Primary Ocular Tumor Research Articles

Uncommon Association: Primary Malignant Melanoma of the Eyelid and Palpebral Conjunctiva

Ocular melanoma of the eyelid and conjunctival is extremely rare primary ocular malignant tumor in adults. The simultaneous occurrence of both lesions in one eye are uncommonly seen in practice. We report a case of ocular melanoma of the eyelid and conjunctival developed on one eye of a 71-year-old male patient that the reported had grown in size over the last four years

Evolving systemic targeted therapy strategies in uveal melanoma and implications for ophthalmic management: a review.

Uveal melanoma (UM) is the most common primary ocular tumour in adults. Despite good local control of the primary tumour with current methods, survival after the development of metastasis has remained poor over the last 30 years. After cutaneous melanoma, UM is the most common type of melanoma, and an ongoing debate exists regarding whether these conditions should be considered separate entities, particularly in the context of targeted therapy, where many of the initial trials for patients with metatatic cutaneous melanoma excluded metastatic UM. This paper will review the recent and ongoing investigations designed to validate systemic targeted therapy and immunotherapy in patients with metastatic UM and suggests ways in which these developments may affect management of UM by ophthalmologists in the near future.

Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations.

Animal models serve as powerful tools for investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic agents. They have facilitated rapid scientific progress in many tumor entities. However, for establishing a powerful animal model of uveal melanoma fundamental challenges remain. To date, no animal model offers specific genetic attributes as well as histologic, immunologic, and metastatic features of uveal melanoma. Syngeneic models with intraocular injection of cutaneous melanoma cells may suit best for investigating immunologic/tumor biology aspects. However, differences between cutaneous and uveal melanoma regarding genetics and metastasis remain problematic. Human xenograft models are widely used for evaluating novel therapeutics but require immunosuppression to allow tumor growth. New approaches aim to establish transgenic mouse models of spontaneous uveal melanoma which recently provided preliminary promising results. Each model provides certain benefits and may render them suitable for answering a respective scientific question. However, all existing models also exhibit relevant limitations which may have led to delayed research progress. Despite refined therapeutic options for the primary ocular tumor, patients' prognosis has not improved since the 1970s. Basic research needs to further focus on a refinement of a potent animal model which mimics uveal melanoma specific mechanisms of progression and metastasis. This review will summarise and interpret existing animal models of uveal melanoma including recent advances in the field.

Establishment and Characterization of Orthotopic Mouse Models for Human Uveal Melanoma Hepatic Colonization

Uveal melanoma (UM) is a rare type of melanoma, although it is the most common primary ocular malignant tumor in adults. Nearly one-half the patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, no treatment is effective for UM hepatic metastasis, and the prognosis is universally poor. The main challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We developed two orthotopic mouse models for human UM hepatic metastases: direct hepatic implantation model (intrahepatic dissemination model) and splenic-implantation model (hematogenous dissemination model) and investigated the tumorgenesis in the liver. A human UM cell line, established from a hepatic metastasis and nonobese diabetic severe combined immunodeficient γ mice, were used for development of invivo tumor models. In the direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about one-half of cases. However, in the splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently seeded intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. These orthotopic mouse models offer useful tools to investigate thebiological behavior of human UM cells in the liver.

Abstract 3228: Establishment and characterization of orthotopic mouse models for human uveal melanoma hepatic metastases

Abstract Uveal melanoma (UM) is a rare type of melanoma although it is the most common primary ocular malignant tumor in adults. Nearly half of patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, there is no effective treatment for UM hepatic metastasis and the prognosis is universally poor. The major challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We have developed two orthotopic mouse models for human UM hepatic metastases: (1) Direct hepatic implantation model (intra-hepatic dissemination model), and (2) Splenic-implantation model (hematogenous dissemination model) and investigated the tumor genesis in the liver. A human UM cell line, established from a hepatic metastasis and NSG mice were used for development of in vivo tumor models. In direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about half of cases. On the other hand, in splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently developed intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. In addition, there are broad extracellular matrix connecting the blood vessels lined with endothelium in the hepatic tumors. These structures are assumed to be so called “vasculogenic mimicry (VM)” formed by the the tumor cells themselves. Notably, we found tumor cells in the liver begin to form VM, despite a small number of them and eventually develop a broad network of VM in the tumor. Thus, VM might contribute to the microcirculation in the tumor preceding development of vessels lined with endothelium. Moreover, we have generated orange-red fluorescence protein (td-Tomato fluorescent protein) expressing cell line using the same UM cell line and developed the same mouse models. This allowed us to monitor the growth of hepatic metastasis over time by in vivo live-imaging system. These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver. Citation Format: Shinji Ozaki, Mizue Terai, Ken Kageyama, Hanyin Cheng, Masahiro Ohara, Andrew E. Aplin, Michael J. Mastranjelo, Takami Sato. Establishment and characterization of orthotopic mouse models for human uveal melanoma hepatic metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3228. doi:10.1158/1538-7445.AM2015-3228

