The most frequent site of ocular metastasis is the choroid. The occurrence of choroidal metastases has increased steadily due to the longer survival of metastatic patients and the improvement of ...diagnostic tools. Fundoscopy, ultrasonography, and fluorescein angiography are now complemented by indocyanine green angiography and optical coherence tomography. Choroidal tumor biopsy may also confirm the metastatic nature of the tumor and help to determine the site of the primary malignancy.
There is currently no consensus on the treatment strategy. Most patients have a limited life expectancy and for these complex treatments are generally not recommended. However, recent advances in systemic therapy have significantly improved survival of certain patients who may benefit from an aggressive ocular approach that could preserve vision. Although external beam radiation therapy is the most widely used treatment, more advanced forms of radiotherapy that are associated with fewer side effects can be proposed in select cases.
In patients with a shorter life expectancy, systemic therapies such as those targeting oncogenic drivers, or immunotherapy can induce a regression of the choroidal metastases, and may be sufficient to temporarily decrease visual symptoms. However, they often acquire resistance to systemic treatment and ocular relapse usually requires radiotherapy for durable control. Less invasive office-based treatments, such as photodynamic therapy and intravitreal injection of anti-VEGF, may also help to preserve vision while reducing time spent in medical settings for patients in palliative care.
The aim of this review is to summarize the current knowledge on choroidal metastases, with emphasis on the most recent findings in epidemiology, pathogenesis, diagnosis and treatment.
•Choroid is the most common ocular site for metastatic spread, especially for breast and lung cancer.•Enhanced imaging of the choroid allows better understanding and precise diagnosis of choroidal metastases.•In case the primary remains unknown, tumor biopsy may help identify the primary and guide treatment.•To date, fractionated radiotherapy remains the treatment of choice for choroidal metastases.•The place of systemic targeted therapy and “office-based” treatment such as PDT or intravitreal antiVEGF should be considered.
Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their ...biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.
In parapapillary melanoma patients, radiation-induced optic complications are frequent and visual acuity is often compromised. We investigated dose-effect relationships for the optic nerve with ...respect to visual acuity after proton therapy.
Of 5205 patients treated between 1991 and 2014, those treated using computed tomography (CT)-based planning to 52 Gy (prescribed dose, not accounting for relative biologic effectiveness correction of 1.1) in 4 fractions, with minimal 6-month follow-up and documented initial and last visual acuity, were included. Deterioration of ≥0.3 logMAR between initial and last visual acuity results was reported.
A total of 865 consecutive patients were included. Median follow-up was 69 months, mean age was 61.7 years, tumor abutted the papilla in 35.1% of patients, and tumor-to-fovea distance was ≤3 mm in 74.2% of patients. Five-year relapse-free survival rate was 92.7%. Visual acuity was ≥20/200 in 72.6% of patients initially and 47.2% at last follow-up. A wedge filter was used in 47.8% of the patients, with a positive impact on vision and no impact on relapse. Glaucoma, radiation-induced optic neuropathy, maculopathy were reported in 17.9%, 47.5%, and 33.6% of patients, respectively. On multivariate analysis, age, diabetes, thickness, initial visual acuity and percentage of macula receiving 26 Gy were predictive of visual acuity. Furthermore, patients irradiated to ≥80% of their papilla had better visual acuity when limiting the 50% (30-Gy) and 20% (12-Gy) isodoses to ≤2 mm and 6 mm of optic nerve length, respectively.
A personalized proton therapy plan with optic nerve and macular sparing can be used efficiently with good oncological and functional results in parapapillary melanoma patients.
Purpose
The use of planar ultra‐widefield fundus photography (UWF) may result in distortions and inaccurate measurement. The aim of the study was to evaluate the accuracy of UWF instead of the ...standard narrow field (SF) for the treatment planning phase of ocular tumours.
Methods
Distortions between conformal SF and UWF were assessed in 43 patients with choroidal melanoma treated with either proton therapy or brachytherapy. imagej software was used to measure distortion.
