RU2782134C1 - Method for differential diagnosis of progressive nevus and conjunctival melanoma - Google Patents

Abstract

FIELD: ophthalmology.

SUBSTANCE: invention relates to ophthalmology and is intended for the differential diagnosis of nevus and melanoma of the conjunctiva. Optical coherence tomography is performed in angiography mode. The distribution density of blood vessels and the presence of "lace pattern" zones are determined, as well as the local vascular density (VD) and the number of "lace pattern" zones. If the local vascular density is less than 50% and less than 7 zones of the "lace pattern" are detected, a progressive nevus is diagnosed. With a local vascular density of 50% or more and the detection of 7 or more zones of the "lace pattern" or the presence of at least one zone of the "confluent pattern" - melanoma of the conjunctiva.

EFFECT: method provides early differential diagnosis of nevus and conjunctival melanoma for timely selection of treatment tactics.

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Description

The present invention relates to ophthalmology and is intended for the differential diagnosis of melanocytic neoplasms of the conjunctiva based on the assessment of the qualitative and quantitative characteristics of blood flow in the area of neoplasia in order to optimize treatment tactics.

Tumors of the adnexal apparatus of the eye occupy more than 50% in the structure of ophthalmic oncological pathology, of which 40% are epibulbar formations. Most of them have a benign genesis, in 11% of cases they are malformations [Saakyan S.V., Tatskov R.A., Ivanova O.A., Tsygankov A.Yu., Maybogin A.M. Surgical treatment of epibulbar malformations. Ophthalmology. 2019; 16(3):289-295]. Despite the fact that in the vast majority of cases, neoplasms of this localization have low mitotic activity and slow growth, they are also prone to recurrence and are characterized by a high degree of malignancy [Balayan M.L. Radio wave surgery in the treatment of formations of tumor and pseudotumor nature of the eyelids, conjunctiva and cornea: abstract of diss. cand. honey. Sciences: / Balayan Marina Leonidovna. - Moscow. 2005. - 25.].

Given the histological features of the conjunctiva and its blood supply, neoplasms of this localization are very diverse: dermoids and lipodermoids, papillomas, cysts, hemangiomas, lymphangiomas, lymphomas, histiocytomas, Kaposi's sarcoma, cancers, Bowen's epithelioma. A special group is represented by melanocytic lesions of the conjunctiva. According to L. Shields et al. [Shields CL, Alset AE, Boal NS, Casey MG, Knapp AN, Sugarman JA, Schoen MA, Gordon PS, Douglass AM, Sioufi K, Say EA, Shields JA. Conjunctival Tumors in 5002 Cases. Comparative Analysis of Benign Versus Malignant Counterparts. The 2016 James D. Allen Lecture. Am J Ophthalmol. Jan 2017; 173:106-133], in children and young patients, one of the most common melanocytic neoplasms of the conjunctiva is a nevus. With age, the number of cases of malignant neoplasia of this localization, including conjunctival melanoma, increases.

Given the degree of malignancy of melanoma, the issue of its timely detection is relevant. Differential diagnosis of progressive nevus and conjunctival melanoma, especially in non-pigmented or, conversely, densely pigmented neoplasms, can be difficult and requires a comprehensive approach from the doctor using the maximum possible arsenal of diagnostic methods [Ivanova, O.A. Clinical features of conjunctival nevi in the age aspect and optimization of their early treatment: dissertation of candidate med. Sciences: 14.01.07 / Ivanova Olga Andreevna; scientific hands Sahakyan S.V. - Moscow, 2011. - 107 p.].