A Review of Advanced Genetic Testing for Clinical Prognostication in Uveal Melanoma

Uveal melanoma (UM) has a strong propensity to metastasize and the prognosis for metastatic disease is very poor. It has been suggested that occult micrometastases are already present, but undetectable, in many patients at the time when the primary ocular tumor is diagnosed and treated. To identify high-risk patients for close monitoring and early intervention with prophylactic adjuvant systemic therapy, an accurate predictive system is necessary for stratifying those patients at risk of developing metastatic disease. To date, many clinical and histopathological features, molecular pathway characteristics, and genetic fingerprints of UM have been suggested for disease prognostication. Among the newest of them, tumor genetics has received the most attention in demonstrating promise as a prognostic tool. Because of the plethora of recent developments, we summarize and compare in this review the important standard and more advanced cytogenetic prognostic markers. We further describe the variety of genetic tests available for prognostication of UM, and provide a critical assessment of the respective advantages and disadvantages of these tools.

Value of positron emission tomography/computed tomography in diagnosis and staging of primary ocular and orbital tumors

Accurate and reliable staging methods are crucial for optimal care of patients with ocular and orbital malignancies. Positron emission tomography/computed tomography (PET/CT) has recently emerged as a staging tool in the field of ophthalmic oncology. For detecting primary ocular or orbital lesions, PET/CT does not seem to provide an advantage over clinical ophthalmologic examination or conventional imaging studies such as CT or magnetic resonance imaging of the orbit. However, PET/CT may detect distant metastatic lesions that conventional imaging studies miss. For orbital and ocular adnexal lymphoma, use of PET/CT has been proven to be feasible and is now accepted both as a standard part of the initial staging work-up and for the assessment of response to therapy. For other ophthalmic tumors, PET/CT seems most appropriate for advanced metastatic tumors of the orbit, eyelid, and eye, for which the detection of distant metastasis with 1 comprehensive study may be preferable to performing multiple CT scans with contrast.

Canine ocular tumors following ciliary body ablation with intravitreal gentamicin

Iridociliary tumors are the second most common primary ocular tumor in dogs and are usually benign. A review of the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) database in 2009 suggested a potential correlation between malignant iridociliary epithelial tumors and ciliary body ablation by intravitreal gentamicin injection for the treatment of glaucoma. The purpose of this case series was to determine whether there is evidence of such a correlation in the COPLOW collection. Mining of the COPLOW database revealed that a significant number (39.5%) of canine globes with a history of ciliary body ablation were subsequently diagnosed with primary ocular tumors at enucleation, most commonly iridociliary epithelial tumors and melanocytic tumors. It is possible that neoplasia was present but unrecognized at the time of ciliary body ablation. These tumors had a higher than expected incidence of malignancy. These cases underscore the importance of reserving ciliary body ablation with gentamicin for disease-free eyes.

High-risk uveal melanoma: A prospective study evaluating the role of magnetic resonance imaging of the liver.

8564 Background: Almost 50% of uveal melanomas are fatal. Metastatic death occurs almost exclusively with tumours showing chromosome 3 loss and 8q gain. Metastases, which almost always involve the liver, are resectable in some patients. They are rarely detectable when the patient presents with the primary ocular tumour. Screening is therefore necessary, but there is no consensus as to who should be screened, how often, and for how long. Methods: Uveal melanoma patients with ECOG performance status 0-2 were eligible if their risk of metastatic death at 5 years exceeded 50%. Survival probability was estimated by multivariate analysis of tumour stage, histological grade and genetic tumour type. Patients underwent screening 6monthly, clinical examination, non-contrast liver MRI and liver function tests for at least five years. Results: Between Jan 2000 and November 2010, 279 high-risk patients were referred for screening. Of these, 188 (84 male, 104 female) accepted screening and underwent as least 1 MRI. The median age was 63 years (IQR 16.5). Median basal tumour diameter was 16.5mm (IQR 5.25). Chromosome 3 loss was detected in 175 tumours. Median follow up time was 28.8 months (IQR 29.1). Median relapse-free survival was 33 months (95% CI 28-38) with a 35% relapse-free survival at 5 years. After a median of 18 months (IQR 20), screening detected metastases in 90/188 (48%), 83 of whom were asymptomatic. 12 patients underwent R0 liver resection, which increased the median survival from 10 (95% CI 8.1 - 11.9) to 24 (95% CI 20.2- 27.8) months. The screening programme stimulated a UK NCRI portfolio of clinical trials in which 23 of these patients were subsequently treated. Conclusions: Six-monthly liver MRI detects metastases from uveal melanoma at an early stage, thereby enhancing opportunities for surgical metastatectomy, clinical trial participation and prolonging life.