Results
The median interquartile range (IQR) distortion for all cases was 3.7% 1.7–10.8. For cases with tumours within 6 mm of the optic disc, distortions appeared clinically nonsignificant. For peripheral and/or large tumours, significantly larger distortions were observed on UWF (median 4.4% 2.7–22.6 for tumours ≥6 mm from the optic disc versus 3.3% 1.6–9.9 for those <6 mm, p = 0.04). Images can be subdivided into three groups: minimal distortion (79.1% of eyes), similar level of major distortion for both measured distances (11.6%) and distortion with unequal level of distortion between the measured distances (9.3%).
Conclusion
Distortions with UWF appeared minimal in posterior regions of the fundus and increased with the distance from the posterior pole. UWF could therefore be used for treatment planning of ocular tumours as the planned radiation dose to the macula and optic disc are not impacted.
To determine the size at which choroidal melanomas can metastasize and to report the characteristics of small fatal choroidal melanomas (SFCM).
Retrospective case series.
Ten ocular oncology services ...submitted 45 patients with a choroidal melanoma 3 mm or less in thickness and 9 mm or less in largest basal diameter (LBD), when treated, who developed metastases.
Median tumor thickness was 2.4 mm (range, 1.0–3.0 mm) and LBD 7.3 mm (range, 3.0–9.0 mm). Of 14 (31%) tumors that were first observed, 12 grew a median of 0.5 mm (range, 0.1–1.2 mm) in thickness and 1.0 mm (range, 0–3.0 mm) in LBD within a median of 7 months; 3 were initially smaller than 3 mm in LBD. Number of risk factors for growth and metastasis was 0 for 4% of the tumors; 60% were over 2 mm in thickness, 63% had subretinal fluid, 84% caused symptoms, 57% had orange pigment, and 92% were within 3 mm of the disc. Local recurrence occurred in 8 of 31 eyes (26%) treated conservatively. Median metastasis-free survival was 4.5 years (range, 0.8–15.7 years). Kaplan-Meier estimate of metastasis developing was 15% (95% confidence interval CI, 7–26), 51% (95% CI, 36–64) and 85% (95% CI, 71–92) by 2, 5, and 10 years, respectively. By the time of analysis, 37 patients had died of metastasis after a median of 7 months.
Choroidal melanomas less than 3.0 mm in LBD are highly unlikely to metastasize. Risk factors of an SFCM are similar to those for all choroidal melanomas of similar size.
•Choroidal melanomas more than 3.0 mm in diameter are able to metastasize.•Observation beyond this size limit may alter survival.•Small fatal melanomas appear clinically similar to reported small nonfatal ones.
Ocular surface squamous neoplasia includes a spectrum of diseases from dysplasia to invasive squamous cell carcinoma (SCC) of the conjunctiva. Whether the degree of invasion influences outcomes is ...debated. We evaluated the outcomes and management of conjunctival carcinomas defined as ≤0.2 mm invasion of the chorion (microinvasive; miSCC) or over (SCC).
Retrospective case series.
Clinical, tumor, and therapeutic characteristics and outcomes were collected for consecutive patients with histology-proven invasive conjunctival miSCC/SCC treated between 2002 and 2017.
Patients were 70% men, ≥70 years old (56%), with carcinomas of the bulbar conjunctiva (83.0%). Limbal, corneal, and/or scleral involvement were present in 70.4%, 42.6%, and 27.8%, respectively. Patient characteristics, tumor characteristics, and no-touch surgery rates were similar between the 39 SCC and 15 miSCC. However, mitomycin was performed in 93.3% and 20.5% of miSCC and SCC, respectively (P < .001). Proton therapy was performed in 0% and 92.0% of miSCC and SCC, respectively (P < .001). SCC received mitomycin in case of tumoral resection margins, respectively (P = .018). The 24-month incidence of local relapse was 14.8%, including 20% and 12% for miSCC and SCC, respectively (P = .079). Irradiation was the only prognostic factor associated with a lower risk for local relapse (hazard ratio 0.25; P = .045). There were 2 cancer-related deaths (2%). Mild/moderate anterior segment complications occurred in one third of the patients.
miSCC had slightly worse relapse rates compared with SCC. Postoperative proton therapy, performed in SCC only, was associated with a lower risk for relapse.
