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Clinical study on eye metastasis in patients with breast cancer Ji Guangyan, Xing Lei, Huang Jianbo, Kong Lingquan*,Wang Ziwei, Ren Guosheng, Wu Kainan Department of General Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, The People’s Republic Of China *Corresponding author:Kong Lingquan Department of General Surgery the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016,The People’s Republic Of China (Tel: 13101380893 Email:[email protected]) Abstract: Uveal metastasis from carcinoma which is the most common type of ocular malignancy in adults is found in an increasing number of patients, mostly with breast and lung cancer. The reported prevalence of clinically evident uveal metastases from metastatic breast carcinoma ranges from 5% to 9%, while about 5%~30% patients with uveal metastases are asymptomatic. According to documents analysis, the discovery rate of eye metastasis from breast carcinoma in china was relatively lower than that of western countries. Clinical Manifestations are depended on the sites of metastasis related to the eye. The most common symptoms of ocular metastasis were blurred vision (88%), floaters (5%) and photopsia (5%). The paraneoplastic effects and cancer associated retinopathy of breast cancer on the eye are rare but significative. Diagnosis of ocular metastasis from breast carcinoma mainly based on ophthalmoscopic examination such as fundus examination, ultrasonography, Ultra wide-field imaging, optical coherence tomography, fluorescein angiography, autofluorescence with HRA-II (Heidelberg Retina Angiograph), optical coherence tomography(OCT), CT/MRI and even position emission tomography of the eye. When sight is threatened by the uveal metastases, patients should require emergent restaging and treatment to avoid loss of vision. Choroidal metastases have been treated with systemic treatments (chemotherapy, endocrine therapy, targeted therapy and immunotherapy), local therapies (radiotherapy, intravitreal injection, laser therapy , cryotherapy) and even enucleation. Overall, the prognosis for patients with eye metastases remains poor. Routine screening of these patients for uveal involvement might be a useful strategy. Early diagnosis and timely appropriate treatment are therefore of paramount importance to maintain patients’ quality of life. [Key Words] breast cancer; choroidal metastasis; treatment; eyes examination -1 Metastasis is one of the most common manifestations of malignancy. As the treat ment options and life expectancy of the cancer patients are improving, the numbers of different metastatic lesions , including those uncommon metastatic sites are expected to increase. Uveal metastasis from carcinoma, which is the most common type of ocular malignancy in adults, is found in an increasing number of patients, mostly with breast and lung cancer1. Uveal metastasis from breast carcinoma is the smallest metastatic lesions whereas uvea is the most highly favoured target site in the whole body for the development of metastases per unit of cancer cells delivered through the arterial route2. The predilection of metastases to the uvea maybe related to the vascular architecture and local microenvironmental factors. The reported prevalence of clinically evident uveal metastases in metastatic cancer patients ranges from 3% to 9.2 %, specially for metastatic breast carcinoma the prevalence is 5% to 9%1,3. While about 5%~30% patients with uveal metastases are asymptomatic4, especially in patients with metastatic disease in other organ that dominates the clinical picture. In the past, some symptomatic patients experiencing blurred or reduced vision , “floaters” or pain in the eye5, haven’t been identified in metastases to the eye6. Considering the high prevalence of uveal metastases in patients with metastatic carcinoma7,8, and rapid sight threatening usually caused by uveal metastases, routine screening of these patients for uveal involvement might be a useful strategy. Early diagnosis and timely appropriate treatment are therefore of paramount importance to maintain patients’ quality of life. The purpose of this article is to provide a review of clinical study on the eye manifestations of breast cancer patients. And with the increasing incidence of the metastases, should we suggested that all women with metastatic breast cancer be screened for choroidal metastasis 9? Although this issue is controversial10. EPIDEMIOLOGY The true incidence of ocular metastasis is difficult to estimate as its subclinical manifestations are frequently unnoticed and the characteristics of study populations and methodology are different. Some studies suggested that the frequency of -2 choroidal metastases of the metastatic breast cancer was about 1%–5% of breast cancer patients8, while it is indicated in recent prospective studies that :as high as 37% of disseminated breast cancer patients were diagnosed with choroidal metastases in one study1. However ,most of the clinical studies estimated the prevalence of uveal metastases from all forms of metastatic carcinoma at between 2.3% and 9.2%. In metastatic breast carcinoma