Jpn J Ophthalmol (2015) 59:48–54 DOI 10.1007/s10384-014-0351-3
CLINICAL INVESTIGATION
Noninvasive diagnostics supporting system for choroidal melanoma: a pilot study Ori Kameyama • Yoshihiko Usui • Keisuke Kimura Atsushi Nakamura • Takayuki Sota • Hiroshi Goto
•
Received: 3 March 2014 / Accepted: 21 August 2014 / Published online: 8 October 2014 Ó Japanese Ophthalmological Society 2014
Abstract Purpose To examine the usefulness of a near-infrared hyperspectral imager (NIR-HSI) system in discriminating uveal melanoma from other intraocular tumors. Method The NIR-HSI, which had been developed as a screening system for age-related macular degeneration, was used to measure near-infrared hyperspectral data (NIRHSD) of a lesion located at the ocular fundus of 17 Japanese patients, including 5 with choroidal melanoma and 12 with other intraocular tumors. The index was derived from each NIR-HSD. Non-parametric statistical analysis was performed. Results Diagnostic accuracy of 94.1 % was achieved when the threshold value of the index was set to minimize the average value of false-positive and -negative fractions. Conclusions The NIR-HSI system is useful as a noninvasive diagnostic supporting system for choroidal melanoma. Keywords Near-Infrared hyperspectral imager Choroidal melanoma
O. Kameyama T. Sota Department of Electrical Engineering and Bioscience, Waseda University, Shinjuku, Tokyo 169-8555, Japan Y. Usui (&) K. Kimura H. Goto Department of Ophthalmology, Tokyo Medical University Hospital, Shinjuku, Tokyo 160-0023, Japan e-mail: [email protected] A. Nakamura T. Sota Research Institute for Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan
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Introduction Uveal melanoma is the most common primary intraocular malignant tumor. According to one report, the incidence of uveal melanoma in the USA between 1973 and 1997 was 4.3 per million, and most cases (97.8 %) occurred in the white population [1]. In Japan, the estimated annual incidence of uveal melanoma is 0.25 per million [2]. Reports state that choroidal melanoma-related mortality depends not only on the apical height and basal diameter of the tumor, but also on the distance between the proximal tumor border and the optic disc [3, 4]. It is difficult to discriminate a small choroidal melanoma from other intraocular tumors, such as choroidal nevus, melanocytoma, hemangioma and metastasis, even with the combination of slit-lamp biomicroscopy, binocular fundus examination, ultrasonography and magnetic resonance imaging [5, 6]. To arrive at a definitive diagnosis, single-photon emission computed tomography (SPECT) with N-isopropyl-p-[123I] indoamphetamine (123I-IMP) is considered the most promising diagnostic tool in Japan [6–12]. Possible drawbacks of 123IIMP SPECT imaging are the usage of a radioisotope and the ambiguity in image processing. Shields et al. [13–15] retrospectively studied clinical risk factors of growth and metastases of small pigmented choroidal tumors and of choroidal nevus transformation into melanoma. They report that clinically important factors include tumor thickness greater than 2.0 mm, posterior tumor margin touching the disc, visual symptoms, orange pigment and subretinal fluid. Ultrasonographic hollowness and hollow absence should be added in examining a possibility of choroidal nevus transformation into melanoma. These authors identified the numerical value of each risk factor using multivariate analysis [14, 15]. The relative risk, i.e., the risk for tumor growth, in comparison with
Diagnosis system for choroidal melanoma
cases without any factors was calculated combining various clinical factors. The relative risk was considered useful in consulting patients with small suspicious choroidal melanocytic tumors. Although their findings are important and useful in consultations with patients with small suspicious choroidal melanocytic tumors, they are still limited to empirical diagnosis and do not fully reflect the pathological condition of each patient. Clinical diagnosis of a pigmented melanoma depends on the ABCD rule of dermoscopy [16, 17], Menzies’ method [18, 19] and the 7-point checklist [20]. Although all of these tests are useful, they cannot avoid subjectivity in reading lesions and/or scoring procedures. Additionally, experts in dermatology read lesions based on variegation in the lesion morphology, essential for diagnosing melanoma. The morphology of pigmented skin lesions, including melanoma, is predominantly a result of varying concentrations and distributions of pigmented molecules such as melanin and hemoglobin. Based on these differences, Nagaoka et al. [21, 22] proposed a new concept in machine diagnostics for melanoma and developed a noninvasive hyperspectral diagnostic supporting system for pigmented melanoma. This system uses information about the pigmented morphology of a lesion at the molecular level, which is contained in the cutaneous spectra. The hyperspectral diagnostic supporting system acquires hyperspectral data (HSD) of a lesion, simultaneously storing spectral information and two-dimensional space information [23, 24]. They also proposed a melanoma discrimination index (DI) derived from the HSD and demonstrated that its performance is practical in discriminating melanoma from other pigmented skin lesions because the HSD contains information about the molecules responsible for producing the morphology of pigmented skin lesions. Recently, Yamauchi et al. [25] developed a near-infrared hyperspectral imager (NIR-HSI) for the ocular fundus by customizing a commercially available fundus camera so that it could acquire HSD about the ocular fundus in a 50° image field within 5 s. Although this system was originally used as automated screening for age-related macular degeneration, it could be useful as a noninvasive diagnostic supporting system for choroidal melanoma because HSD provides information about pigmented molecules, including melanin and hemoglobin, in the near-infrared wavelength region and because the essential feature of melanoma is invariably independent of anatomic site. Indeed, the color tone of choroidal melanoma is inhomogeneous. In this article, we examine the use of the NIR-HSI system as a noninvasive diagnostic supporting system for choroidal melanoma if an index derived from the NIRHSD is used in conjunction with the previously proposed concept [21, 22].