Ocular Melanoma

Abstract Context—Intraocular melanoma of the ciliary body and choroid is the most common primary ocular malignant tumor in adults and the most common noncutaneous melanoma. Objective—To describe the most salient clinical features, histopathologic findings, and treatment modalities of intraocular melanoma, as well as the novel therapies currently being tested. Data Sources—Clinically, it is important to determine which lesions carry a worse prognosis so as to offer patients the best treatment modalities available. Tumor location, size, histopathology, cytogenetic abnormalities, and tumor profiling are all used in determining the risk of death from metastatic disease of uveal melanocytic lesions. Despite successful local tumor control, up to 50% of patients have metastatic disease within 15 years of diagnosis; there is no effective treatment for metastatic disease. Conclusions—Pathologists should be aware of the importance of tumor gross description, cellular histopathology classification, the use of fine-needle aspiration biopsy coupled with cytogenetics, and the new classification of uveal malignant melanomas that is based on chromosome 3 status.

Melanocytic Lesions: Current State of Knowledge

Melanocytic Lesions: Current State of Knowledge

Rituximab Immunotherapy for Ocular Adnexal Lymphoma: Clinicopathologic Correlation With 5-Year Follow-Up

Two patients with primary ocular adnexal mucosa-associated lymphoid tumor lymphoma were treated with rituximab immunotherapy. One patient had refused radiotherapy. The other had bilateral ischemic retinopathy, a relative contraindication to radiotherapy. Biopsies were performed 6 months after treatment. One patient had complete resolution of local disease, and the other had a partial response, remaining stable without signs of progression. During the 5 years of clinical follow-up, there was no evidence of systemic disease in either patient. Rituximab immunotherapy is an alternative to regional radiotherapy for ocular adnexal mucosa-associated lymphoid tumor lymphoma.

Outcomes after 125I Plaque Brachytherapy for Ocular Melanoma: The Yale Cancer Center Experience

To determine the outcome of 125I plaque brachytherapy for primary ocular melanoma tumors at the Yale Cancer Center. To compare the outcomes for medium vs. large tumor size and the impact of transpupillary thermotherapy (TTT), as an adjunct, on outcome, and toxicity.

Choroidal mass as the presenting sign of small cell lung carcinoma

Case report: To report the case of a 58-year-old man with blurred vision and metamorphopsia who had an amelanotic choroidal mass in the right eye as the presenting sign of a small cell lung carcinoma. Systemic screening failed to reveal a tumor elsewhere, and the lesion was initially treated as a primary ocular tumor. Discovery of the primary site was made 10 months after the ocular diagnosis, and the patient was then treated with systemic chemotherapy and local radiation therapy. Comments: The ophthalmologist has a crucial role not only in the management of ocular metastases but also in the diagnosis of the primary nonocular malignancies that present as a choroidal mass.The possibility of ocular metastases in patients with choroidal masses should always be considered whether or not there is a diagnosis of cancer elsewhere.

Accumulation of Immunosuppressive CD11b+ Myeloid Cells Correlates with the Failure to Prevent Tumor Growth in the Anterior Chamber of the Eye