the prevalence was 5%–9% (mean 7%) and for lung cancer, 2%–7% (mean 5%). The relatively lower prevalence from lung carcinoma when compared with breast carcinoma is probably due to the low survival rate of lung carcinoma11.Another review of 112 patients (141 eyes) presenting with a metastasis to the eye or orbit revealed that breast cancer was the most common primary tumor (49.1%)12.In china ,it is reported by Wang GL et al that of 49 patients (66eyes) with choroidal metastasis, primary tumors were found in 40 cases (81.6%),consisting of breast carcinoma in 16 cases (32.7%), lung carcinoma in 14 cases(28.6%), hepatoma and cholangio carcinoma in 3 cases and nasopharyngeal carcinoma in 1 case (2%)13. While It was found by Yan JH et al that of 46 patients with cancer metastatic to the orbits in southern china , the most common primary cancer that metastasizes to the orbit was nasopharygeal carcinoma (30.34%),the possible reasons were that it was prospective study and compared to nasopharyngeal carcinoma ,not all the breast cancer patients routinely had CT examination of head and neck14. Geographical variations exist in breast cancer incidence rates, with higher rates in Europe, North America and Oceania and lower rates in Asia and Africa15.Male breast cancer is rare, the incidence is 0.8–1.5 cases per 100000 male population, accounting for 1% of all breast cancer diagnoses. Ocular manifestations of male breast cancer can occur and this differential diagnosis should not be over looked16,17. According to documents analysis . The discovery rate of eye metastasis from breast carcinoma in china was relatively lower than that of western countries. The 1 Some patients with uveal metastases were possible reasons may be as follows:○ 2 Not all women with metastatic breast cancer were screened for asymptomatic1,4;○ 3 Not all the clinicians were familiar with the manifestations of choroidal metastasis;○ uveal metastases,when some patients experiencing blurred or reduced vision, floaters 4 Patients with or pain in the eye, haven’t been identified in eye metastases ;○ apparently localized breast carcinoma may harbour subclinical micrometastases which -3 maybe controlled after systemic treatment such as chemotherapy, endocrinotherapy or targeted therapy;⑤ Geographical variations . Clinical Manifestations Metastatic disease to the eye from breast carcinoma was first described by Johann Friedrich Horner in 186418. Since then, reports of ocular involvement from cancer patients have steadily increased in living patients as well as in histopathological studies on postmortem subjects19. It is reported that the interval from breast cancer diagnosis to ocular metastasis is 20~40 months4,20, and non ocular metastases usually preceded ocular involvement by 10 months in most cases21,22. Ocular metastasis from breast cancer was usually preceded by metastasis to other organs, primarily the lungs. At the time of diagnosis of ocular metastasis, 85% of patients also had pulmonary involvement23. In disseminated breast cancer the incidence of choroidal metastases increased to 11% when more than one organ were involved in metastatic spread. Risk factors for choroidal metastases were dissemination of cavcer in more than one organ and the presence of lung and brain metastases24. On the other hand, eye could be the first metastatic disease, which should always be kept in mind in breast cancer patients with visual symptoms. Some studies had shown that the prevalence of asymptomatic ocular metastases in patients with known metastatic breast cancer ranged from 5% and 30%25. Prospective screening study showed that choroidal metastases were found more frequently in patients already known to have metastasis in other organs1. The distribution of metastases within the eye itself varies considerably(Table 1), The choroid is predominantly affected (81% of ocular metastases),with much lower rates in the multiple uveal sites 11%,optic disk (5%), iris(3%),eyelid metastasis (1%), and conjunctiva and orbita(<1%),ciliary body (<1%), the most common symptoms of ocular metastasis were blurred vision (88%), floaters (5%) and photopsia (5%)24. For choroidal metastases, blured vision is usually caused by the associated retinal detachment or progressive hypermetropia, and for iris or ciliary body metastases it is -4 caused by seeding of tumour material in the anterior chamber and/or retinal detachment from coexisting choroidal metastases. Ocular pain may be a feature of uveal metastases from breast cancer (up to 16%), but quite rare in other uveal malignancies. It may be produced by inflammation and tumour necrosis, glaucoma or microscopic scleral involvement and invasion of the ciliary nerves8. Patients with choroid metastasis usually suffered decreased visual acuity when complicated with retinal detachment . Ocular metastasis can also represent the initial manifestation of breast carcinoma. Tumour metastases may give rise to both intra and extraocular sequelae. -5 Table 1. Sites and symptoms of metastasis related to the eye. Site Incidence Choroid 81% Symptoms Signs Asymptomatic Yellow placoid lesions (usually superior and temporal) Blurred