For an objective assessment of the characteristics of the epibulbar neoplasm, methods such as ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT) are used [Ultrasound in ophthalmology: A guide for doctors / edited by V.V. Neroeva and T.N. Kiseleva. 1st edition. M: IKAR Publishing House. 2019. 322 p.; Zakharova M.A., Kuroyedov A.V. Optical coherence tomography: a technology that has become a reality // BC. Clinical ophthalmology. 2015. No. 4. S.204-21; Konopińska J., Lisowski Ł., Wasiluk E., Mariak Z., Obuchowska I. The Effectiveness of Ultrasound Biomicroscopic and Anterior Segment Optical Coherence Tomography in the Assessment of Anterior Segment Tumors: Long-Term Follow-Up.J Ophthalmol. 2020 Jun 16; 2020:9053737]. Their high resolution makes it possible to assess the size of neoplasia, its structure, and the condition of the underlying tissues.

One of the main clinical signs characterizing the vital prognosis of a tumor is the degree of its vascularization. So, according to various authors, it is with the development of an active vascular network that neoplasia acquires a metastatic potential [Skalet AH, Li Y, Lu CD, et al. Optical Coherence Tomography Angiography Characteristics of Iris Melanocyte Tumors. Ophthalmology. 2017; 124(2): 197-204., Amiryan A.G., Sahakyan S.V. Prognosis factors for uveal melanoma. Bulletin of ophthalmology. 2015; 131(1):90-95]. Other authors, studying neoplasms of IH, believe that a geometrically correctly organized vascular network may indicate its benign nature, and a chaotically organized, irregular vascular network indicates a malignant process. However, the literature data presented are based on little clinical material and are controversial [Allegrini D, Montesano G, Rese A. Optical Coherence Tomography Angiography of Iris Nevus: A Case Report. Case Rep Ophthalmol. 2016; 7(3):172-178], which requires further research in this direction. At the same time, despite the obvious advantages of UBM and OCT, these methods do not allow assessing the state of blood flow in the neoplasm.

Until recently, the main method for objectively assessing the blood flow of the eye was fluorescein angiography (FA), which is based on the observation of the distribution of a contrast agent in the vessels of the retina and choroid after its intravenous administration or application on the surface of the eye [Petraevsky A.V., Gndoyan I.A. Patent for the invention "Method for studying the blood circulation of the anterior segment of the eye" 2403857, 2010]. The possibilities of FAG make it possible to study changes in the vascular bed of the eye, primarily in the pathology of the fundus (degenerative changes in the retina determined by age or genetic factors, diabetic retinopathy, acute circulatory disorders in the vessels of the retina. To a lesser extent, the FAG method is used to assess the blood flow of the anterior part of the eye (POH), and with epibulbar localization of the pathological process - it is practically not used.

To study the state of the vascular bed of IOH, such non-invasive methods as optical biomicroscopy, photographic recording, video biomicroscopy, television biomicroscopy of blood vessels, dark-field imaging, various types of non-invasive FAG are used [Kiseleva T.N., Kotelin V.I., Losanova O.A., Lugovkina K .AT. Non-invasive methods for assessing the hemodynamics of the anterior segment of the eye: prospects for application in clinical practice. Ophthalmology. 2017; 14(4):283-290]. However, the use of these methods may be limited by the need to use special equipment and special training of the researcher, the duration of the study, and the insufficient information content of the obtained qualitative and quantitative characteristics of blood flow.

To date, a modern non-invasive and highly informative method for assessing the microcirculatory bed of the eye has appeared in the practice of an ophthalmologist - optical coherence tomography with angiography mode (OCTA), which does not have the above disadvantages. The method is based on the analysis of the difference in the amplitudes of the laser beam reflected from the selected point during repeated scans. [Lumbroso B, Huang D, Jia Y, Fujimoto J, Rispoli M. Clinical Guide To Angio-OCT: Non Invasive, Dyeless OCT Angiography. New Delhi: Jaypee Brothers, Medical Publishers; 2014]. In addition to the non-invasiveness of the method and the absence of the need to use fluorescent dyes, the advantages of OCTA include the high speed of the study and the possibility of its repeated repetition, obtaining a three-dimensional image of the vascular bed of the eye, the possibility of recording not only qualitative, but also quantitative indicators of the state of ocular blood flow. This makes it possible to effectively use OCTA for visualization of superficial vessels of the eye, including neoplastic processes.

