Diagnosis and treatment of premalignant changes of photodamaged skin : novel hyperspectral imaging and new therapeutical aspects

ABSTRACT Background and purpose: As the skin cancer burden continues to increase, there is an urgent need for novel methods for the early detection of skin cancers, and for new cost-effective treatments. The hyperspectral imaging system (HIS) is a novel technique which offers the dual advantages of allowing the imaging of large skin areas rapidly and non-invasively. Daylight photodynamic therapy (DL-PDT), with the advantages of excellent tolerability and convenience, is an attaractive therapy for actinic keratoses (AK) and field cancerization.This thesis aimed to enable early and effective treatment of common premalignancies of photo-damaged skin.The first purpose of this thesis was to evaluate the feasibility of HIS in the detection of field cancerized skin and in the detection of ill-defined borders of lentigo maligna (LM) and lentigo maligna melanoma (LMM). In addition, this thesis aimed to further develop the treatment of field cancerized skin with photodynamic therapy using a novel photosensitizer in combination with daylight (DL-PDT), and to evaluate the cost-effectiveness of DL-PDT. Methods: This thesis included four non-sponsored prospective clinical studies. The novel prototype HIS, used in studies I-II, was developed for the study at the VTT Technical Research Centre of Finland. The technique enabled in vivo imaging of the skin prior to surgical procedures and produced abundance maps of the affected skin areas. The results were verified by histopathology. Study III was randomized double-blinded intra-individual split-face trial comparing novel photosensitizer formulation, 5-aminolaevulinate nanoemulsion (BF-200 ALA) with methyl-5-aminolaevulinate (MAL) in DL-PDT of AKs. In addition to blinded clinical and histological treatment efficacy, tolerability of the treatment was assessed. Study IV evaluated the cost-effectiveness of MAL-DL-PDT compared to conventional MAL-LED-PDT. Results: In studies I-II HIS showed its feasibility in both the detection of subclinical borders of ill-defined lentigo malignas (LM) and lentigo maligna melanomas (LMM), and in the detection of early subclinical actinic keratoses (AK). In study I HIS accurately detected 20 of 23 (87%) of the LM/LMM borders as confirmed by histology. HIS was useful i.e. detected the lesion borders more accurately than a clinician using Wood s light in 11 of 23 (47.8%) cases. Six re-excisions could have been avoided with HIS. In 3/23 cases (13%) HIS was not in concordance with the histopathology, which in two cases HIS showed lesion extension which was not verified histologically (wrong positive) and in one case HIS missed the subclinical extension (wrong negative). In study II with 12 patients and 52 clinical AKs, HIS accurately detected all the clinical lesions in addition to numerous areas of subclinical damage. HIS findings matched the histopathological findings in all 33 biopsied areas (AK, n=28, photo-damaged skin, n=5), revealing 16 subclinical lesions of which 10 were not detected by fluorescence diagnosis. In study III (13 patients, 177 lesions) in a per patient (half-face) analysis BF-200 ALA cleared thin AKs more effectively than did MAL (p=0.027). In per lesion analysis the complete clearance rates were 84.5% for BF-200 ALA, and 74.2% for MAL (p=ns). The area response rates, including also the new appeared lesions (i.e.preventive effect), were 79.8% for BF-200 ALA and 65.6% for MAL, p=0.044. Histologically, DL-PDT effectively cleared all the signs of dysplasia in 61.5% lesions treated with BF-200 ALA and in 38.5% with MAL (p=ns). The mean decrease in p53 expression was 54.4% with BF-200 ALA, 34 % with MAL (p=ns). DL-treatment was nearly painless with both photosensitizers. BF-200 ALA and MAL DL-treatments were similarly tolerated as regards to adverse reactions. In study IV 70 patients (210 target lesions) randomized to receive DL-PDT or LED-PDT with MAL, at six months the patient complete response rates were 15 of 35 (42.9%) and 24 of 35 (68.6%), (p=0.030) and lesion clearance rates were 72.4% and 89.2%, respectively (p=0.0025). DL-PDT required significantly less time at the clinic (p less than 0.0001) and could be used with lower total costs ( 132) compared to conventional LED-PDT ( 