Locally advanced choroidal melanoma with favorable molecular prognosis - case report.

Uveal malignant melanoma is a rare malignant tumor comprising less than 5% of melanoma cases. It is nevertheless the intraocular tumor with the highest incidence in adults, that arises from the melanocytes in the uveal tract. The authors present the case of a patient with locally advanced choroidal melanoma: from presentation to diagnosis, treatment, and prognosis. A 63-year-old female patient presented in the Ambulatory of the Emergency County Hospital, Craiova, Romania, on the February 1, 2021, accusing visual acuity drop and photophobia in her left eye for about three weeks. Pathology examination in Hematoxylin-Eosin (HE) staining reveals a dense cell proliferation, with small and medium spindle cells and pigment production. The following immunohistochemical markers were used in our study: human melanoma black 45 (HMB45), Ki67, cyclin D1, B-cell lymphoma 2 (Bcl2), S100, Wilms' tumor 1 (WT1), p16, and p53. Uveal melanoma is a malignant tumor that can arise in all the uveal components: iris, ciliary body, and choroid. Out of the three components, iris melanomas have the best prognosis, while ciliary body melanomas have the worst prognosis. It is mandatory for the patient to respect the follow-up schedule, as follow-ups can provide early diagnosis of eventual metastasis.

[Mesectodermal leiomyoma. Unusual tumor of the ciliary body]. / Leiomioma mesoectodérmico. Un tumor poco frecuente del cuerpo ciliar.

BACKGROUND: Mesectodermal leiomyoma is a benign tumor of smooth muscle of the ciliary body, which is derived from the neural crest. CLINICAL CASE: We report the case of a 35-year-old Mexican woman with visually impaired and blurred vision of the right eye of 2 months duration. The clinical and imaging presuntional diagnosis was adenoma of the non pigmented epithelium of the ciliary body and it was surgically resected. Microscopically, the tumor was composed of cells with round nuclei and scant cytoplasm without atypia or mitosis, arranged in a fibrillary background. The immunohistochemical markers for vimentin, muscle specific actin, smooth muscle actin and calponin were strongly positive in the cytoplasm of the neoplastic cells, while for glial fibrillary acidic protein and S-100 protein were negative in the same cellular population. CONCLUSIONS: Mesectodermal leiomyoma of the ciliary body is benign tumor of smooth muscle extremely rare in this location. Until now, there are just 25 previous reported cases in the literature and, the main differential diagnosis is uveal malignant melanoma, therefore some eyes were enucleated. The ultrabiomicroscopy, A and B-scan imaging studies are useful in the evaluation, however, is mandatory the microsocpic examination with routine and histochemical stains as well as the use of immunohistochemical markers such as vimentin, specific muscle actin, smooth muscle actin andcalponin to stablish the smooth muscle origin of this neoplasm, and rule out other malignant neoplams such as malignant melanoma.

Antecedentes: el leiomioma mesoectodérmico es un tumor benigno excepcional que se origina en el músculo liso del cuerpo ciliar y deriva de la cresta neural. Caso clínico: se comunica el caso de una mujer de 35 años, con disminución de la agudeza visual y visión borrosa de 2 meses de evolución en el ojo derecho. El diagnóstico presuncional clínico e imagenológico fue: adenoma del epitelio no pigmentado del cuerpo ciliar, por lo que se resecó quirúrgicamente. Microscópicamente, el tumor estaba formado por células de núcleos redondos de escaso citoplasma sin atipia ni mitosis, dispuestas en una matriz fibrilar. Los inmunomarcadores para vimentina, actina músculo específica, actina de músculo liso y calponina fueron todos positivos en el citoplasma de las células neoplásicas, excepto de los inmunomarcadores para la proteína ácida gliofibrilar y la proteína S-100 que resultaron negativos en la misma población celular. Conclusiones: el leiomioma mesoectodérmico del cuerpo ciliar es un tumor benigno de músculo liso extremadamente raro en esta localización. Hasta el momento, sólo hay 25 casos informados en la bibliografía médica y su principal diagnóstico diferencial es melanoma uveal, motivo por el que algunos ojos se enuclearon. Los estudios de ultrabiomicroscopia y ecografía modos A y B son útiles en la evaluación; sin embargo, es obligado el estudio microscópico con tinciones de rutina, y el uso de marcadores inmunohistoquímicos, como los utilizados en este caso para establecer la naturaleza del músculo liso de esta neoplasia y descartar algunas otras, como el melanoma.

Usefulness of a red chromagen in the diagnosis of melanocytic lesions of the conjunctiva.