The purpose of these studies is to determine why an immunogenic tumor grows unchecked in the anterior chamber (a.c.) of the eye. The OVA-expressing EL4 tumor, E.G7-OVA, was injected into the a.c. or skin of immunocompetent and immunodeficient mice. Tumor growth and tumor-specific immune responses were monitored. Ocular tumor-infiltrating leukocytes were characterized phenotypically and functionally. Growth of E.G7-OVA was inhibited when limiting numbers of cells were injected in the skin but not in the a.c. of C57BL/6 mice, although both routes primed OVA-specific immune responses, which prevented the growth of a subsequent injection with E.G7-OVA in the skin or opposite eye. Tumor regression was OVA-specific because growth of the parental EL-4 tumor was not inhibited in primed mice. E.G7-OVA growth in the skin was not inhibited in immunodeficient Rag(-/-) or CD8 T cell-deficient mice, suggesting that CD8(+) CTLs mediate tumor elimination. CD8(+) T cell numbers were significantly increased in eyes of mice primed with E.G7-OVA, but few were detected in primary ocular tumors. Nevertheless, growth of E.G7-OVA was retarded in the a.c. of TCR-transgenic OT-I mice, and CD8(+) T cell numbers were increased within eyes, suggesting that tumor-specific CD8(+) CTLs migrated into and controlled primary ocular tumor growth. E.G7-OVA did not lose antigenicity or become immunosuppressive after 13 days of growth in the eye. However, CD11b(+) cells accumulated in primary ocular tumors and contained potent immunosuppressive activity when assayed in vitro. Thus, CD11b(+) cells that accumulate within the eye as tumors develop in the a.c. may contribute to immune evasion by primary ocular tumors by inhibiting CTLs within the eye.

Treatment options for choroidal malignant melanoma: a case report featuring transpupillary thermotherapy

Choroidal melanoma is the most common primary ocular tumor in adults. These tumors are almost always unilateral and develop spontaneously or arise from pre-existing nevi. Historically, treatment for choroidal melanoma was enucleation. New therapies have been developed to treat choroidal melanoma and to preserve the eye. Currently, these treatment options include brachytherapy and transpupillary thermotherapy. A 51-year-old man came to the eye clinic with symptoms of mildly decreased fluctuating vision and floaters with no flashes in the temporal visual field of the right eye. Best-corrected visual acuities were 20/30 O.D. and 20/20 O.S. A small-to-medium choroidal lesion was found in the right eye. Ultrasonography and A-scan showed this lesion to be a choroidal malignant melanoma. The patient's surgical options included enucleation, brachytherapy, and transpupillary thermotherapy. The patient opted to have transpupillary thermotherapy to preserve the eye, and subsequently underwent two procedures that eventually obliterated the melanoma, resulting in best-corrected visual acuity of 20/40. Transpupillary thermotherapy is an excellent option for treatment of small-to-medium choroidal melanomas. Brachytherapy is also an option for treatment, but with increased ocular side effects and complications. Enucleation is still commonly performed on medium and/or large choroidal melanomas.

Ocular immune privilege and CTL tolerance.

The introduction of antigens into the anterior chamber (AC) of the eye, an immune-privileged site, induces immune responses that effectively eliminate ocular pathogens while minimizing tissue damage that can cause blindness. This specialized immune response, termed AC associated immune deviation (ACAID) is thought to be an evolutionary compromise to preserve the delicate microanatomy of the eye while maintaining ocular immune responses. The injection of soluble antigen in the AC of mice results in systemic tolerance characterized by reduced priming for antigen-specific delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses. Similarly, the injection of histo incompatible tumors into the AC of mice reduces priming for DTH responses specific to minor antigens. However, robust tumor-specific CTL responses are induced systemically following this treatment that are capable of eliminating a subsequent injection of the same tumors in the skin or the opposite eye. Interestingly, CTL responses induced by administration of tumors in the AC fail to eliminate the primary ocular tumor. In this review, we compare and contrast CTL responses generated by the injection of soluble or tumor-associated antigens in the AC and discuss mechanisms employed to induce ocular CTL tolerance.

Depsipeptide (FR901228) inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines.