170), p=0.022. However, in terms of cost-effectiveness MAL-DL-PDT was found to give less value for money compared to MAL-LED-PDT. The incrementl cost-effectiveness ratio (ICER) showed the monetary gain of 147 per unit of effectiveness lost. Thus, the use of DL-PDT instead of LED-PDT would decrease the healing probability but only low incremental cost savings would be achieved. The costs per complete responder were 308 for MAL DL-PDT and 248 for MAL LED-PDT, p= 0.004. Conclusions: The more accurate pre-surgical assessment of the subclinical borders of LM and LMM with HIS could lead to fewer re-excixions, which furthermore could reduce the burden to both patients and clinics. In addition, the early non-invasive detection of skin field cancerization could enhance the treatment process by revealing the as yet subclinical areas in need of treatment, and could possibly aid the monitoring of treatment efficacy. Even though HIS was found to be useful in these two indications, more studies are warranted to qualify the optimal mathematical algorithms for diagnostic use.The use of novel a photosensitizer formulation, BF-200 ALA, in DL-PDT could lead in lower costs and increase the efficacy. Interestingly, the efficacy of DL-PDT with BF-200 ALA was approaching the efficacy achieved with conventional LED-PDT. As field cancerized skin should be treated as a chronic disease requiring repeated treatments, DL-PDT offers a painless and convenient option for this purpose. However, DL-PDT with MAL provided less value for money compared to conventional MAL-PDT. The cost-effectiveness of BF-200 ALA in DL-PDT for AKs needs further studies.TIIVISTELMÄ Ihosyöpien määrä on jatkuvassa räjähdysmäisessä kasvussa maailmanlaajuisesti. Tämä kuormittaa terveydenhuoltoa merkittävästi. Taudinmäärityksen kehittäminen, siten että ihosyövät pystytään tunnistamaan jo varhaisessa vaiheessa sekä hoitoalueiden aiempaa tarkempi määrittäminen lisähoitojen välttämiseksi, ovat keskeisiä keinoja rajoittaa hoitokustannuksia. Lisäksi on tarve uusille, helposti toteutettaville ja kustannusvaikuttaville hoitomuodoille. Väitöstyössä tutkittiin uutta Suomessa kehitettyä hyperspektritekniikkaa ihon okasolusyövän varhaisasteiden, ns. subkliinisten aktiinikeratoosien, tunnistamisessa, sekä huonosti rajautuvien ihon pintamelanoomien, ns. lentigo malignojen, rajojen määrittämisessä lisäleikkausten välttämiseksi. Väitöstyössä selvitettiin myös uuden päivänvalolla toteutettavan fotodynaamisen hoidon (päivänvalo-PDT) tehoa ja turvallisuutta, sekä kustannusvaikuttavuutta ihon okasolusyövän esiasteiden eli aktiinikeratoosien hoidossa. Tutkimuksessa tutkittiin kahta iholle levitettävää valoherkistäjävoidetta, joista toista ei aiemmin ole käytetty tällä indikaatiolla. Tutkimuksella haluttiin kehittää ihosyöpien varhaisvaiheiden hoitoprosessia resursseja ja kustannuksia säästäväksi, sekä löytää uusia, hyvin siedettyjä mutta tehokkaita hoitomuotoja. Väitöskirjatyöhön sisältyi neljä prospektiivista kliinistä tutkimusta. Hyperspektrikuvantaminen todettiin hyödylliseksi varhaisten, silmälle vielä näkymättömien, aktiinikeratoosien havaitsemisessa. Lisäksi hyperspektrikuvantamisen avulla kyettiin havaitsemaan silmälle näkymättömiä lentigo maligna-kasvainten rajoja. Tämä auttaa entistä tarkemmin määrittämään hoitoalueet ja saattaa mahdollistaa entistä tarkemman hoidon seurannan. Turhilta lisäleikkauksilta saatetaan välttyä. Päivänvalo-PDT osoittautui tehokkaaksi, turvalliseksi ja paremmin siedetyksi kuin perinteinen fotodynaaminen hoito (keinovalo-PDT), missä valolähteenä on keinovalo. Päivänvalo-PDT vei vähemmän sekä poliklinikan henkilökunnan että potilaan aikaa. Keinovalo-PDT osoittautui kuitenkin kustannustehokkaammaksi kuin päivänvalohoito, kun lääkkeenä oli perinteinen valoherkistäjä, metyyliaminolevulinaatti (MAL). Uusi valoherkistäjälääkkeet, aminolevulinaatti nanoemulsio (BF-200 ALA), osoittautui tehokkaaksi ja turvallisia aktiinikeratoosien päivänvalo-PDT:ssa. Hyperspektrikuvantaminen on lupaava uusi tekniikka silmälle näkymättömien ihosyöpien varhaisvaiheiden havaitsemissa sekä hoitoa tarvitsevan ihosyöpäalueen määrittämisessä. Päivänvalo-PDT mahdollistaa laajojen valovaurioalueiden hoidon tehokkaasti ja kivuttomasti. Uusien tehokkaiden valoherkistäjien käyttö saattaa parantaa hoitotehoa, laskea hoitokustannuksia ja siten lisätä hoidon kustannustehokkuutta