•The degree of invasion does not influence clinical presentation.•Microinvasive conjunctival carcinoma does not have better prognosis than invasive carcinoma.•Conjunctival carcinoma may benefit from adjuvant proton therapy regardless of degree of invasion.
Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We ...performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT).
Retrospective study from single, large referral center.
We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients.
Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes.
Dose-response relationship for VA deterioration and late complications.
Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland.
VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures.
Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, ...“no-touch” surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with “medical” eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.
To report new indications for deep temporalis fascia (DTF) grafts in the ophthalmic field.
Monocentric retrospective interventional case series study. All the patients who underwent a DTF graft in an ...unpublished new indication over the study period (May 2020-October 2023) were included. For each patient, gender, age, graft indication, outcomes, complications, and follow-up duration were collected. In most cases, the DTF graft was covered by a vascularized flap.
Eight patients underwent a DTF graft over the study period. The indications were: radiotherapy-induced scleral necrosis in three cases, tendinoplasty to replace the inferior rectus muscle tendon invaded by a locally advanced conjunctival carcinoma in one case, Ahmed glaucoma valve tube exposure in one case, intraocular lens with scleral fixation exposure in one case, orbital cerebrospinal fluid fistula (orbitorrhea) in one case, and post-traumatic complete corneal graft loss in one case. The DTF graft was successful in 87.5% of cases after a mean follow-up of 11.4 months. No complications were observed.
DTF graft is a highly versatile graft that can be easily harvested. New indications for DTF grafts may include the repair of radiotherapy-induced scleral necrosis, the creation of oculomotor tendon and the temporary packing of large ocular tissue loss in an emergency context. Further studies with a longer follow-up are needed to confirm our preliminary results.
To evaluate the use of the Lens Opacities Classification System III grading (LOCS III) for the characterization of radiation-induced cataract, and to correlate the proton beam projection onto the ...lens with cataract location and grade as defined by the LOCS III.
Prospective, interventional case series.
Fifty-two consecutive patients with cataract following proton therapy were included. All cataracts were graded using LOCS III. Relationships between proton beam and cataract subtypes, as well as between dose, proportion of lens irradiated, and extent of cataracts, were assessed.
Tumor diameter, volume, stage, and equatorial tumor location were associated with extent of posterior subcapsular cataracts (PSC) that were diagnosed at a median (interquartile range) 36 months (22;83) after treatment. In multivariate analysis, the tumor volume (P < .01) and an equatorial tumor location (P = .01) were risk factors for extensive PSC. Lens irradiation was avoided in 10 patients. In the remaining 42 patients (81%), the extent of PSC significantly correlated with the dose to the lens receiving 10, 26, and 47 Gy (P = .03, P = .03, and P = .04, respectively), the dose to the lens periphery receiving 10 and 26 Gy (P = .02 and P = .02, respectively), and the dose to the ciliary body receiving 10 and 26 Gy (P = .03 and P = .02, respectively). Nuclear color significantly correlated with the dose to the ciliary body receiving 10 Gy (P = .03) and 26 Gy (P = .02). After adjustment of the results on tumor volume and tumor location, the volume of lens receiving 10 Gy (P = .04) and 26 Gy (P = .03) remained significantly associated with the extent of PSC.
Proton dose correlated with the occurrence of PSC and nuclear color cataracts as defined by LOCS III grading. Better characterization of cataracts with the LOCS III after irradiation may help to further fill gaps in the current understanding of the mechanisms of radiation-induced cataracts.
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