IMPORTANCE: Immunohistochemical analyses may assist in the diagnosis of precancerous and cancerous conjunctival lesions. OBJECTIVE: To use Vector Red (VR) to identify an immunologic marker that is sensitive for all melanocytes and another that is sensitive and specific for activated and/or atypical conjunctival melanocytic lesions (MLs). DESIGN, SETTING, AND PARTICIPANTS: Eight specimens each of control lesions (normal conjunctiva and normal uvea as well as choroidal melanoma) and 8 from the diagnostic categories (conjunctival nevus, primary acquired melanosis with mild or no atypia, primary acquired melanosis with moderate to severe atypia, and conjunctival melanoma) that provided sufficient quantity and quality of tissue were available for processing. The specimens were obtained from the Ophthalmic Pathology Laboratory, The Ottawa Hospital, from 2005 to 2013. The specimens were immunolabeled with human melanoma black 45 (HMB45), melanoma antigen recognized by T cells 1 (Melan-A), S100, and Ki67 using VR and a double panmelanoma cocktail (dPANMEL) using 3,3'-diaminobenzidine (DAB) and VR. The HMB45-immunolabeled specimens were additionally developed with DAB, with and without overnight bleaching with hydrogen peroxide, 4%. Data were collected by 2 pathologists who were masked to sample grouping. MAIN OUTCOMES AND MEASURES: Differentiation between benign and malignant MLs based on immunomarker profile. RESULTS: Immunoreactivity was best visualized in specimens with VR. Melan-A labeled all melanocytes (100% sensitivity; panmelanocyte marker) without discriminating between benign and malignant lesions (0% specificity). Atypical melanocytes were most specifically labeled with HMB45 (96% specificity, 97% sensitivity; atypia marker). In primary acquired melanosis specimens, we found that the percentage of HMB45 (P < .001), S100 (P < .001), and Ki67 (P ≤ .02) positivity increased significantly with worsening atypia. CONCLUSIONS AND RELEVANCE: We recommend VR, which rarely requires specimen bleaching, as the standard substrate for immunohistochemical analysis of conjunctival MLs. We found Melan-A and HMB45 to best characterize MLs. In conjunctival MLs, the use of VR with Melan-A and HMB45 provides substantial sensitivity for all melanocytes and for atypical melanocytes, respectively, and reduces specimen-processing time for laboratories performing immunohistochemistry on MLs.

Uveal melanoma: A pathologist's perspective and review of translational developments.

The eye and periorbital soft tissue are derived from the neuroectodermal neural crest, leading to a wide range of tumor types that arise at this site. The uveal tract (iris, ciliary body, and choroid) normally contains melanocytes, and thus both benign nevi and malignant melanoma can arise there, the choroid being the most frequent site. Uveal melanoma (UM) in adults and retinoblastoma (in young children) are the 2 most common primary intraocular malignancies. Retinoblastoma is the most common eye cancer worldwide, but the most common ocular cancer in the United States and Europe is UM. This review will focus on UM and will include the epidemiology, pathologic findings, prognosis and treatment, and review of ongoing molecular discoveries aimed at elucidating the pathways that could lead to adjuvant therapy. These tumors are not uncommon to dedicated ocular pathologists and may occasionally be encountered by general pathologists as well. First, a short word about metastases to the uveal tract is in order, because of its importance in the differential diagnosis. Although the most common primary malignancy in the adult eye is UM, the most frequent adult intraocular malignancy identified in autopsy studies is metastatic carcinoma to the uveal tract. Metastases usually occur late, and the eye is thus rarely enucleated in this setting. However it is important to be aware of this as sometimes, the ophthalmologist cannot determine clinically if an amelanotic tumor represents melanoma or metastasis, possibly from an unknown primary. Shields and colleagues reported on their experience and found that the most common primary sites for uveal metastasis are breast, followed by lung, and then the gastrointestinal tract. Immunohistochemical stains for cytokeratin or more specific markers such as CK7, CK20, TTF-1, BRST-2, CDX2, and PSA may be helpful if there is no known primary. Metastases to the eye also occur in the orbit, eyelid, and rarely to the retina.

Transscleral optical spectroscopy of uveal melanoma in enucleated human eyes.

