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Abstract
Background Uveal metastasis is the most common intraocular malignancy.
Methods This was a retrospective study of all patients with uveal metastases referred to the Liverpool Ocular Oncology Centre between January 2007 and December 2012. Biopsy was performed as a primary investigation if the clinical examination suggested metastasis with no evidence of any extraocular metastases.
Results Ninety-six patients (109 eyes) were included. Breast and lung carcinomas were the most common primary malignancies, affecting 41 and 27 patients, respectively. The median time interval between detection of primary cancer and uveal metastasis was 24 months (range 1–288 months). Thirty-nine patients underwent ocular biopsy, confirming the diagnosis in all patients. The biopsy indicated the site of origin in 24 out of the 27 without a known primary tumour. In 7 of these 27 cases, previous systemic investigations had failed to identify the primary tumour. Seventy-three patients received external beam irradiation; two patients received photodynamic therapy; and two patients had Ru-106 plaque radiotherapy. The visual acuity was stable or improved in 75.5% of the cases.
Conclusions Immediate biopsy provides a quick diagnosis that may expedite treatment and improve any opportunities for conserving vision while facilitating the general oncologic management on these patients.
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Introduction
Uveal metastasis (UM) is the most common intraocular malignancy and often the first sign of tumour dissemination. An estimated 8–10% of patients with metastases have uveal involvement.1 ,2 Breast and lung cancers are the most common primary malignancies that metastasise to the uvea.3 ,4 The conventional practice is to perform systemic investigations in the first instance, resorting to biopsy only if such tests are inconclusive. Few advocate early biopsy,5 a policy we have followed for 20 years. We believe that our approach provides a quick diagnosis expediting treatment and improving any opportunities for conserving vision while facilitating the general oncologic management of these patients. Treatment options of uveal metastases have increased over the past decade with radiotherapy being replaced by various forms of chemotherapy.6
We report the results of an audit of 96 patients with uveal metastasis, who were managed at the Liverpool Ocular Oncology Centre (LOOC) from 2007 to 2012.
The aim of this study was to assess the characteristics of our uveal metastasis patients and to determine the safety profile of tumour biopsy and its success rate in indicating the nature of the lesion and its origin. Furthermore, we evaluated the impact of the results of early biopsy to the general oncologic management of these patients.
Methodology
This was a retrospective study of all patients with uveal metastases who were referred to the LOOC of the Royal Liverpool University Hospital between January 2007 and December 2012.
Data collected included the following: patient age at diagnosis, gender, site of primary tumour, ocular treatment and time interval from treatment of the primary tumour to ocular metastasis. We also documented ocular symptoms and their duration prior to diagnosis of ocular metastasis. The ocular features evaluated included visual acuity (VA), intraocular pressure (IOP), tumour laterality, number of tumours per eye, quadrant location of tumour epicentre, largest basal tumour dimension and thickness, colour, Bruch's membrane rupture, and exudative retinal detachment. Tumour basal diameter and tumour thickness were evaluated by ocular B-scan ultrasonography. All patients were documented with fundus photography, ultrasonography and, in recent years, optical coherence tomography.
Patients were asked to give their written permission for information, images and surplus tissue to be used for audit, research and teaching.
Biopsy was performed as a primary investigation if the clinical features suggested uveal metastasis, and if there was no obvious clinical evidence of any extraocular disease. The aims of the biopsy were to (1) confirm that the intraocular tumour was a metastasis (2) determine the most likely site of primary malignancy, if this was not known, in order to plan imaging and other investigations accordingly.
All patients were offered biopsy. The risks and benefits were clearly explained to each patient. The patients decided about biopsy according to their personal wishes and concerns taking into consideration their general health status.
The biopsy technique has been described previously.7 Briefly, a tumour sample was obtained using the 25-gauge, sutureless, 3-port system. The vitreous cutter was introduced into the tumour through the overlying retina and this was done without vitrectomy, photocoagulation or tamponade. The aspirate was flushed into a bottle containing sterile saline water.
Features recorded at each follow-up visit included VA, extent of retinal detachment, complications and tumour response. The VA at each follow-up visit was compared with the baseline VA. The VAs were converted to logarithm of the minimum angle of resolution (log-MAR) for statistical analysis. To determine the equivalent mean decimal acuities log-MAR values were converted back to decimal notation. VAs of counting fingers and hand movements at two feet were valued two and three log MAR units, respectively.8
In all cases, the patients were referred to a general oncologist for further investigations and further management. The general work-up and systemic treatment needed for each case was determined by the general oncologist.