vision Serous retinal detachment Metamorphopsia Alteration of retinal pigment epithelium Pain, diplopia (rare) Choroidal detachment Glaucoma Iris 9% Asymptomatic Blurred vision Iris mass (usually superior) Uveitis Glaucoma Pseudo-hypopyon Optic disc 5% Asymptomatic Blurred vision Diffuse or localized disc swelling Disc haemorrhages Disc oedema Ciliary body 2% Asymptomatic Dome-shaped or sessile mass (usually inferiorly) Blurred vision, pain Uveitis Glaucoma Sectorial cataract Lens subluxation Shallow anterior chamber Vitreous Rare Floaters Blurred vision Vitriti Retinal Rare Blurred vision Floaters Vitritis Black infiltrative retinal mass with retinitis-like appearance Diplopia Proptosis or enophthalmos Heterotropia Extraocular Rare Cerebral Rare Field defects Strabismus Hemineglect Field loss Abnormal colour vision Blurred vision Diplopia Optic nerve involvement may be the result of either metastatic emboli deposited in the microcirculation of the papilla, or the direct extension of adjacent choroidal tumor. Both nerves may be affected simultaneously. When there is tumor invasion to the level of the lamina cribrosa or more posteriorly, the condition may resemble a meningioma or central retinal vein occlusion. Bilateral involvement may mimic papilloedema26. In their retrospective study of 660 patients with intraocular metastasis, found that optic nerve head involvement accounted for 5% of all intraocular metastases27. A retrospective study on the medical records of Metastatic orbital tumors in -6 southern China during an 18-year period showed that: The most common primary cancer that metastasizes to the orbit was nasopharyngeal carcinoma (30.34%), followed by lung cancer (8.70%), liver cancer (6.52%), breast carcinoma (4.35%), renal cell cancer (4.35%) , medullary thyroidcarcinoma(2.17%) ,lacrimal gland carcinoma (2.17%), stomach carcinoma (2.17%) , mediastinum carcinoma (2.17%) , other forms(6.52%), and unknown carcinomas (30.34%). The five most common clinical manifestations at the initial increased orbital pressure(54.35%), diplopia (54.35%) and limited ocular motility (52.17%), followed by swollen eyelid (50%), visible mass or swelling(46%),blurred vision (41%), conjunctival hyperemia and edema(35%), pain(28%), blepharoptosis (20%), papilledema (17%) and vasodilatation of the retina (7%)28. The paraneoplastic effects of breast cancer on the eye are rare, but may cause ocular movement disorders and visual loss, which may precede the diagnosis of the underlying malignancy29. These ‘remote effects’ are not due to metastases but are thought to represent immunological responses against tumour antigens which are expressed by normal cells30. Cancer associated retinopathy (CAR) is a paraneoplastic neurological syndrome (PNS) resulting in progressive loss of vision and clinical signs of retinal degeneration, that may occur with breast cancer31.The primary manifestation of CAR is rapid progressive visual loss due to both rod and cone dysfunction, Patients may experience bilateral visual loss with ring scotoma, photopsia and night blindness, and rapid progression to complete visual loss32.The results of ophthalmologic examination often showed a triad of signs: photosensitivity,ring scotomatous visual field loss ,and attenuated retinal arteriole caliber . Similarly to other PNS,CAR is considered to be an autoimmune disorder that involves cross-reaction between autoantibodies and retinal proteins,besides antibodies,cytotoxic cells may also mediate paraneoplastic associated syndrome. TREATMENT MODALITIES When sight is threatened by the uveal metastases, patients should require emergent restaging and treatment to avoid loss of vision. Management of these -7 patients requires a multidisciplinary approach with close liaison between the patient’s ophthalmologist, oncologist and other members of the healthcare team including radiation oncologist and neuroradiologist, Indications for treatment of uveal metastases include:①Visual symptoms attributable to the lesion (e.g. blurred vision, scotoma, flashes, floaters, dysmorphopsia, etc.);②Lesions close to the optic nerve or macula with signs of active disease, (progressive visual symptoms attributable to the lesion, clinical or angiographic presence of subretinal fluid and tumour cell dispersion);③ Enlargement of lesion(s) despite systemic chemotherapy; ④Painful lesions11. Systemic treatments At the time of uveal diagnosis up to 88% of patients have metastatic lesions elsewhere in the body. Further more patients with apparently localized breast disease may harbour subclinical micrometastases. These microscopic deposits are not affected by surgical resection or radiation therapy and may eventually become clinically significant33. Because the choroid is external to the blood ocular barrier, systemic medications diffuse freely into the choroid via the fenestrated endothelium of the choriocapillaris. Systemic chemotherapy has been reported to reduce the rate of failure of radiotherapy when administered sequentially7. Systemic therapy may include chemotherapy, endocrine therapy or targeted therapy and immunotherapy . Effective control of choroidal metastases has