Hyperspectral Imaging Reveals Spectral Differences and Can Distinguish Malignant Melanoma from Pigmented Basal Cell Carcinomas : A Pilot Study

Pigmented basal cell carcinomas can be difficult to distinguish from melanocytic tumours. Hyperspectral imaging is a non-invasive imaging technique that measures the reflectance spectra of skin in vivo. The aim of this prospective pilot study was to use a convolutional neural network classifier in hyperspectral images for differential diagnosis between pigmented basal cell carcinomas and melanoma. A total of 26 pigmented lesions (10 pigmented basal cell carcinomas, 12 melanomas in situ, 4 invasive melanomas) were imaged with hyperspectral imaging and excised for histopatho-logical diagnosis. For 2-class classifier (melano-cytic tumours vs pigmented basal cell carcinomas) using the majority of the pixels to predict the class of the whole lesion, the results showed a sensitivity of 100% (95% confidence interval 81-100%), specificity of 90% (95% confidence interval 60-98%) and positive predictive value of 94% (95% confidence interval 73-99%). These results indicate that a convolutional neural network classifier can differentiate melanocytic tumours from pigmented basal cell carcinomas in hyperspectral images. Further studies are warranted in order to confirm these preliminary results, using larger samples and multiple tumour types, including all types of melanocytic lesions.Peer reviewe

Long-term Outcome of Low-concentration Hexyl-5-aminolaevulinate Daylight Photodynamic Therapy for Treatment of Actinic Keratoses

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Long-term Outcome of Daylight Photodynamic Therapy with Amino-5-laevulinate Nanoemulsion vs. Methyl-5-aminolaevulinate for Actinic Keratoses

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Safety of Novel Amino-5-laevulinate Photosensitizer Precursors in Photodynamic Therapy on Healthy Human Skin

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Photodynamic Therapy for Actinic Keratoses : A Randomized Prospective Non-sponsored Cost-effectiveness Study of Daylight-mediated Treatment Compared with Light-emitting Diode Treatment