Ocular biopsy was performed within a day of the initial assessment in our unit, and the patient was rapidly referred to a general oncologist for further general management.
Information about survival status at the end of this study (31 December 2012) was obtained by communication with the oncologist, family doctor, or the National Health Service Cancer registry. The date and cause of death were recorded.
All data were analysed using JMP statistical software (V.10 for Mac OS X). A p value 0.05 was considered to be statistically significant.
Results
Baseline patients’ characteristics
The study included 96 patients (109 eyes). Fifty-three (55.2%) patients were females and 43 patients (44.8%) were males. The median ages at diagnosis of primary cancer and ocular metastasis were 58 years (range 20–89) and 61 years (range 21–89), respectively.
Symptoms included blurring or loss of vision (53 patients, 55.2%), metamorphopsia (11 patients, 11.5%), ocular pain (11 patients, 11.5%), floaters (11 patients, 11.5%), photopsia (13 patients, 13.5%) and visual field defect (15 patients, 15.6%). Thirteen patients (13.5%) were asymptomatic.
Forty-four (45.8%) patients had concurrent evidence of systemic metastasis at the time of diagnosis of choroidal metastasis. These involved liver (12 cases), lung (18), brain (6), bone (14), spine (6), stomach (2), skin (1), bowel (1) and lymph nodes (3). Concurrent systemic metastasis at presentation was observed in: 22 (53.7%) of the 41 cases of breast malignancy; 7 (25.9%) of the 27 cases with lung cancer; 3 (37.5%) of the 8 cases of oesophageal cancer; 4 (80%) of the 5 cases of prostate cancer.
Primary tumour
Breast carcinoma was the most common primary malignancy (41 patients; 42.7% overall and 75.5% (40 patients) of the 53 women in the cohort. Lung carcinoma was the second most common primary malignancy overall (27 patients; 28.1%), and the most common primary malignancy among the male patients (21 men; 48.8%). (table 1 summarises the distribution of primary malignancies among the male and female patients).
Distribution of primary malignancies among the male and female patients
Twenty-nine patients (30.2%) did not have any evidence of extraocular malignancy at the time of the diagnosis of choroidal metastasis.
Uveal metastasis characteristics
Among the four most common primary tumours, uveal metastases from prostate had the longest time interval between detection of primary cancer and presentation with ocular disease with a median of 78 months (range 36–120 months). Uveal metastases from breast carcinoma developed after a median of 24 months (range 1–288 months). Metastases from lung arose after a median of 12 months (range 1–120 months).
Metastases involved the choroid in 97 eyes (89%), iris in 10 (9.2%) and ciliary body in 3 eyes (2.8%). In one patient, choroidal and iris metastasis coexisted in the same eye.
The uveal metastases were bilateral in 15 cases (15.6%), and unilateral in 81 (84.4%), occurring in the right eye in 40 (49.4%) patients and the left eye in 41 (50.6%). Eight (53.3%) of the patients with bilateral uveal metastases had breast cancer and four (26.6%) had lung cancer.
The median number of uveal metastases was 1.4 (range 1–6). Furthermore, 12 (24.5%) of 49 eyes with metastases from breast cancer had multiple tumours per eye as compared with 3 (9.6%) of 31 eyes with metastases from lung.
The median largest basal tumour diameter was 12.4 mm (range 0.7–22.2), and the median tumour thickness was 2.6 mm (range 0.6–14.4). The prostatic metastases were significantly larger than metastases from breast and lung (paired t-test, p<0.05). There was no significant difference in the uveal tumour thickness among the different groups (tables 2 and 3).
Baseline features of uveal metastases related to four most prevalent primary cancer sites
Baseline characteristics
The quadrant affected by the largest metastasis in each eye was: super-nasal (9 eyes, 8.3%), supero-temporal (8 eyes, 7.3%) and infero-nasal (5 eyes, 4.6%), nasal (9 eyes, 8.3%), infero-temporal (5 eyes, 4.6%), inferior (9 eyes, 8.3%), temporal (10 eyes, 9.1%), superior (8 eyes, 7.3%), and macula (46 eyes, 42.2%).
Three tumours (2.7%) had ruptured Bruch's membrane and these had originated from leiomyosarcoma, neuroendocrine carcinoma, and adenocarcinoma, all pulmonary in origin. Thirty-one (28.4%) eyes showed subretinal fluid over the tumour, detectable with optical coherence tomography (OCT). Twenty-nine eyes (26.6%) had an associated exudative retinal detachment. The metastases appeared to be pigmented in 4 (3.7%) eyes and non-pigmented in 105 (96.3%) eyes. In the four eyes (3 cases) with pigmented tumour, the histologically proven metastases arose from breast carcinoma in two eyes (1 case) and lung carcinoma in two eyes (2 cases).