PURPOSE: The aims of this study were to use transscleral optical spectroscopy to analyze normal and tumor-infiltrated areas of enucleated human eyes, and to characterize the spectral properties of uveal melanomas in relation to various morphological features. METHODS: Nine consecutive eyes enucleated for uveal melanoma were examined by transscleral spectroscopy, using a fiber-optic probe that exerted a fixed pressure on the scleral surface. Spectroscopic measurements, covering the wavelength range of 400-1100 nm, were sequentially performed over the uveal melanoma and on the opposite (normal) side of each eye. The eyes were then processed for histological and immunohistochemical analyses. Comparisons between spectral and morphological parameters were performed by Spearman's rank correlation coefficient and unpaired t-test. RESULTS: The average reflection intensity obtained from the normal side of the eyes was higher than that from the tumors. The spectral imprint of hemoglobin was lower and that of water was considerably stronger when compared with the tumor side. The diffuse reflection spectra from the melanomas showed a strong correlation with the degree of tumor pigmentation (Spearman's rho = -0.87, P < 0.0001). A weaker correlation was observed between the amount of hemoglobin-related absorption and the density of intratumoral blood vessels (Spearman's rho = -0.25, P = 0.023). The mean diffuse reflection intensity obtained from the spindle cell melanomas was significantly higher than that from the mixed and epithelioid cell melanomas (P < 0.0001). CONCLUSIONS: Although future in vivo studies are required, these data suggest that transscleral optical spectroscopy is a feasible method for identification and morphological assessment of choroidal tumors.

Receiver operating characteristic analysis: calculation for the marker 'melanoma inhibitory activity' in metastatic uveal melanoma patients.

The serological marker melanoma inhibitory activity (MIA) has been shown to be significantly higher in the serum of patients suffering from metastatic uveal melanoma than in progression-free patients. The objective of this study was to calculate a meaningful receiver operating characteristic (ROC) curve for MIA based on a large patient collective and to find an appropriate threshold value. MIA tumor marker levels of 503 outpatients suffering from uveal melanoma were evaluated using enzyme-linked immunosorbent assay. Fifty-four patients had confirmed metastases and 449 patients showed no overt metastatic disease at the time the blood sample was taken. ROC analysis was performed and the area under the curve (AUC) was calculated. Metastatic patients showed significantly higher MIA levels (median 11.69 ng/ml) than patients in the group without overt metastatic disease (median 6.97 ng/ml) (the Mann-Whitney test, P<0.001). The AUC was 0.84 (95% confidence interval: 0.76-0.91). The ROC resulting from our study can be applied for test comparison by means of AUC. The AUC value of 0.84 for MIA demonstrates the accurate performance of the test. On the basis of this ROC curve, we propose a MIA threshold value for uveal melanoma patients of 8.3 ng/ml (with a corresponding sensitivity of 82% and specificity of 77%, positive predictive value of 0.30 and negative predictive value of 0.97). In patients with higher MIA serum levels, further diagnostics should be initiated.

Fine needle aspiration biopsy with liquid-based cytology and adjunct immunohistochemistry in intraocular melanocytic tumors.

PURPOSE: To determine the efficacy of liquid-based cytology (LBC) and immunohistochemistry in the evaluation of fine needle aspiration biopsy (FNAB) of intraocular melanocytic tumors. METHODS: Cytologic diagnosis was necessary in 25 patients with intraocular melanocytic tumors to deliver a therapeutic course of treatment. The patients' clinical, cytologic, and histologic diagnoses were correlated. All samples were stained with hematoxylin and eosin, and studied through standardized monolayer techniques, with a mean cellular concentration of 60,000 cells/mm2. Immunohistochemistry was performed using Vimentin, S 100, HMB 45, Melan A, cytokeratin, and as prognostic factors, B and T lymphocyte, CD68 (macrophage), and antibody Ki 67 (growth factor). RESULTS: The positive predictive value was 100%; the negative predictive value was 80%. Sensitivity and specificity of LBC for detecting malignancy were 95.2% and 100%, respectively. The FNAB LBC with immunohistochemistry findings resulted in a revision of treatment in 32% of patients. There was no evidence of local tumor dissemination or a recurrence associated with biopsy in any patient. CONCLUSIONS: Fine needle aspiration biopsy (LBC and immunohistochemistry) is a safe, sensitive, and specific method of establishing tissue diagnosis in a subset of patients with intraocular melanocytic tumors, particularly in cases where sample material is scarce. The routine use of immunohistochemical stain increases the diagnostic utility, and prognosis factor determination may change clinical management.

Transscleral visible/near-infrared spectroscopy for quantitative assessment of melanin in a uveal melanoma phantom of ex vivo porcine eyes.