Uveal melanoma (UM) is the most common primary malignant ocular tumor in adults. No effective chemotherapy regimens are available for either intraocular or metastatic uveal melanoma. Therefore, the ability of the histone deacetylase inhibitors (HDACIs), depsipeptide, sodium butyrate (NaB) and trichostatin A (TSA), to induce apoptosis and inhibit cell growth of UM cell lines in vitro was examined. Three primary and two metastatic UM cell lines were treated in vitro with different concentrations of histone deacetylase inhibitors (HDACIs). Cell proliferation was studied in 24-well plates. Induction of apoptosis was studied by flow cytometry. Changes in gene expression of Fas/FasL, p21(Waf/Cip1), and p27(Kip1) were studied by RT-PCR. Western blot analysis was used to study histone acetylation, Fas/FasL, p21(Waf/Cip1), p27(Kip1) and caspase-3 protein levels. Real-time PCR was used to study changes in bcl-2/bax gene expression. A dose-dependent increase in histone acetylation was observed in all cell lines. This corresponded to significant inhibition of cell growth and induction of apoptosis in all melanoma cell lines in a concentration-dependent manner. Western blot analysis revealed dose-dependent increases in the amount of caspase-3, Fas/FasL, p21(Waf/Cip1), and p27(Kip1) proteins. However, no changes in bcl-2/bax gene expression were detected by real-time PCR. HDACIs are potent inhibitors of primary and metastatic UM cell growth in vitro. The apoptosis is probably mediated through the Fas/FasL signaling pathway, whereas bcl-2 appears not to be involved. These data support further clinical evaluation of depsipeptide and other HDACIs in patients with primary and metastatic UM.

Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts).

Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and conventional malignant melanoma may demonstrate significant morphologic overlap at the light microscopic and ultrastructural level. Consequently, the clinically relevant distinction between primary clear cell sarcoma and metastatic melanoma in the absence of a known primary cutaneous, mucosal or ocular tumour may occasionally cause diagnostic problems. A balanced translocation, t(12;22)(q13;q13), which can be detected, amongst others, using the reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH), has been identified in a high percentage (50–75%) of clear cell sarcomas and is presumed to be tumour specific. Whether this chromosomal rearrangement is present in malignant melanoma has, to date, not as yet been studied by molecular genetic or molecular cytogenetic techniques. Using RT-PCR and FISH, a series of metastases from 25 known cutaneous melanomas and 8 melanoma cell lines (5 uveal and 3 cutaneous) were screened for the t(12;22)(q13;q13) translocation. Primers for RT-PCR were chosen based upon published breakpoint sequences. The Cosmids G9 and CCS2.2, corresponding to the 5′ region of EWS and 3′ region of ATF-1 respectively, were used as probes. The translocation was not identified in any of the melanomas or melanoma cell lines analysed in this study; in contrast this translocation was identified in 3 out of 5 clear cell sarcomas using these techniques. This allows distinction between translocation positive cases of clear cell sarcoma and malignant melanoma at a molecular genetic level. Consequently, in diagnostically challenging cases, this represents a valuable tool for the clinicopathologic differentiation between these two entities, with an important impact on patient management and prognosis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Fine-needle aspiration for the diagnosis of primary epithelial tumors of the lacrimal gland and ocular adnexa.

Results of fine-needle aspiration (FNA) of solid-tissue neoplasms arising in the periocular glands are infrequently reported in the literature. To our knowledge, no previous series relating to this topic exist. Neoplastic processes that arise in the semiconfined area of the orbit behave as space-occupying lesions. Such lesions can exert significant pressure on the globe, be responsible for altered vision, and result in proptosis. When noninvasive techniques fail to confirm or rule out the suspicion of a neoplastic lacrimal or adnexal lesion, FNA may be of use in establishing a diagnosis in an efficient, reliable, timely, cost-effective, and safe manner. During the 14-yr interval from 1986-1999, 77 orbital/ocular needle aspiration biopsies were conducted by staff ophthalmologists at Allegheny General Hospital (Pittsburgh, PA). Review of the diagnoses for these specimens revealed seven primary solid-tissue lesions of the lacrimal gland and other adnexal glands, all arising in adult patients (age range, 45-92 yr; mean age, 74 yr). Primary lacrimal and adnexal gland neoplasms were found to represent approximately 9% of orbital fine-needle aspirations (7/79). The 7 cases included 3 lacrimal gland lesions diagnosed as benign mixed tumors, 3 lesions diagnosed as adenoid cystic carcinoma of the lacrimal gland, and 1 tumor diagnosed as sebaceous carcinoma of the meibomian holocrine glands. Cytologic diagnoses were rendered using standard criteria for salivary gland-type tumors. Tissue confirmation was available from surgical follow-up in 4 of the 7 cases, with 100% correlation. Although primary neoplasms of the lacrimal gland and glands of the eyelids are rare, accurate diagnoses of such lesions may be established with minimally invasive aspiration techniques. Preoperative aspiration biopsy diagnoses provide a great advantage to ophthalmic surgeons who routinely operate in a conservative fashion in an area of the body requiring great attention to cosmesis. Our experience indicates that FNA is a reliable and effective tool in the diagnosis and management of primary lacrimal and ocular adnexal tumors.