VA and IOP
The initial VA was 6/9 or better in 31 (28.5%) of the affected eyes, 6/9 to 6/24 in 30 (27.5%) eyes, 6/24 to 6/60 in 24 (22%) eyes and worse than 6/60 in 24 (22%) eyes (table 3).
The mean IOP at presentation was 17.2 mm Hg (range 7–42 mm Hg). The IOP was higher in the 10 patients with iris metastasis (median, 21.5 mm Hg, range 12–42) with three eyes having an IOP of 30 mm Hg or more.
Diagnostic biopsy
Thirty-nine (40.6%) patients underwent ocular tumour biopsy; 12 with history of previous malignancy and 27 without a known primary tumour at the time of the referral to our hospital.
The biopsy results confirmed the diagnosis of uveal metastasis in all patients. The biopsy indicated the site of origin in 24 out of these 27 (88%) patients with an unknown primary tumour. In these 24 patients, the primary tumour was lung adenocarcinoma (14 cases), small cell neuroendocrine lung carcinoma (1), non-small cell lung carcinoma (1) (figure 1), breast carcinoma (4), renal cell carcinoma (1), and bronchial carcinoma, not otherwise specified (3). Prior to referral to our hospital, the metastatic nature of the ocular tumour had been suspected in seven of these 24 patients, and these seven patients had thorough systemic investigations at their local hospital that had failed to detect a primary tumour. Tumour biopsy in these seven cases successfully confirmed the metastatic nature of the lesion and identified its origin, revealing breast carcinoma in three and lung carcinoma in four.
(A) Cytospin stained with May–Grunewald–Giemsa demonstrating large atypical cells of a non-small cell carcinoma of the lung on a haemorrhagic background (40× objective). (B) Immunocytochemical staining showing positivity for pancytokeratin, confirming the epithelial origin of the tumour cells (peroxidase-anti-peroxidase (PAP) immunostaining 40× magnification). The carcinoma cells were also positive for thyroid transcription factor-1 (not shown), and were negative for the melanocytic marker, MelanA.
Routinely, confirmation of the metastasis was reported orally by the pathologist within 1 day of the biopsy, with additional histological and immunohistochemical information being provided within 2 or 3 days.
The median time from first assessment at LOOC to the final written histological report was 5 days (range 2–16 days).
In 3 of the 27 patients with an unknown primary tumour, intraocular biopsy showed metastatic poorly differentiated carcinoma without clear indication of the primary tumour site. Subsequent systemic investigations after referral to the general oncologist revealed breast carcinoma in two patients but failed to identify the primary site in the third patient.
Ocular complications of biopsy included two cases of moderate vitreous haemorrhage, which did not require further treatment, and one case of anterior segment haemorrhage after an iris biopsy, which needed anterior segment washout.
Two patients without a known primary tumour refused ocular biopsy. Subsequent investigations revealed an oesphageal cancer in one patient while in the other case the primary site could not be identified.
Treatment and follow-up
Seventy-three patients (76%) received external beam radiotherapy (EBRT), two (2.1%) patients received photodynamic therapy, two (2.1%) patients had Ru-106 plaque radiotherapy, three (3.1%) patients underwent enucleation (because of extraocular extension in two patients and neovascular glaucoma in the third case).
Sixteen (16.7%) patients were kept under observation without treatment (figures 2 and 3 show two selected cases of patients received EBRT).
(A) A patient underwent left radical mastectomy for breast cancer and received radiotherapy and adjunctive chemotherapy. Approximately 2 years later, she was referred to our hospital with choroidal tumour measuring 8.9×6.9 mm basally with a thickness of 1.5 mm. Ultrasonography showed medium to high internal reflectivity (B). Diagnostic biopsy confirmed breast-related metastasis and the patient received external beam radiotherapy (EBRT). (C) Two months after EBRT, the tumour regressed to a thickness of 0.9 mm (D), while the visual acuity remained at 6/6.
