com/wp-content/uploads/2017/12/Summary- of-Nevisense-Labeling-Information.pdf
9. Globocan. Global Cancer Observatory Lithuania [Internet]. Global Cancer Observatory.
2018 [cited 2019Oct17]. Available from:
https://gco.iarc.fr/today/data/factsheets/populations/440-lithuania-fact-sheets.pdf
10. Globocan. Global Cancer Observatory Germany [Internet]. Global Cancer Observatory.
2018 [cited 2019Oct17]. Available from:
https://gco.iarc.fr/today/data/factsheets/populations/276-germany-fact-sheets.pdf
11. Welzel J, Sattler E, editors. Nichtinvasive physikalische Diagnostik in der Dermatologie.
Springer Berlin Heidelberg; 2016.
12. Malvehy J, Hauschild A, Curiel-Lewandrowski C, Mohr P, Hofmann-Wellenhof R, Motley R, et al. Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety. British Journal of Dermatology [Internet]. 2014 [cited
2019Oct22];171(5):1099–107. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257502/pdf/bjd0171-1099.pdf
13. Henderson C, Pees B. Utilisation of an Electrical Impedance Spectroscopy System in an NHS setting in a pigmented lesion clinic as an adjuvant to dermoscopy and clinical history. University Hospital Southampton, editor. Utilisation of an Electrical Impedance Spectroscopy System in an NHS setting in a pigmented lesion clinic as an adjuvant to dermoscopy and clinical history. Liverpool; 2017.
14. Rocha L, Menzies S, Lo S, Avramidis M, Khoury R, Jackett L, et al. Analysis of an electrical impedance spectroscopy system in short‐term digital dermoscopy imaging of melanocytic lesions. British Journal of Dermatology. 2017Nov;177(5):1432–8.
15. Altmeyer P, Buhles N, Nersisyan V. Melanom - Altmeyers Enzyklopädie - Fachbereich Dermatologie [Internet]. Melanom - Altmeyers Enzyklopädie - Fachbereich
Dermatologie. 2019 [cited 2019Oct16]. Available from: https://www.enzyklopaedie- dermatologie.de/dermatologie/melanom-2410
16. Britannica TEof E. Electrical impedance [Internet]. Encyclopædia Britannica.
Encyclopædia Britannica, inc.; 2008 [cited 2019May28]. Available from:
https://www.britannica.com/science/electrical-impedance
17. Meer FVD. Near-infrared laboratory spectroscopy of mineral chemistry: A review.
International Journal of Applied Earth Observation and Geoinformation. 2018;65:71–8.
18. Stolz W. ABCD rule [Internet]. Dermoscopedia.org. 2019 [cited 2019Nov7]. Available from: https://dermoscopedia.org/ABCD_rule
19. Walter FM, Prevost AT, Vasconcelos J, Hall PN, Burrows NP, Morris HC, et al. Using the 7-point checklist as a diagnostic aid for pigmented skin lesions in general practice: a diagnostic validation study. British Journal of General Practice. 2013;63(610).
20. Benellii C, Roscetti E, Dal Pozzo V. The dermoscopic (7FFM) versus the clinical (ABCDE) diagnosis of small diameter melanoma [Internet]. European journal of
dermatology: EJD. U.S. National Library of Medicine; 2000 [cited 2019Nov7]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10846255
21. Ranaweera A. Electrical impedance spectroscopy for melanoma diagnosis [Internet].
Oakley A, editor. Electrical impedance spectroscopy for melanoma diagnosis | DermNet
22. Kardorff B. Selbstzahlerleistungen in der Dermatologie und der ästhetischen Medizin.
Heidelberg: Springer; 2014.
23. SciBase. Limitiertes Bundle-Angebot zum Sonderdruck ”EIS: Atypien von Hautveränderungen präzise messen” . https://scibase.com/wp-
content/uploads/2018/11/SCB0127_Tysk-mailing_Guideline_181120.pdf. 2018.
24. Hautzentrum Sellspeicher Kiel. Leistungen [Internet]. Hautzentrum Sellspeicher Kiel.
[cited 2019Oct22]. Available from: https://www.hautzentrum- kiel.de/leistungen/hautkrebs-vorsorge/nevisense.html
25. Sidhu S, Bodger O, Williams N, Roberts DL. The number of benign moles excised for each malignant melanoma: the number needed to treat [Internet]. Clinical and
experimental dermatology. U.S. National Library of Medicine; 2012 [cited 2019Oct28].
Available from: https://www.ncbi.nlm.nih.gov/pubmed/21981313
26. Altamura D, Avramidis M, Menzies SW. Assessment of the Optimal Interval for and Sensitivity of Short-term Sequential Digital Dermoscopy Monitoring for the Diagnosis of Melanoma. Archives of Dermatology. 2008Jan;144(4).
Appendix
Honorable Declaration
I certify that:
(a) the thesis being submitted for examination is my own account of my own research (b) my research has been conducted ethically
(c) the data and results presented are the genuine data and results actually obtained by me during the conduct of the research
(d) where I have drawn on the work, ideas and results of others this has been appropriately acknowledged in the thesis
(e) where any collaboration has taken place with other researchers, I have clearly stated in the thesis my own personal share in the investigation
(f) the thesis has not been presented to any other examination committee before (g) the thesis has not been published before.
Place: Würzburg (Germany) / Date: 10.03.2020
Signature