Thus, in case of melanocytic neoplasms of the conjunctiva, the use of only one imaging method (OCT or UBM) without assessing blood flow in the area of the pathological process presents difficulties for the differential diagnosis of progressive nevus and conjunctival melanoma and dictates the need to develop an additional method for obtaining information not only about the size and structure of neoplasia , but also about the features of its blood supply in order to further optimize treatment tactics.

Currently, OCTA is widely used in the diagnosis of pathology of the posterior part of the eye, however, the method has great potential for diagnosing the state of the IOH microvasculature, both in normal conditions and in pathology. The method allows not only to visualize the complex of vessels, but also to measure its area, to determine the shape (lace, coral-shaped, "spokes of the wheel", jellyfish-like, umbrella-like, "dead tree"), branching, the presence of anastomoses and loops [Anikina M., Matnenko T. , Lebedev O. Optical coherence tomography-angiography: a promising method in ophthalmic diagnostics. Practical medicine. 2018; 114(3):7-10].

To date, there have been reports in the literature about the study of the possibilities of OCTA in patients with corneal or graft vascularization (Ang M., Sim D. A., Keane P. A. et al. Optical coherence tomography angiography for anterior segment vasculature imaging. Ophthalmology. 2015; 122(9): 1740-1747; Lee W. D., Devarajan K., Chua J., Schmetterer L. et al. Optical coherence tomography angiography for the anterior segment. Eye Vis (Lond). 2019; 6:4; Liu Z., Wang H., Jiang H. et al. Quantitative analysis of conjunctival microvasculature imaged using optical coherence tomography angiography. Eye Vis (Lond) 2019; 6:5; Akagi T., Uji A., Huang A. S. et al. Conjunctival and Intrascleral Vasculatures Assessed Using Anterior Segment Optical Coherence Tomography Angiography in Normal Eyes Am J Ophthalmol 2018;196:1-9). There is information on the use of OCTA in assessing the vascularization of IOH neoplasms (Allegrini D., Montesano G., Rese A. Optical Coherence Tomography Angiography of Iris Nevus: A Case Report. Case Rep Ophthalmol. 2016;7(3):172-178; Binotti W.W., Mills H., Nosé R.M. et al., Anterior segment optical coherence tomography angiography in the assessment of ocular surface lesions. Ocul Surf. 2021; 22:86-93; Nampei K, Oie Y, Kiritoshi S et al. Comparison of ocular surface squamous neoplasia and pterygium using anterior segment optical coherence tomography angiography Am J Ophthalmol Case Rep.2020;20:100902].

The closest analogue of the present invention is a method of the same purpose, including the differential diagnosis of tumors of the conjunctiva using OCTA to visualize perifocal vascular neoplasia with an assessment of their diameter and depth. At the same time, malignant neoplasms of the conjunctiva are characterized by a greater depth of occurrence and a larger diameter of the studied vessels than with a benign nature of the process.

The authors identified criteria for the differential diagnosis of conjunctival tumors: for the depth of the vessels, sensitivity of 90.9% and specificity of 100.0% were calculated with a threshold value of 236.5 μm. For vessel diameter, a sensitivity of 100.0% and a specificity of 88.9% were calculated with a cut-off value of 53.9 µm. (Binotti WW, Mills H, Nose RM, Wu HK, Duker JS, Hamrah P. Anterior segment optical coherence tomography angiography in the assessment of ocular surface lesions. Ocul Surf. 2021 Jul 30;22:86-93).

Despite the advantages of this method for assessing various neoplastic processes of the conjunctiva, it has a number of limitations. Firstly, these are technical difficulties in performing the study (manual selection and measurement of the diameter of the vessels), requiring a certain skill from the operator. Secondly, the method does not take into account the qualitative and quantitative characteristics of the neoplasm's own vascular network, which is important, since the angioarchitectonics of a malignant tumor presumably has features that indicate the active growth of the neoplasm.

The objective of the invention is to develop an informative method for the differential diagnosis of nevus and melanoma of the conjunctiva.