Optical spectroscopy has been used as a supplement to conventional techniques for analyzing and diagnosing cancer in many human organs. Because ocular tumors may be characterized by their different melanin content, we investigated the feasibility of using transscleral visible/near-infrared spectroscopy (Vis/NIRS) to estimate the quantity of melanin in a novel uveal melanoma phantom of ex vivo porcine eyes. The phantoms were made by injecting a freshly prepared suspension of 15% (wt/vol) gelatin, 10 mg/ml titanium dioxide (TiO(2)), and natural melanin, isolated from the ink sac of cuttlefish (Sepia officinalis), into the suprachoroidal space of 30 enucleated porcine eyes. The melanin concentrations used were 1 mg/ml, 2 mg/ml, and 3 mg/ml, with 10 eyes in each group. After gelation, the size and location of the phantoms were documented by B-scan ultrasonography and transillumination. Vis/NIRS recordings, covering the wavelength region from 550 to 1000 nm, were performed with two optical fibers separated by 6 mm to deliver and collect the light through the sclera. During all measurements, the exact pressure exerted by the fiber probe on the scleral surface was monitored by placing the eye on an electronic scale. Transscleral Vis/NIRS was performed across the phantom inclusion, as well as on the opposite (normal) side of each eye. A total of three consecutive measurements were carried out alternately on each side of the globe. The spectral data were analyzed using partial least squares regression. In the melanin concentration groups of 1 mg/ml (n = 10), 2 mg/ml (n = 10), and 3 mg/ml (n = 10), the largest basal phantom diameters (mean +/- SD) were 14.9 +/- 1.6 mm, 14.6 +/- 1.5 mm, and 14.3 +/- 1.0 mm, respectively (p > 0.05). The largest phantom thicknesses (mean +/- SD) were 4.0 +/- 0.5 mm, 4.4 +/- 0.7 mm, and 4.5 +/- 0.5 mm, respectively (p > 0.05). Statistical regression modeling of the Vis/NIRS data revealed that it was possible to correctly classify the phantoms according to their melanin concentrations in 84.4% of cases. The correct classification rate for phantoms with the lowest (1 mg/ml) and highest (3 mg/ml) melanin concentrations was 99.2%. The study demonstrates that transscleral Vis/NIRS is a feasible and accurate method for predicting the content of melanin in choroidal lesions.

Adenoma of the non-pigmented ciliary epithelium: a rare intraocular tumor with unusual immunohistochemical findings.

A case of adenoma of the non-pigmented ciliary epithelium with smooth muscle differentiation is reported. This uncommon ocular tumor affected a 36-year-old woman, and had caused decreased visual acuity and a total cataract. Ultrasound biomicroscopy disclosed an associated persistent hyperplasic primary vitreous (PHPV). Sectoral cyclectomy with removal of the mass and intracapsular cataract extraction were performed. The tumor was diffusely positive for vimentin, smooth muscle actin, NSE, and S-100, focally for CD68 and Melan-A, and was negative for desmin, EMA, HMB-45, and CD99. Occasional cells reacted for cytokeratin. The proliferation index, as assessed by Ki-67, was below 10%. The overlying non-neoplastic ciliary epithelium was positive for vimentin, NSE, and S-100. Myofilaments are not totally unexpected in ciliary adenomas; however, such a diffuse and strong positivity for smooth muscle actin, as in the present case, has only been observed in one case before, but should be considered in the differential diagnosis of these neoplasms.

Astrocytoma of the ciliary body.

PURPOSE: To report the occurrence of an astrocytoma of the ciliary body. METHODS: The patient was evaluated by ophthalmoscopic examination (including color ultrasonography and ultrasound biomicroscopy) as well as operating therapy. Histopathology and immunocytochemical analysis were performed. RESULTS: A 29-year-old woman was found to have a left ciliary body tumor. Color ultrasonography revealed a 12 x 10 mm size, a low-level echo boundary, and a bright echogenic band. Ultrasound biomicroscopy showed that the lesion was located in the superior temporal quadrant of the ciliary body and extended backward for 6 mm from the limbus. The tumor was carefully dissected free and completely removed via episcleral incision. Histopathology revealed a fibrillary astrocytoma. Staining for glial fibrillary acidic protein yielded positive results and neuron-specific enolase yielded negative results. CONCLUSIONS: We describe an astrocytoma of the ciliary body in a patient, which is an extremely rare ocular tumor. Histopathology and immunocytochemical analysis were required to establish the diagnosis.

Ocular central nervous system lymphoma mimicking choroidal neovascularization.