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Patients and methods Patients This study was approved by the Ethics Committee of Tokyo Medical University and performed in accordance with the Declaration of Helsinki [26]. An explanation of the nature and consequences of the study was provided. A total of 17 patients took part in this study after written informed consent had been obtained from each. There were ten women and seven men, whose ages ranged from 49 to 81 years, with a median of 58 years. All patients were of Japanese descent and had visited the ophthalmology outpatient clinic of Tokyo Medical University Hospital between August 2008 and August 2013. This study excluded patients who had received previous treatment. Lesions of five patients (3 women and 2 men), aged from 57 to 81 years (median 71 years), were highly suspected as having choroidal melanoma from follow-up observations. Two of these patients, who had lost most of their eyesight, also gave consent for enucleation; the pathological diagnosis was melanoma. Lesions of the other 12 patients (7 women and 5 men), aged 49–80 years (median 57 years), were clinically diagnosed as having choroidal nevus (n = 5), choroidal hemangioma (n = 4), metastatic choroidal tumor (n = 2) and melanocytoma (n = 1). Equipment A NIR-HSI for the fundus was used for this study, as described elsewhere [25]. Briefly, a commercially available fundus camera was customized according to the following specifications: spectral resolution, 0.97 nm; full spectral range, 720–950 nm; measurement area, 50° fundus image field; spatial resolution, 33 lm along the vertical axis and 16 lm along the horizontal axis of the retina; measurement time, approximately 5 s; estimated power on the corneal surface, 43 mW. The HSD was basically measured under the condition that a lesion was located within or closer to a center of the 50° fundus image field. When the size of the lesion was larger than the field, the HSD was measured in a field of view where the ratio of the tumor and ordinary fundus is approximately 1:1 [21, 22]. The melanoma DI was derived from the HSD as described below and according to reports from Nagaoka et al. [21, 22] and Yamauchi et al. [25]. A spectrum consisting of the light intensity of every wavelength can be regarded as a vector, and the vector is characterized by its direction and length. For each lesion, a self-reference spectrum was used. A spectrum averaged over an area as large as possible
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O. Kameyama et al.
Fig. 1 Color fundus photographs (top panels), single wavelength images (middle panels) and spectra included within and around lesions (bottom panels). Color fundus photographs (top panels) for typical a choroidal nevus, b hemangioma and c melanoma. Single wavelength images (middle panels) for typical d choroidal nevus, e hemangioma and f melanoma. The single wavelength images were constructed using reflectance spectra averaged over the wavelength
band from 795 to 805 nm. Near-infrared spectra (bottom panels) within and around lesions for typical g choroidal nevus, h hemangioma and i melanoma. Each bottom panel shows a spectrum averaged spatially within the same color box in the corresponding middle panel. Spectra are roughly categorized into the two kinds of spectra for choroidal nevus and hemangioma, while there is no regularity in the spectra for melanoma; arb. units stands for arbitrary units
included within the field of view, except for the nerve head and peripheral region, was defined as the self-reference spectrum. The pretreatment was effective for noise reduction. The difference between any spectrum under consideration and the self-reference spectrum was parameterized using the concept of spectral angle [27]. A larger spectral angle indicates that the spectrum is different from the selfreference spectrum. The normalized distribution of the spectral angle was parameterized using the concept of entropy to obtain a DI, which was used to discriminate melanoma from other lesions. As the spectral angle distribution becomes wider,
the DI increases, indicating that the DI represents the variation of the spectra under study, i.e., the irregularity, disorder and variation in morphology and color tone of the lesion.
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Statistical evaluation Statistically significant differences in DIs between the melanoma and other intraocular tumor groups were analyzed using the Mann-Whitney U test. A p value less than 0.05 was considered statistically significant. The threshold value of DI was defined as the value of DI that minimized a
Diagnosis system for choroidal melanoma
balanced error rate (BER), which is an average value of the false-positive fraction (FPF) and the false-negative fraction (FNF).