The technical result of the invention is to improve the accuracy of the differential diagnosis of nevus and conjunctival melanoma at the clinical stage for subsequent optimization of treatment tactics.

The technical result is achieved by determining the specific characteristics of blood flow in the area of the pathological process using OCTA.

The proposed method makes it possible to objectively assess the nature of blood flow in the area of the conjunctival neoplasm and timely conduct a differential diagnosis of the nevus of this localization and melanoma even before the development of obvious clinical differences between them, which in practical terms will allow the patient to timely prescribe adequate treatment.

In the period from 2020 to 2021, we examined 40 people, of which 20 were healthy volunteers and 20 patients with conjunctival neoplasms. 13 patients were diagnosed with conjunctival nevus and 7 with conjunctival melanoma. We have developed an algorithm for studying the qualitative and quantitative parameters of the vascular network of conjunctival neoplasia for the differential diagnosis of a malignant and benign process.

The study of the state of blood flow in the tumor was carried out using OCTA.

Normally, in all quadrants of the bulbar conjunctiva, the vascular pattern was characterized mainly by the radial course of the vessels, their slight tortuosity with a uniform caliber of the lumen throughout. The zones of "lace" and "drain" patterns were absent.

For conjunctival neoplasms, a characteristic picture was obtained: own convoluted vessels of irregular course and different caliber.

On the obtained angiograms, using the Navis-Ex software version 1.8 (Nidek), the local density of the newly formed vascular network - VD and the presence of "lacy" and "confluent" pattern zones), as well as the quantitative characteristics of the neoplasia blood flow - VD and the number of "lace pattern" zones ".

The term "lace pattern" denoted areas of accumulation of vessels forming anastomoses like lace, which, presumably, is a sign of active neoplasm growth.

The “confluence pattern” was understood as the confluence of vessel shadows on the tomogram due to their dense distribution in the tumor tissue. This type of vascular pattern excludes the possibility of assessing other characteristics of blood flow.

The obtained scans were quantitatively analyzed using the ImageJ software [https://imagej.net/]. Angiograms were binarized, thresholding was performed according to the previously described Otsu method [Mehta N, Liu K, Alibhai AY, et al. Impact of Binarization Thresholding and Brightness/Contrast Adjustment Methodology on Optical Coherence Tomography Angiography Image Quantification. Am J Ophthalmol. 2019; 205:54-65].

The VD value of the conjunctiva in the normal quadrants was: upper - 35.8%; upper internal - 34.6%; domestic - 38.4%; lower internal -36.9%; lower - 33.4%; lower outer - 35.7%; external - 37.7%; upper outer - 32.8%. Thus, the minimum density of vessels was registered in the upper outer quadrant, and the maximum - in the inner one.

Quantitative characteristics of local vascular density and "lace" and "drain" patterns were different for melanoma and nevus. This was the basis for considering these characteristics as differential diagnostic features.

With nevus, the VD indicator exceeded normal values, however, the average value was less than 50%, and the number of zones of the "lace pattern" did not exceed 7. Zones of the "confluent pattern" were not determined. In melanoma, the mean VD value was 50% or more, and the number of “lace pattern” zones was 7 or more. In a number of cases, zones of a "confluent pattern" were observed.

A retrospective comparative analysis of histological data with OCTA data showed the accuracy of the method and its effectiveness in relation to the differential diagnosis of nevus and conjunctival melanoma.

The method is carried out as follows. Optical coherence tomography is performed in the angiography mode in the neoplasm zone. The local density of the newly formed vascular network, the presence and number of zones of accumulation of vessels forming anastomoses according to the type of lace - "lace pattern" and zones of fusion of vessel shadows - "drain pattern" are assessed. When the local density of the newly formed vascular network is less than 50% and less than 7 zones of the "lace pattern" are detected, a progressive nevus is diagnosed. With a local density of the newly formed vascular network of 50% or more and the detection of 7 or more zones of the "lace pattern" or the presence of at least one zone of the "confluent pattern" - melanoma of the conjunctiva.