Two patients evaluated for metamorphopsia were noted to have inferotemporal retinal pigment epithelium elevations formed by a yellowish lesion. Fluorescein angiography showed granular hyperfluorescence with late leakage, which was interpreted as an occult choroidal neovascularization. One patient underwent photodynamic therapy. In both patients, neither vitreous cells nor neurologic manifestations were evident on presentation. Subsequent neurological signs appeared that prompted performance of brain imaging, which confirmed a space-occupying lesion. In both patients, the tumor was proven on histopathologic examination of brain tissue to be central nervous system lymphoma. Awareness of other possible underlying pathologies is warranted in cases of atypical choroidal neovascularization.

Unusual primary ocular neoplasm in a child: leiomyosarcoma of the ciliary body.

Primary uveal-tract neoplasms are extremely rare in childhood; the most common lesions found are melanocytic. We report here the case of a 7-year-old girl who underwent enucleation of the right eye with clinical suspicion of choroid melanoma as a result of a ciliary body mass that extended to the posterior chamber. Histologically, the neoplasm featured spindle cell morphology, atypia, and mitoses. The tumor expressed smooth muscle alpha actin, pan-actin HHF-35, and desmin, whereas immunohistochemistry for melanocytic markers, such as S-100, Melan-A, and HMB-45, was negative. Based on these features, the diagnosis of leiomyosarcoma of the ciliary body was firmly established. Although several leiomyomas have been reported in the literature, there are only 2 previously reported cases of primary leiomyosarcoma of the uveal tract. Immunohistochemical expression of muscle proteins allowed distinction from the most common melanocytic tumors arising in this location.

Biomarker discovery from uveal melanoma secretomes: identification of gp100 and cathepsin D in patient serum.

There is a necessity to better characterize uveal melanoma (UM) tumors according to their metastasis potential at an early stage. In this study we report the identification of potential biomarkers by a combination of proteomics-related approaches: the characterization of UM cell secretomes, the analysis of UM autoantibodies, and the differential depleted serum proteome analysis. We describe a possible role of cathepsin D, syntenin, and gp100 in UM as potential biomarkers.

Sequential bilateral solitary extramedullary plasmacytoma of the ciliary body.

PURPOSE: To report bilateral plasmacytoma of the ciliary body in a healthy patient. METHODS: Clinicopathologic report. RESULTS: A 55-year-old woman with iritis developed an iridociliary mass in the left eye. Systemic evaluation was normal. Fine-needle aspiration (FNAB) of the mass revealed atypical, binucleate plasmacytoid cells with positive leukocyte common antigen staining, suggestive of plasmacytoma. The tumor was treated with 4000 cGy by using custom-designed plaque radiotherapy. The tumor completely resolved. Two years later, a similar iridociliary mass was noted in the right eye, and FNAB confirmed plasmacytoma. Plaque radiotherapy of 4000 cGy was delivered. At the 3-year follow-up, there has been no local recurrence or evidence of systemic multiple myeloma or monoclonal gammopathy. CONCLUSIONS: Extramedullary plasmacytoma can involve the uvea and rarely manifest multiplicity. Long-term monitoring for systemic plasma cell dyscrasia is warranted.

Medulloepithelioma masquerading as chronic anterior granulomatous uveitis.

CASE REPORT: We report a rare clinical case of unilateral ciliary body teratoid medulloepithelioma presented first with infantile cataract, subsequently masquerading as chronic granulomatous anterior uveitis, followed by appearance of a tumour over the iris surface. COMMENTS: Diagnosis of the tumour in the early stages allows proper management and avoids enucleation.

Proteomic analysis of uveal melanoma reveals novel potential markers involved in tumor progression.

PURPOSE: Patient survival in uveal melanoma may benefit from earlier recognition of potential metastases to the liver, but as yet, proper markers indicating metastases are not available. Identification of metastasis markers would therefore be of great value. The proteins that are expressed in two cell lines originating from two liver metastases were compared with the proteins expressed in a cell line obtained from the primary uveal melanoma of the same patient, to identify proteins that play a role in tumor progression as well as proteins that are expressed specifically in metastases. METHODS: Protein analysis was performed by using two-dimensional gel electrophoresis. A subset of proteins was subsequently identified with mass spectrometry. RESULTS: A set of 24 proteins was differentially expressed in both of the two metastatic cell lines compared with the cell line derived from the primary tumor. These proteins were subdivided into groups according to cellular function, with important roles in tumor development. CONCLUSIONS: Tumor progression and development of metastases is a multicomplex system. Comparing protein expression in two cell lines derived from metastases with a cell line derived from a primary uveal melanoma from the same patient identified proteins involved in tumor progression, and proteins specifically expressed in the metastases, which have the potential of becoming clinically useful biomarkers.