been observed with systemic medications alone. It was reported that choroidal tumour regression in response to cytotoxic drugs and/or hormone therapy was 65%24. Complete regression of choroidal metastases has been described in response to newer therapeutic agents such as taxanes34,35. Conventional chemotherapy interferes with cell division and does not discriminate effectively between rapidly dividing tumor cells and normal cells, leading to toxic side effects such as myelo supression, hepatotoxicity, and nephrotoxicity. While targeted therapies are aimed at distinct molecular pathways involved intumor growth, proliferation , and metastases. They have more specificity towards tumor cells than normal cells and can provide a broader therapeutic window -8 with less toxicity. The receptor tyrosine kinase CerBb2, also known as human epidermal growth factor receptor 2 (HER2), has also become an important target because it is over expressed in up to 20%--30% of breast cancer patients. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular juxtamembrane domain of HER2 and prevents its activation36. It was reported that trastuzumab in combination with other systemic therapies led to the regression of choroidal metastases within 1-2 months37,38. The majority of breast cancers in postmenopausal women express estrogen or progesterone receptors, and, as a result, endocrine therapy with tamoxifen and aromatase inhibitors (anastrozole, letrozole, and exemestane) plays an important role in treatment of choroidal metastases from breast carcinoma. Manquez et al39found choroidal metastases regression with aromatase inhibitors treatment in 10 out of 17 patients with hormone receptor positive breast cancer over a mean follow-up of 20 months. Tamoxifen is prescribed for both premenopausal and postmenopausal breast cancer women with positive estrogen receptor and/or progesterone receptor and is the treatment of choice for premenopausal women with metastatic disease. The incidence of symptomatic ocular toxicity is low and does not warrant the routine examination of all patients on tamoxifen for ocular problems. Clinicians ,however ,should be aware of the possibility of ocular problems and patients complaining of altered vision should be referred for urgent ophthalmological examination. While some clinicians do suggest regular follow-up of ocular problems caused by tamoxifen40.With aromatase inhibitors treatment bone loss secondary to estrogen deficiency may be seen, although it was reported by Manquez et al39that no toxicity or intolerance to aromatase inhibitors was observed over a mean follow-up of 20 months. Local therapies Therapy can be limited to the eye if systemic metastases are absent24. If the metastatic lesions appear to regress completely after systemic treatment, no specific ocular treatment is necessary. However, local therapy to the affected eye may be beneficial if response is incomplete and signs of disease activity persist. Common practice has been to wait at least 6weeks to see the effects of systemic therapy on lesion regression41. If the choroidal lesions is enlarging during this observation period, -9 locally delivered therapy such as external beam radiation is recommended8. Local therapy may compromise radiotherapy (external bean ,plaque brachytherapy, Gamma knife and proton beam), intravitreal injection ,laser therapy , cryotherapy. Since first applied in 1979, external bean radiotherapy(EBRT) has become a well established and widely available treatment for uveal metastases that fail to regress despite systemic therapy42. In a prospective study of the effects of ERBT .65 eyes (50 patients with either breast or lung carcinoma)43,found stabilization of vision in 50% of patients and improvement in visual acuity in 36% of patients. Another retrospective study found that: Visual acuity was improved or stabilized in 62% of patients, with also significantly better results when doses of 30—50 Gy were administered44. Complications from radiotherapy, such as cataracts, exposure keratopathy, iris neovascularization, radiation retinopathy, optic neuropathy, and radiation papillopathy, were about 12%. Over a median of 5.8 months of follow-up, patients who live longer may have a statistically higher probability of developing these side effects45. In addition to ocular toxicity ,another disadvantage of EBRT is the need for repeated daily treatments (at least 10 daily fractionated treatments).For these drawbacks46,other radio therapeutic techniques such as plaque brachytherapy47, Gamma knife, CyberKnife, and proton beam radiotherapy48,etc. that promise less ocular toxicity or shorter treatment times have been applied to choroidal metastases. In a randomized trial, the use of intravitreal bevacizumab a kind of intravitreal VEGF inhibitor therapy was proved to be effective in combination with paclitaxel for the treatment of patients with metastatic breast carcinoma49. Amselem et al reported that 3 weeks after intravitreal injection of 4mg bevacizumab for patients with choroidal metastasis secondary to breast carcinoma, the fundus angiography showed decreased lesion size and reduced leakage in the late