Results Figure 1 shows color fundus photographs, grayscale single wavelength images and spectra for the typical choroidal nevus, hemangioma and melanoma. The grayscale single wavelength images for each lesion indicate that the peripheral region is different in image quality from the other regions, which is a main reason why the spectra in the peripheral region were excluded from the analysis. Regarding the spectral features for the three typical lesions, the variation of spectra increased (in order) from choroidal nevus, to hemangioma to melanoma. This characteristic feature is verified using the normalized distribution of spectral angles for choroidal nevus, hemangioma and melanoma (Fig. 2). These distributions were parameterized using the entropy concept [21, 22] to obtain a DI of 3.59 for choroidal nevus, of 3.20 for hemangioma and of 4.96 for melanoma. Similar to pigmented skin lesions, the value for choroidal melanoma is larger compared to other pigmented ocular lesions [21, 22]. Table 1 summarizes the features, clinical diagnosis and DI value for each lesion, and the distributions of the DIs for the melanoma and other intraocular tumor groups are
Fig. 2 Comparison of normalized distributions of spectral angles. Spectral angle distributions for choroidal nevus (black dotted curves, color online), hemangioma (green dashed curve, color online) and melanoma (red solid curve, color online). Reflecting characteristics of spectra are included in hyperspectral data (HSD), while spectral angles distribute in a narrow range for choroidal nevus and hemangioma and in a wider range for melanoma. A narrower distribution of spectral angles leads to a smaller discrimination index (DI), while a wider distribution leads to a larger DI
51
shown in Fig. 3, where the median, 25th percentile and 75th percentile for each group are indicated by horizontal bars. The difference in DIs for the two groups was statistically significant (p = 0.0022). When the FPF and FNF were drawn as a function of the DI, the BER reached its minimum value at a DI of 4.12 when BER was calculated as (FPF ? FNF)/2. When this value was regarded as the threshold value of DI, a sensitivity of 100 % (5/5), specificity of 91.7 % (11/12) and diagnostic accuracy of 94.1 % (16/17) were achieved. These results demonstrate that the proposed DI is a good index for discriminating melanoma from other intraocular tumors. A false-positive case was clinically diagnosed as a melanocytoma at the present stage. Figure 4 shows the color fundus photograph, grayscale single wavelength image and spectra for the melanocytoma. A variety of spectra existed for this case.
Discussion The present NIR-HSI was developed based on a commercially available fundus camera, making it easy to handle. The proposed DI, which is derived from the HSD and works well for differentiating melanoma from other pigmented skin lesions [21, 22], reflects objective and quantitative information about the pigmentation in lesions at the molecular level. Diagnosis of uveal melanoma is usually based on ophthalmoscopic examination and various imaging information, including results from ultrasonography, magnetic resonance imaging and optical coherent tomography. The clinical diagnosis is thus based on appearance and morphology and is somewhat subjective. While 123I-IMP SPECT imaging is unique in its ability to provide semiquantitative and objective measures of the pathology of melanoma, it is invasive because a radioactive isotope is used. In contrast, possible benefits of the presently proposed examination with NIR-HSI are objective and quantitative as well as simple and noninvasive. It is recognized that 123I-IMP SPECT imaging is an effective modality for definitively diagnosing choroidal melanoma [8–11]. The efficacy of 123I-IMP SPECT imaging depends on the nature of IMP in that IMP accumulates predominantly in melanoma cells that are actively producing melanin. The performance of 123I-IMP SPECT examination is reported to achieve a sensitivity of 73.5–100 % and the corresponding specificity of 92.6–70.4 %, depending on the method used to analyze the IMP accumulation in the area and the selection of cutoff point (threshold value) [11, 12]. Performance of the present NIR-HSI system compares favorably with that of 123I-IMP SPECT, although the present statistical population is small.
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52 Table 1 Demographic data, features of tumors, clinical diagnosis and discrimination index (DI) for cases in the current study
RD retinal detachment, RPE retinal pigment epithelium, NA not available
O. Kameyama et al.
Case
Sex/age (years)
Diameter (mm)
Serous RD
RPE atrophy
Clinical diagnosis
DI
1
F/81
9.5 9 7.0
4.2
?
?
Melanoma
4.96
2
F/68
9.5 9 7.0
3.4
?
?
Melanoma
4.52
3
M/71
8.0 9 8.0
9.2
?
?
Melanoma
4.72
4
F/57
Diffuse
NA
?
?
Melanoma
4.12
5
M/75
8.8 9 8.3
3.1
?
?
Melanoma
4.23
6
M/52
1.5 9 1.5
NA
-
-
Choroidal nevus
2.16
7
F/68
5.7 9 5.7
3.3
-
?
Choroidal nevus
3.18
8
M/80
7.5 9 4.5
1.0
-
-
Choroidal nevus
4.05
9
F/55
1.5 9 3.0
NA
-
-
Choroidal nevus
3.59
10
M/58
1.5 9 1.5
NA
-
-
Choroidal nevus
3.00
11 12
M/50 F/50
6.0 9 6.0 5.5 9 5.5
NA NA
? ?
? ?
Hemangioma Hemangioma
3.20 3.82
13
F/49
4.2 9 6.0
4.2
?
?
Hemangioma
3.60
14
M/62
6.0 9 4.5
NA
-
?
Hemangioma
3.87
15
F/75
13 9 12
12
?
?
Metastatic choroidal tumor
3.82
16
F/57
13 9 13
4.5
?
?