Daylight-mediated photodynamic therapy (DL-PDT) is considered as effective as conventional PDT using artificial light (light-emitting diode (LED)-PDT) for treatment of actinic keratoses (AK). This randomized prospective non-sponsored study assessed the cost-effectiveness of DL-PDT compared with LED-PDT. Seventy patients with 210 AKs were randomized to DL-PDT or LED-PDT groups. Effectiveness was assessed at 6 months. The costs included societal costs and private costs, including the time patients spent in treatment. Results are presented as incremental cost-effectiveness ratio (ICER). The total costs per patient were significantly lower for DL-PDT ((sic) 132) compared with LED-PDT ((sic) 170), giving a cost saving of (sic)38 (p = 0.022). The estimated probabilities for patients' complete response were 0.429 for DL-PDT and 0.686 for LED-PDT; a difference in probability of being healed of 0.257. ICER showed a monetary gain of (sic) 147 per unit of effectiveness lost. DL-PDT is less costly and less effective than LED-PDT. In terms of cost-effectiveness analysis, DL-PDT provides lower value for money compared with LED-PDT.Peer reviewe

Delineating Margins of Lentigo Maligna Using a Hyperspectral Imaging System

Lentigo maligna (LM) is an in situ form of melanoma which can progress into invasive lentigo maligna melanoma (LMM). Variations in the pigmentation and thus visibility of the tumour make assessment of lesion borders challenging. We tested hyperspectral imaging system (HIS) in in vivo preoperative delineation of LM and LMM margins. We compared lesion margins delineated by HIS with those estimated clinically, and confirmed histologically. A total of 14 LMs and 5 LIVIMs in 19 patients were included. HIS analysis matched the histopathological analysis in 18/19 (94.7%) cases while in 1/19 (5.3%) cases HIS showed lesion extension not confirmed by histopathology (false positives). Compared to clinical examination, HIS defined lesion borders more accurately in 10/19 (52.6%) of cases (wider, n=7 or smaller, n=3) while in 8/19 (42.1%) cases lesion borders were the same as delineated clinically as confirmed histologically. Thus, HIS is useful for the detection of subclinical LM/LMM borders.Peer reviewe

Convolutional neural networks in skin cancer detection using spatial and spectral domain

Skin cancers are world wide deathly health problem, where significant life and cost savings could be achieved if detection of cancer can be done in early phase. Hypespectral imaging is prominent tool for non-invasive screening. In this study we compare how use of both spectral and spatial domain increase classification performance of convolutional neural networks. We compare five different neural network architectures for real patient data. Our models gain same or slightly better positive predictive value as clinicians. Towards more general and reliable model more data is needed and collection of training data should be systematic.peerReviewe

Generating Hyperspectral Skin Cancer Imagery using Generative Adversarial Neural Network

In this study we develop a proof of concept of using generative adversarial neural networks in hyperspectral skin cancer imagery production. Generative adversarial neural network is a neural network, where two neural networks compete. The generator tries to produce data that is similar to the measured data, and the discriminator tries to correctly classify the data as fake or real. This is a reinforcement learning model, where both models get reinforcement based on their performance. In the training of the discriminator we use data measured from skin cancer patients. The aim for the study is to develop a generator for augmenting hyperspectral skin cancer imagery.peerReviewe

Unsupervised Numerical Characterization in Determining the Borders of Malignant Skin Tumors from Spectral Imagery

For accurate removal of malignant skin tumors, it is crucial to assure the complete removal of the lesions. In the case of certain ill-defined tumors, it is clinically challenging to see the true borders of the tumor. In this paper, we introduce several computationally efficient approaches based on spectral imaging to guide clinicians in delineating tumor borders. First, we present algorithms that can be used effectively with simulated skin reflectance data. By using simulated data, we gain detailed information about the sensitivity of the different approaches and how variables defined by algorithms act in the skin model. Second, we demonstrate the performance of the algorithms with spectral images taken in-vivo and representing two types of skin cancers with ill-defined borders, namely lentigo maligna and aggressive basal cell carcinoma. The results can be used as a guideline for developing software for the fast delineation of skin cancers.peerReviewe