(A) A patient with an unknown primary tumour was referred with a choroidal tumour involving the optic nerve and the fovea, measuring 10.2×11.1 mm basally with a thickness of 2.6 mm. The visual acuity was count fingers (CF) at 30 cm at presentation. Transretinal 25G biopsy demonstrated breast adenocarcinoma, and subsequently, general investigations revealed multiple, small, breast tumours. (B) The patient received external beam radiotherapy (EBRT). Six months after treatment, the tumour had regressed, but the visual acuity remained CF at 30 cm.
Forty-seven patients (53 eyes) had at least one follow-up ophthalmic evaluation after the baseline evaluation. Forty-nine patients had no follow-up examination for various reasons, which included death, poor systemic condition, and patient's preference (because of prognosis or because the VA improved). The median follow-up in these 53 patients was 4 months (range 1–60 months).
After ocular treatment, the VA was stable or improved in 40 (75.5%) of these 53 eyes. In 13 (25.5%) eyes, the VA deteriorated (figure 4). The causes of visual loss included exudative retinal detachment (2), radiation-induced maculopathy (1), increased subretinal fluid at the macula (2), tumour growth or new tumour formation (3 cases), hyphaema from the tumour biopsy (1) and uncertain in four cases.
Histogram depicting visual acuity (VA) at presentation and at the last follow-up of 53 eyes that had at least 1 follow-up ophthalmic evaluation after the baseline evaluation. Mean follow-up for these 53 patients was 7.1 months (median: 4 months, SD: 10.5, range from 1–60 months). Mean visual acuity of this group improved from a mean 0.72 logMAR (SD: 0.8, range 0–3 logMar units) to a mean of 0.61 logMAR (SD: 0.78, range 0–3 logMar units. Visual acuity was stable or improved in 40 of these 53 eyes (75.5%). In 13 eyes (25.5%), VA decreased.
The tumour thickness decreased in 50 (94.3%) patients, after EBRT in 48 patients and with chemotherapy in two patients. Three patients were observed without treatment, with two subsequently requiring EBRT because of documented tumour growth. In 12 (22.6%) eyes, the metastasis was undetectable on ultrasonography after EBRT. One patient developed local tumour recurrence after EBRT, which was treated with photodynamic therapy. A choroidal metastasis from primary pulmonary leiomyosarcoma did not respond to EBRT and was therefore treated by trans-scleral local resection, which was successful.9
Seventy-nine patients (82.3%) had died by the time the study closed. The median time between diagnosis of choroidal metastasis and death was 6 months (range 0.5–47 months).
Discussion
Main findings
We found that tumour biopsy established the diagnosis in all 39 patients who underwent this procedure. Furthermore, biopsy correctly identified the site of origin in 24 out of 27 (88%) patients in whom the metastatic nature of the uveal tumour and, consequently, the primary malignancy was not known at the time of the referral to our hospital. Interestingly, there were seven patients who, prior to referral to our hospital, had undergone thorough systemic investigations, which had failed to identify a primary tumour, which was quickly identified by biopsy. These results support our policy of performing intraocular tumour biopsy as a primary procedure. This approach provides a diagnosis more quickly and conclusively than systemic investigations. Biopsy also narrows the differential diagnosis making it possible to plan systemic examination accordingly.
Ocular tumour biopsy
In most of the other centres, intraocular biopsy is considered only in: patients with clinical suspicion of uveal metastasis but no evidence of primary malignancy despite systemic evaluation; patients demanding histopathological confirmation of the diagnosis; and tumours with major diagnostic uncertainty.5 ,10 ,11
Identification of the primary malignancy is important because this influences therapy.12 Such therapy may therefore expedited by immediate biopsy. Because metastases grow rapidly, early treatment may also enhance any opportunities for conserving vision, which is particularly important to those patients in the advanced stages of their disease.
Additionally, histopathological evaluation can be a valuable tool, identifying patients that could benefit from specific treatment modalities. For example, in cases of localised breast cancer, histopathological evaluation can identify patients with HER2/neu-positive disease, which is associated with a higher risk of recurrence, and may benefit from adjuvant anti-HER2/neu-directed therapy.13 Furthermore, histopathological evaluation can identify oestrogen receptor- and/or progesterone receptor-positive tumour cells, predicting benefit from endocrine therapy.14
In cases of non-small cell lung cancer, DNA can be extracted from the residual biopsy material and assessed for the presence/absence of epidermal growth factor receptor (EGFR) mutations. Those patients with EGFR-mutated bronchial carcinomas could have improved survival benefit through EGFR-tyrosine kinase inhibitors (gefitinib and erlotinib), in keeping with more personalised treatment strategies.15 ,16
As far as we are aware, and at least for the patients managed for their systemic disease in Liverpool, biopsy of the primary cancer was required in none of the patients who had histologic confirmation of the primary site through ocular biopsy in our study.