Metastatic choroidal tumor
2.98
17
F/57
1.5 9 1.5
2.3
-
NA
Melanocytoma
4.19
Fig. 3 Distribution of discrimination index (DI) values. Comparison of the DI values between the melanoma and other intraocular tumor groups. The DIs of the two groups were significantly different (p = 0.0022), demonstrating that the present DI is useful for discriminating choroidal melanoma from other intraocular tumor lesions
The DI threshold value of 4.12 at the minimum BER resulted in a false-positive case, clinically diagnosed as melanocytoma; the value of the DI for this case was 4.19. We considered possible reasons for these higher values. As shown in Fig. 4b, c, the dark area fades out toward the outside from the center of the lesion, and there is variation in the spectra. For this case, the higher DI was attributed to
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Thickness (mm)
the variation in spectra, which may be caused by the variation in melanin content; we cannot, however, rule out the possibility that the case is a melanoma. Choroidal hemangioma is occasionally accompanied by retinal edema. Spectra from the edema filled with serous fluid must vary from point to point within the edema because of differing amounts of serous fluid; the existence of various kinds of spectra may lead to the higher DI, which may be a possible reason choroidal hemangioma is included in the false-positive cases, although the present case is excluded. A low signal-to-noise ratio of spectra may also lead to a higher DI. Thus, a possible drawback of the present system is that it may not be suitable to analyze lesions with a high elevation because the focus of the commercially available fundus camera does not fit the elevated lesions. However, this problem is not considered serious because there are major doubts concerning whether lesions with such high elevation are actually late stage melanoma. According to Shields et al. [28], choroidal nevus, or melanocytoma, still accounts for most pseudomelanoma, and its differentiation from small melanoma remains a clinical dilemma. Inversely, there seems to remain a possibility that during the follow-up period small melanoma will be misdiagnosed as melanocytoma. This clinical dilemma cannot be solved by the proposed system. A separate study is needed to determine the possibilities of the present system as a dependable diagnostic tool in the follow-up of cases.
Diagnosis system for choroidal melanoma
53
information of a pigmented lesion at the molecular level through HSD is objective and quantitative. Thus, the DI may also be used to evaluate responses to therapy and for clinical follow-up. These findings and perspectives should be confirmed in future multicenter clinical trials. Conflicts of interest O. Kameyama, None; Y. Usui, None; K. Kimura, None; A. Nakamura, None; T. Sota, None; H. Goto, None.
References
Fig. 4 Color fundus photograph (top), single wavelength images (middle) and spectra included within and around a lesion (bottom) for a false-positive case. A false-positive case resulted when the discrimination index (DI) threshold value of 4.12 was used; this case was clinically diagnosed as a melanocytoma. a Color fundus photographs (top panels) of the melanocytoma. b Single wavelength images (middle panels) of the melanocytoma. The single wavelength images were constructed similar to those shown in Fig. 1. c Nearinfrared spectra within and around lesions (bottom panels) for the melanocytoma. Spectra are lacking in regularity, which is considered to lead to the larger DI observed for this case
We presented a noninvasive diagnostic supporting system for choroidal melanoma. The DI derived from HSD in the near-infrared wavelength region had a sensitivity of 100 %, specificity of 91.7 % and diagnostic accuracy of 94.1 %. Although a further study with a larger population is needed to confirm its performance, the DI-reflecting
1. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology. 2003;110:956–61. 2. Kaneko A. Incidence of malignant melanoma of the eye in Japan. Rinsho Ganka. 1979;33:941–7 (in Japanese). 3. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognosis factors: COMS report no. 28. Arch Ophthalmol. 2006;124:1684–93. 4. Hawkins BS, Collaborative Ocular Melanoma Study Group. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality finding and prognostic factors. COMS report number 24. Am J Ophthalmol. 2004;138:936–51. 5. Scheidler J, Leinsinger G, Kirsch CM, Scheiffarth OF, Stefani FH, Riedel KG. Immunoimaging of choroidal melanoma: assessment of its diagnostic accuracy and limitations in 101 cases. Br J Opthalmol. 1992;76:457–60. 6. Holman BL, Zimmerman RE, Schapiro JR, Kaplan ML, Jones AG, Hill TC. Biodistribution and dosimetry of N-Isopropyl-p[123I] iodoamphetamine in the primate. J Nucl Med. 1983;24: 922–31. 7. Holman BL, Wick MM, Kaplan ML, Hill TC, Lee RG, Wu JL, et al. The relationship of the eye uptake of N-isopropyl-p-[123I] iodoamphetamine to melanin production. J Nucl Med. 1984;25: 315–9. 8. Goto H, Usui M, Ishii I. Efficacy of (123)N-isopropyl-p-[(123)I]iodoamphetamine single photon emission computed tomography for the diagnosis of uveal malignant melanoma. Am J Ophthalmol. 2001;132:937–9. 9. Goto H. Clinical efficacy of 123I-IMP SPECT for the diagnosis of malignant uveal melanoma. Int J Clin Oncol. 2004;9:74–8. 10. Sou R, Oku N, Ohguro N, Hibino S, Fujikado T, Tano Y. The clinical role of n-isopropyl-p-[123I]-iodoamthetamine single photon emission computed tomography in the follow-up of choroidal melanoma after radiotherapy. Jpn J Ophthalmol. 2004;48: 54–8. 11. Yoshimura M, Kanesaka N, Saito K, Koizumi K, Tokuuye K, Goto H. Diagnosis of uveal malignant melanoma by a new semiquantitative assessment of N-isopropyl-p-[123I]-iodoamphetamine. Jpn J Ophthalmol. 2011;55:148–54. 12. Morimoto K, Yoshimura M, Goto H, Koizumi K, Abe K. Semiquantitative evaluation of uveal malignant melanoma with N-isopropyl-p-[123I]-iodoamphetamine (I-123 IMP). J Tokyo Med Univ. 2007;65:137–43. 13. Shields CL, Shields JA, Kiratli H, De Potter P, Cater JR. Risk factors for growth and metastasis of small choroidal melanocytic lesion. Ophthalmology. 1995;102:1351–61. 14. Shields CL, Cater J, Shields JA, Singh AD, Santos MCM, Carvalho C. Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol. 2000;118:360–4.