The method is illustrated by the following clinical examples.

Clinical example 1

Patient A., aged 47, turned to an ophthalmologist with complaints about the presence of a neoplasm of the conjunctiva. There were no other complaints or changes in the organ of vision. From the anamnesis: the neoplasm appeared several years ago, gradually increasing in size. OCTA was performed using an OCT scanner Nidek RS-3000 Advance 2 (Japan) with an adapter for IOH and Macula mar protocol.

According to the OCTA method, an increase in the number of visualized vessels, a violation of their course, and pathological tortuosity were determined. Local VD was 43%. The number of zones "lace pattern" - 5 - Fig.1, indicating the presence of a nevus. Radioexcision of the neoplasm was performed. According to the results of histopathological examination, a diagnosis of a complex nevus of the conjunctiva was made.

Clinical example 2

Patient B., 25 years old, turned to an ophthalmologist with complaints about the presence of a neoplasm of the conjunctiva. There were no other complaints or changes in the organ of vision. From the anamnesis: the neoplasm appeared a few months ago after intense artificial ultraviolet irradiation without the use of eye protection. According to the OCTA method, the tumor's own vascular network was determined, consisting of intertwining vessels, which differed from the adjacent tissues. Local VD was 40.8%. The number of zones of the "lace pattern" - 4 - Fig. 2, which corresponded to the picture of the nevus. Radioexcision of the neoplasm was performed. According to the results of histopathological examination, a blue nevus of the conjunctiva was diagnosed.

Clinical Case 3

Patient V., aged 74, turned to an ophthalmologist with complaints about the presence of a neoplasm of the conjunctiva. There were no other complaints or changes in the organ of vision. From the anamnesis: education appeared several years ago, noted its gradual increase. According to the OCTA data, a large number of visualized vessels, a violation of their course, and pathological tortuosity were determined. Local VD was 65%. Number of "lace pattern" zones - 9 - Fig. 3, indicating melanoma.

Radioexcision of the neoplasm was performed. According to the results of histopathological examination, a diagnosis of melanoma of the conjunctiva was made.

Clinical Case 4

Patient S., aged 53, turned to an ophthalmologist with complaints about the presence of a neoplasm of the conjunctiva. There were no other complaints or changes in the organ of vision. From the anamnesis: the formation appeared several years ago, there was a gradual increase in size. According to the OCTA data, the tumor's own vascular network was determined, almost completely represented by a network of communicating vessels. Local VD was 50%. The number of zones of the "lace pattern" - 11 - Fig. 4, which indicated melanoma. Radioexcision of the neoplasm was performed. According to the results of histopathological examination, a diagnosis of melanoma of the conjunctiva was made.

Clinical Case 5

Patient D., 66 years old, turned to an ophthalmologist with complaints about the presence of a neoplasm of the bulbar conjunctiva, consisting of several foci. The tumor probably developed from a pre-existing melanosis of the conjunctiva. The rest of the ophthalmological status had no features. According to the OCTA data, a dense distribution of vessels in the tumor tissue was determined, which did not allow an analysis of the qualitative characteristics of the neoplasm's own vascular network - a "confluent pattern". Local VD was 53.8% - FIG. 5. Based on clinical data and instrumental examination data, the patient was diagnosed with conjunctival melanoma.

Claims (1)

A method for the differential diagnosis of progressive nevus and conjunctival melanoma, including optical coherence tomography in the angiography mode (OCTA), characterized in that in the neoplasia zone, the local density of the newly formed vascular network is assessed, the presence and number of zones of accumulation of vessels forming anastomoses according to the type of lace - "lace pattern" and zones of confluence of vascular shadows - "confluent pattern", and if the local density of the newly formed vascular network is less than 50% and if less than 7 zones of the "lace pattern" are detected, a progressive nevus is diagnosed, and if the local density of the newly formed vascular network is 50% or more and 7 and more zones of the "lace pattern" or the presence of at least one zone of the "confluent pattern" - melanoma of the conjunctiva.

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