In general, biopsy of the primary site is more complex and more time consuming, and therefore associated with higher risk of complications. Conversely, the ocular biopsy performed with our technique appears to be a safe and quick procedure with an average operating time of about 10 min that is routinely performed under local anaesthetic, therefore, sparing the need for a more complex systemic procedure that often requires a general anaesthetic.
Comparison of our study with previous studies
The most common primary source of the uveal metastases reported is breast carcinoma, accounting for 39–49% of all tumours.1 ,4 ,17–19 This rate was similar to that seen in our study—43%.
Ocular metastasis from breast cancer typically develops after the diagnosis of the primary tumour and after the development of extraocular systemic metastases. Uveal metastasis was the first sign of breast metastasis in 14.6% of our patients as compared with 4–46% of patients in other studies.18 ,20–22 Symptomatic uveal metastases usually precede the diagnosis of the lung primary cancer.3 In our study, 16 (59.3%) of the 27 cases of lung cancer developed ocular metastasis before detection of the primary cancer.
In a review of 520 eyes, Shields et al4 reported that whereas metastases from breast cancer tended to be bilateral and multifocal, those from the lung were more often unilateral and unifocal. Rosset et al23 reported that multiple lesions tend to be present regardless of the primary tumour site. We found bilateral tumours in 19.5% of breast-related uveal metastases as compared with 14.8% of lung-related metastases. Multiple uveal metastases were present in 24.5% of patients with breast cancer, but only 9.6% of those with lung cancer.
The time between the diagnosis of primary carcinoma to the development of uveal metastases ranges from 0 to 228 months.24 According to Freedman and Folk, this time interval averages 9.2 months and 42.2 months with lung and breast carcinomas, respectively.25 In our study, the time to relapse averaged between 23 months (lung carcinoma) and 58 months (breast carcinoma).
Treatment of ocular metastases
As in previous studies, our results showed that radiotherapy induced regression of almost all uveal metastases, with good improvement in vision in most patients. Our positive experience with plaque radiotherapy reflects that of Shields et al26 who reported a high degree of tumour control (94% lesion regression) in a study of 36 patients. We successfully resected one metastasis, which had not responded to radiotherapy. This was a metastatic pulmonary leiomyosarcoma, which is well known to be radio-resistant.9 When selecting treatment, therefore, the radioresponsiveness of the tumour should be taken into account. Similarly, our successful treatment of two patients (presenting tumour thickness of 1 mm and 1.5 mm, respectively) with photodynamic therapy is in keeping with the good results reported by Kaliki et al, who reported complete tumour control in seven out of nine (78%) choroidal metastases.27 If a patient is about to receive systemic chemotherapy or biologic therapy, the conventional practice is to assess the ocular tumours after 6 weeks, in case ocular therapy is not required.6 Although we observed tumour regression in two patients undergoing systemic therapy, we feel that further studies are required to determine how many patients ultimately require ocular therapy because of tumour regrowth.
Strengths and weaknesses of study
The main strength this study is the large number of patients. The main weakness is that we did not randomise between initial biopsy and initial systemic investigations. We did not feel there was sufficient clinical equipoise to justify such a comparison.
Conclusions
With cancer rates rising and cancer survival improving, it is likely that uveal metastases will become more common. Our study describes the current situation which is evolving as a result of advances in ocular and systemic imaging and therapy. One such advance is biopsy which has become more informative, thanks to developments in immunohistochemistry and molecular pathology, and safer as a result of surgical improvements. Immediate biopsy provides a quick diagnosis that may expedite treatment and enhance any opportunities for conserving vision, especially as these tumours tend to grow rapidly. Early biopsy may also facilitate the general oncologic management of these patients identifying patients who could benefit from specific treatment modalities while sparing these patients from the risks of biopsy of the primary tumour.
References
Footnotes
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Contributors LK reviewed the literature, participated in the analysis and interpretation of data, and prepared the manuscript. IK and IZ participated in the collection of data. LK, SC, HH, CG, BD were involved in the study concept and design. SC and BD revised the manuscript for important intellectual content. BD conceived and supervised the study. All authors read and approved the final manuscript.
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Competing interests None.
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Patient consent Obtained.
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Ethics approval Ethics committee approval was not required. Institutional approval as a service evaluation was obtained for this study (Ref: AC01583).
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Provenance and peer review Not commissioned; externally peer reviewed.