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54 15. Shields CL, Furuta M, Berman EL, Zahler JD, Hoberman DM, Dinh DH, et al. Choroidal nevus transformation into melanoma. Arch Ophthalmol. 2009;127:981–7. 16. Stolz W, Riemann A, Cognetta AB, Pillet L, Abmayr W. ABCD rule of dermatoscopy: a new practical method for early recognition of malignant melanoma. Eur J Dermatol. 1994;4:521–7. 17. Nachbar F, Stolz W, Merkle T, Cognetta AB, Vogt T, Landthaler M, et al. The ABCD rule of dermatoscopy: high prospective value in the diagnosis of doubtful melanocytic skin lesions. J Am Acad Dermatol. 1994;30:551–9. 18. Menzies SW, Ingvar C, Crotty KA, McCarthy WH. Frequency and morphologic characteristics of invasive melanomas lacking specific surface microscopic features. Arch Dermatol. 1996;132: 1178–82. 19. Menzies SW, Ingvar C, McCarthy WH. A sensitivity and specificity analysis of the surface microscopy features of invasive melanoma. Melanoma Res. 1996;6:55–62. 20. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E, Delfino M. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions: comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol. 1998;134:1563–70. 21. Nagaoka T, Nakamura A, Okutani H, Kiyohara Y, Sota T. A possible melanoma discrimination index based on hyperspectral data: a pilot study. Skin Res Technol. 2012;18:301–9.
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O. Kameyama et al. 22. Nagaoka T, Nakamura A, Okutani H, Kiyohara Y, Koga H, Saida T, et al. Hyperspectroscopic screening of melanoma on acral volar skin. Skin Res Technol. 2013;19:e290–6. 23. Vo-Dinh T, Stokes DL, Wabuyele MB, Martin ME, Song JM, Jagannathan R, et al. A hyperspectral imaging system for in vivo optical diagnostics. Hyperspectral imaging basic principles, instrumental systems, and applications of biomedical interest. IEEE Eng Med Biol Mag. 2004;23:40–9. 24. Khoobehi B, Beach JM, Kawano H. Hyperspectral imaging for measurements of oxygen saturation in the optic nerve head. Invest Ophthalmol Vis Sci. 2004;45:1464–72. 25. Yamauchi Y, Kemma H, Goto H, Nakamura A, Nagaoka T, Sota T. Novel automated method for screening age-related macular degeneration. Jpn J Ophthalmol. 2012;56:577–83. 26. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. http:// www.wma.net/en/30publications/10policies/b3/index.html. Accessed 29 Jan 2014. 27. Kruse FA, Lefkoff AB, Boardman JW, Heidebrecht KB, Shapiro AT, Barloon PJ, et al. The spectral image processing system (SIPS)–interactive visualization and analysis of imaging spectrometer data. Remote Sens Environ. 1993;44:145–63. 28. Shields JA, Mashayekhi A, Seong RA, Shields CL. Pseudomelanomas of the posterior uveal tract. Retina. 2005;25:767–71.
CLINICAL INVESTIGATION
Noninvasive diagnostics supporting system for choroidal melanoma: a pilot study Ori Kameyama • Yoshihiko Usui • Keisuke Kimura Atsushi Nakamura • Takayuki Sota • Hiroshi Goto
•
Received: 3 March 2014 / Accepted: 21 August 2014 / Published online: 8 October 2014 Ó Japanese Ophthalmological Society 2014
Abstract Purpose To examine the usefulness of a near-infrared hyperspectral imager (NIR-HSI) system in discriminating uveal melanoma from other intraocular tumors. Method The NIR-HSI, which had been developed as a screening system for age-related macular degeneration, was used to measure near-infrared hyperspectral data (NIRHSD) of a lesion located at the ocular fundus of 17 Japanese patients, including 5 with choroidal melanoma and 12 with other intraocular tumors. The index was derived from each NIR-HSD. Non-parametric statistical analysis was performed. Results Diagnostic accuracy of 94.1 % was achieved when the threshold value of the index was set to minimize the average value of false-positive and -negative fractions. Conclusions The NIR-HSI system is useful as a noninvasive diagnostic supporting system for choroidal melanoma. Keywords Near-Infrared hyperspectral imager Choroidal melanoma
O. Kameyama T. Sota Department of Electrical Engineering and Bioscience, Waseda University, Shinjuku, Tokyo 169-8555, Japan Y. Usui (&) K. Kimura H. Goto Department of Ophthalmology, Tokyo Medical University Hospital, Shinjuku, Tokyo 160-0023, Japan e-mail: [email protected] A. Nakamura T. Sota Research Institute for Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan
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Introduction Uveal melanoma is the most common primary intraocular malignant tumor. According to one report, the incidence of uveal melanoma in the USA between 1973 and 1997 was 4.3 per million, and most cases (97.8 %) occurred in the white population [1]. In Japan, the estimated annual incidence of uveal melanoma is 0.25 per million [2]. Reports state that choroidal melanoma-related mortality depends not only on the apical height and basal diameter of the tumor, but also on the distance between the proximal tumor border and the optic disc [3, 4]. It is difficult to discriminate a small choroidal melanoma from other intraocular tumors, such as choroidal nevus, melanocytoma, hemangioma and metastasis, even with the combination of slit-lamp biomicroscopy, binocular fundus examination, ultrasonography and magnetic resonance imaging [5, 6]. To arrive at a definitive diagnosis, single-photon emission computed tomography (SPECT) with N-isopropyl-p-[123I] indoamphetamine (123I-IMP) is considered the most promising diagnostic tool in Japan [6–12]. Possible drawbacks of 123IIMP SPECT imaging are the usage of a radioisotope and the ambiguity in image processing. Shields et al. [13–15] retrospectively studied clinical risk factors of growth and metastases of small pigmented choroidal tumors and of choroidal nevus transformation into melanoma. They report that clinically important factors include tumor thickness greater than 2.0 mm, posterior tumor margin touching the disc, visual symptoms, orange pigment and subretinal fluid. Ultrasonographic hollowness and hollow absence should be added in examining a possibility of choroidal nevus transformation into melanoma. These authors identified the numerical value of each risk factor using multivariate analysis [14, 15]. The relative risk, i.e., the risk for tumor growth, in comparison with
Diagnosis system for choroidal melanoma
cases without any factors was calculated combining various clinical factors. The relative risk was considered useful in consulting patients with small suspicious choroidal melanocytic tumors. Although their findings are important and useful in consultations with patients with small suspicious choroidal melanocytic tumors, they are still limited to empirical diagnosis and do not fully reflect the pathological condition of each patient. Clinical diagnosis of a pigmented melanoma depends on the ABCD rule of dermoscopy [16, 17], Menzies’ method [18, 19] and the 7-point checklist [20]. Although all of these tests are useful, they cannot avoid subjectivity in reading lesions and/or scoring procedures. Additionally, experts in dermatology read lesions based on variegation in the lesion morphology, essential for diagnosing melanoma. The morphology of pigmented skin lesions, including melanoma, is predominantly a result of varying concentrations and distributions of pigmented molecules such as melanin and hemoglobin. Based on these differences, Nagaoka et al. [21, 22] proposed a new concept in machine diagnostics for melanoma and developed a noninvasive hyperspectral diagnostic supporting system for pigmented melanoma. This system uses information about the pigmented morphology of a lesion at the molecular level, which is contained in the cutaneous spectra. The hyperspectral diagnostic supporting system acquires hyperspectral data (HSD) of a lesion, simultaneously storing spectral information and two-dimensional space information [23, 24]. They also proposed a melanoma discrimination index (DI) derived from the HSD and demonstrated that its performance is practical in discriminating melanoma from other pigmented skin lesions because the HSD contains information about the molecules responsible for producing the morphology of pigmented skin lesions. Recently, Yamauchi et al. [25] developed a near-infrared hyperspectral imager (NIR-HSI) for the ocular fundus by customizing a commercially available fundus camera so that it could acquire HSD about the ocular fundus in a 50° image field within 5 s. Although this system was originally used as automated screening for age-related macular degeneration, it could be useful as a noninvasive diagnostic supporting system for choroidal melanoma because HSD provides information about pigmented molecules, including melanin and hemoglobin, in the near-infrared wavelength region and because the essential feature of melanoma is invariably independent of anatomic site. Indeed, the color tone of choroidal melanoma is inhomogeneous. In this article, we examine the use of the NIR-HSI system as a noninvasive diagnostic supporting system for choroidal melanoma if an index derived from the NIRHSD is used in conjunction with the previously proposed concept [21, 22].
49
Patients and methods Patients This study was approved by the Ethics Committee of Tokyo Medical University and performed in accordance with the Declaration of Helsinki [26]. An explanation of the nature and consequences of the study was provided. A total of 17 patients took part in this study after written informed consent had been obtained from each. There were ten women and seven men, whose ages ranged from 49 to 81 years, with a median of 58 years. All patients were of Japanese descent and had visited the ophthalmology outpatient clinic of Tokyo Medical University Hospital between August 2008 and August 2013. This study excluded patients who had received previous treatment. Lesions of five patients (3 women and 2 men), aged from 57 to 81 years (median 71 years), were highly suspected as having choroidal melanoma from follow-up observations. Two of these patients, who had lost most of their eyesight, also gave consent for enucleation; the pathological diagnosis was melanoma. Lesions of the other 12 patients (7 women and 5 men), aged 49–80 years (median 57 years), were clinically diagnosed as having choroidal nevus (n = 5), choroidal hemangioma (n = 4), metastatic choroidal tumor (n = 2) and melanocytoma (n = 1). Equipment A NIR-HSI for the fundus was used for this study, as described elsewhere [25]. Briefly, a commercially available fundus camera was customized according to the following specifications: spectral resolution, 0.97 nm; full spectral range, 720–950 nm; measurement area, 50° fundus image field; spatial resolution, 33 lm along the vertical axis and 16 lm along the horizontal axis of the retina; measurement time, approximately 5 s; estimated power on the corneal surface, 43 mW. The HSD was basically measured under the condition that a lesion was located within or closer to a center of the 50° fundus image field. When the size of the lesion was larger than the field, the HSD was measured in a field of view where the ratio of the tumor and ordinary fundus is approximately 1:1 [21, 22]. The melanoma DI was derived from the HSD as described below and according to reports from Nagaoka et al. [21, 22] and Yamauchi et al. [25]. A spectrum consisting of the light intensity of every wavelength can be regarded as a vector, and the vector is characterized by its direction and length. For each lesion, a self-reference spectrum was used. A spectrum averaged over an area as large as possible
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50
O. Kameyama et al.
Fig. 1 Color fundus photographs (top panels), single wavelength images (middle panels) and spectra included within and around lesions (bottom panels). Color fundus photographs (top panels) for typical a choroidal nevus, b hemangioma and c melanoma. Single wavelength images (middle panels) for typical d choroidal nevus, e hemangioma and f melanoma. The single wavelength images were constructed using reflectance spectra averaged over the wavelength
band from 795 to 805 nm. Near-infrared spectra (bottom panels) within and around lesions for typical g choroidal nevus, h hemangioma and i melanoma. Each bottom panel shows a spectrum averaged spatially within the same color box in the corresponding middle panel. Spectra are roughly categorized into the two kinds of spectra for choroidal nevus and hemangioma, while there is no regularity in the spectra for melanoma; arb. units stands for arbitrary units
included within the field of view, except for the nerve head and peripheral region, was defined as the self-reference spectrum. The pretreatment was effective for noise reduction. The difference between any spectrum under consideration and the self-reference spectrum was parameterized using the concept of spectral angle [27]. A larger spectral angle indicates that the spectrum is different from the selfreference spectrum. The normalized distribution of the spectral angle was parameterized using the concept of entropy to obtain a DI, which was used to discriminate melanoma from other lesions. As the spectral angle distribution becomes wider,
the DI increases, indicating that the DI represents the variation of the spectra under study, i.e., the irregularity, disorder and variation in morphology and color tone of the lesion.
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Statistical evaluation Statistically significant differences in DIs between the melanoma and other intraocular tumor groups were analyzed using the Mann-Whitney U test. A p value less than 0.05 was considered statistically significant. The threshold value of DI was defined as the value of DI that minimized a
Diagnosis system for choroidal melanoma
balanced error rate (BER), which is an average value of the false-positive fraction (FPF) and the false-negative fraction (FNF).
Results Figure 1 shows color fundus photographs, grayscale single wavelength images and spectra for the typical choroidal nevus, hemangioma and melanoma. The grayscale single wavelength images for each lesion indicate that the peripheral region is different in image quality from the other regions, which is a main reason why the spectra in the peripheral region were excluded from the analysis. Regarding the spectral features for the three typical lesions, the variation of spectra increased (in order) from choroidal nevus, to hemangioma to melanoma. This characteristic feature is verified using the normalized distribution of spectral angles for choroidal nevus, hemangioma and melanoma (Fig. 2). These distributions were parameterized using the entropy concept [21, 22] to obtain a DI of 3.59 for choroidal nevus, of 3.20 for hemangioma and of 4.96 for melanoma. Similar to pigmented skin lesions, the value for choroidal melanoma is larger compared to other pigmented ocular lesions [21, 22]. Table 1 summarizes the features, clinical diagnosis and DI value for each lesion, and the distributions of the DIs for the melanoma and other intraocular tumor groups are
Fig. 2 Comparison of normalized distributions of spectral angles. Spectral angle distributions for choroidal nevus (black dotted curves, color online), hemangioma (green dashed curve, color online) and melanoma (red solid curve, color online). Reflecting characteristics of spectra are included in hyperspectral data (HSD), while spectral angles distribute in a narrow range for choroidal nevus and hemangioma and in a wider range for melanoma. A narrower distribution of spectral angles leads to a smaller discrimination index (DI), while a wider distribution leads to a larger DI
51
shown in Fig. 3, where the median, 25th percentile and 75th percentile for each group are indicated by horizontal bars. The difference in DIs for the two groups was statistically significant (p = 0.0022). When the FPF and FNF were drawn as a function of the DI, the BER reached its minimum value at a DI of 4.12 when BER was calculated as (FPF ? FNF)/2. When this value was regarded as the threshold value of DI, a sensitivity of 100 % (5/5), specificity of 91.7 % (11/12) and diagnostic accuracy of 94.1 % (16/17) were achieved. These results demonstrate that the proposed DI is a good index for discriminating melanoma from other intraocular tumors. A false-positive case was clinically diagnosed as a melanocytoma at the present stage. Figure 4 shows the color fundus photograph, grayscale single wavelength image and spectra for the melanocytoma. A variety of spectra existed for this case.
Discussion The present NIR-HSI was developed based on a commercially available fundus camera, making it easy to handle. The proposed DI, which is derived from the HSD and works well for differentiating melanoma from other pigmented skin lesions [21, 22], reflects objective and quantitative information about the pigmentation in lesions at the molecular level. Diagnosis of uveal melanoma is usually based on ophthalmoscopic examination and various imaging information, including results from ultrasonography, magnetic resonance imaging and optical coherent tomography. The clinical diagnosis is thus based on appearance and morphology and is somewhat subjective. While 123I-IMP SPECT imaging is unique in its ability to provide semiquantitative and objective measures of the pathology of melanoma, it is invasive because a radioactive isotope is used. In contrast, possible benefits of the presently proposed examination with NIR-HSI are objective and quantitative as well as simple and noninvasive. It is recognized that 123I-IMP SPECT imaging is an effective modality for definitively diagnosing choroidal melanoma [8–11]. The efficacy of 123I-IMP SPECT imaging depends on the nature of IMP in that IMP accumulates predominantly in melanoma cells that are actively producing melanin. The performance of 123I-IMP SPECT examination is reported to achieve a sensitivity of 73.5–100 % and the corresponding specificity of 92.6–70.4 %, depending on the method used to analyze the IMP accumulation in the area and the selection of cutoff point (threshold value) [11, 12]. Performance of the present NIR-HSI system compares favorably with that of 123I-IMP SPECT, although the present statistical population is small.
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52 Table 1 Demographic data, features of tumors, clinical diagnosis and discrimination index (DI) for cases in the current study
RD retinal detachment, RPE retinal pigment epithelium, NA not available
O. Kameyama et al.
Case
Sex/age (years)
Diameter (mm)
Serous RD
RPE atrophy
Clinical diagnosis
DI
1
F/81
9.5 9 7.0
4.2
?
?
Melanoma
4.96
2
F/68
9.5 9 7.0
3.4
?
?
Melanoma
4.52
3
M/71
8.0 9 8.0
9.2
?
?
Melanoma
4.72
4
F/57
Diffuse
NA
?
?
Melanoma
4.12
5
M/75
8.8 9 8.3
3.1
?
?
Melanoma
4.23
6
M/52
1.5 9 1.5
NA
-
-
Choroidal nevus
2.16
7
F/68
5.7 9 5.7
3.3
-
?
Choroidal nevus
3.18
8
M/80
7.5 9 4.5
1.0
-
-
Choroidal nevus
4.05
9
F/55
1.5 9 3.0
NA
-
-
Choroidal nevus
3.59
10
M/58
1.5 9 1.5
NA
-
-
Choroidal nevus
3.00
11 12
M/50 F/50
6.0 9 6.0 5.5 9 5.5
NA NA
? ?
? ?
Hemangioma Hemangioma
3.20 3.82
13
F/49
4.2 9 6.0
4.2
?
?
Hemangioma
3.60
14
M/62
6.0 9 4.5
NA
-
?
Hemangioma
3.87
15
F/75
13 9 12
12
?
?
Metastatic choroidal tumor
3.82
16
F/57
13 9 13
4.5
?
?
Metastatic choroidal tumor
2.98
17
F/57
1.5 9 1.5
2.3
-
NA
Melanocytoma
4.19
Fig. 3 Distribution of discrimination index (DI) values. Comparison of the DI values between the melanoma and other intraocular tumor groups. The DIs of the two groups were significantly different (p = 0.0022), demonstrating that the present DI is useful for discriminating choroidal melanoma from other intraocular tumor lesions
The DI threshold value of 4.12 at the minimum BER resulted in a false-positive case, clinically diagnosed as melanocytoma; the value of the DI for this case was 4.19. We considered possible reasons for these higher values. As shown in Fig. 4b, c, the dark area fades out toward the outside from the center of the lesion, and there is variation in the spectra. For this case, the higher DI was attributed to
123
Thickness (mm)
the variation in spectra, which may be caused by the variation in melanin content; we cannot, however, rule out the possibility that the case is a melanoma. Choroidal hemangioma is occasionally accompanied by retinal edema. Spectra from the edema filled with serous fluid must vary from point to point within the edema because of differing amounts of serous fluid; the existence of various kinds of spectra may lead to the higher DI, which may be a possible reason choroidal hemangioma is included in the false-positive cases, although the present case is excluded. A low signal-to-noise ratio of spectra may also lead to a higher DI. Thus, a possible drawback of the present system is that it may not be suitable to analyze lesions with a high elevation because the focus of the commercially available fundus camera does not fit the elevated lesions. However, this problem is not considered serious because there are major doubts concerning whether lesions with such high elevation are actually late stage melanoma. According to Shields et al. [28], choroidal nevus, or melanocytoma, still accounts for most pseudomelanoma, and its differentiation from small melanoma remains a clinical dilemma. Inversely, there seems to remain a possibility that during the follow-up period small melanoma will be misdiagnosed as melanocytoma. This clinical dilemma cannot be solved by the proposed system. A separate study is needed to determine the possibilities of the present system as a dependable diagnostic tool in the follow-up of cases.
Diagnosis system for choroidal melanoma
53
information of a pigmented lesion at the molecular level through HSD is objective and quantitative. Thus, the DI may also be used to evaluate responses to therapy and for clinical follow-up. These findings and perspectives should be confirmed in future multicenter clinical trials. Conflicts of interest O. Kameyama, None; Y. Usui, None; K. Kimura, None; A. Nakamura, None; T. Sota, None; H. Goto, None.
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Fig. 4 Color fundus photograph (top), single wavelength images (middle) and spectra included within and around a lesion (bottom) for a false-positive case. A false-positive case resulted when the discrimination index (DI) threshold value of 4.12 was used; this case was clinically diagnosed as a melanocytoma. a Color fundus photographs (top panels) of the melanocytoma. b Single wavelength images (middle panels) of the melanocytoma. The single wavelength images were constructed similar to those shown in Fig. 1. c Nearinfrared spectra within and around lesions (bottom panels) for the melanocytoma. Spectra are lacking in regularity, which is considered to lead to the larger DI observed for this case
We presented a noninvasive diagnostic supporting system for choroidal melanoma. The DI derived from HSD in the near-infrared wavelength region had a sensitivity of 100 %, specificity of 91.7 % and diagnostic accuracy of 94.1 %. Although a further study with a larger population is needed to confirm its performance, the DI-reflecting
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