phases . The possible mechanisms may involve antiangiogenic and antipermeability effects of intravitreal bevacizumab on tumor angiogenesis in choroidal metastasis50. It was also reported that for a patient with choroidal metastasis from breast cancer, six months after intravitreal injection of 2.5 mg bevacizumab, the subject’s - 10 best corrected visual acuity (BCVA) was improved and fundus examination demonstrated the almost entire regression of the choroidal mass. In addition, there was no recurrent choroidal mass during the 24-month follow-up51. Intravitreal use of bevacizumab provides a potential option for adjuvant therapy in patients with choroidal metastasis for breast cancer. Further studies are necessary to elucidate its optimal uses. Further more choroidal metastases have also been treated with photodynamic therapy52,53,laser photocoagulation54,transpupillary thermotherapy55,cryotherapy, and local excision, enucleation56. Based on the evidence available in the literature, Kanthan et al summarized recommendations for clinical practice(Seen in Table 2)11. - 11 Uveal metastases Is treatment indicated? No Yes Regular observation Is systemic therapy required for widespread disease? Yes No Regression of uveal lesion Complete Incomplete Requires local therapy Coexisting brain metasases Yes Whole brain EBRT 2nd line chemotherapy No Local EBRT 2nd line brachy therapy, TTT, laser photocoagulation, chemotherapy Table 2 : Guidelines for the management of uveal metastases. INVESTIGATIONS Intraocular metastatic tumor is the commonest intraocular malignancy in adults, - 12 early diagnosis and timely appropriate treatment are therefore of paramount importance to maintain patients’ quality of life. Diagnosis of ocular metastasis from breast carcinoma mainly based on ophthalmoscopic examination supplemented by imaging studies. The investigation of choice are fundus examination, ultrasonography , Ultra wide-field imaging57,optical coherence tomography, fluorescein angiography58, autofluorescence with HRA-II (Heidelberg Retina Angiograph), optical coherence tomography(OCT)58, CT/MRI and even position emission tomography of the eye. Differential diagnosis should include amelanotic melanoma or nevus lymphoma , choroidal hemangioma, choroidal osteoma, circumscribed choroidal hemorrhage, posterior scleritis, leukemic deposits, granuloma iritis, retinitis, choroiditis, exudative retinal detachment and cancer related retinopathy. Fundus examination is usually the initial investigation , lesions as small as 1 mm can be detected by ophthalmoscopy. The key features of choroidal metastases from breast carcinoma are solitary, yellow coloured, plateau shaped lesion that may be associated with retinal elevation59. Sometimes initial ocular fundus examination was unremarkable, ultra sonography will be use to look for the architecture of the lesion. A-scan ultrasonography of metastatic lesions shows moderate to high amplitude internal reflectivity, and B-scan ultrasonography demonstrates moderate to high acoustic solidarity, while color Doppler ultrasonography is more accurate than B-scan ultrasonography, In common ophthalmic practice, B-scan ultrasonography especially color Doppler ultrasonography of the eye is preferred over CT or MRI to confirm choroidal metastases. Magnetic resonance imaging may also aid in differentiating metastatic lesions from primary choroidal melanoma because the latter exhibits high signal intensity on T1-weighted images60. However in some atypical cases ,a choroidal metastases lesion may not be easily discernable on an ocular B-scan or color Doppler ultrasound , CT or MRI examination and requires fluoresceine angiography. Fundus autofluorescence ( FAF ) imaging and OCT reveal unique tumor characteristics of choroidal metastasis. FAF imaging revealed hyperautofluorescence in areas of focal pigmentation and subretinal fluid with hypoautofluorescent margins corresponding to OCT evidence of retinal pigment epithelial (RPE) thickening and subretinal fluid. FAF images may change with tumor growth. Hyperautofluorescence - 13 in FAF imaging is correlated to focal hyperpigmentation, subretinal fluid, and advancing tumor edges. FAF imaging best defined surface characteristics and tumor margins. OCT best revealed elevation of the RPE and retina, RPE thickening and folds, and retinal detachment. OCT can also better demonstrated intraretinal findings (atrophy, subretinal fluid, and increased and lost RPE)58. PET CT is a sensitive method to localize choroidal lesions. a preliminary study by Moll et al.showed that PET CT allowed detection of new retinoblastoma and it is feasible to use PET to evaluate recurrence in treated patients61. Solav et al reported a choroidal metastasis from breast carcinoma was detected on PET CT scan62. Systemic evaluation in consultation with the patient’s physician or oncologist and ophthalmologist will usually yield a diagnosis in the majority of patients without the need for biopsy of the ocular lesion .Biopsy may be performed in exceptional and difficult diagnostic situations (e.g. an isolated uveal metastasis from an unknown primary site), although there is a risk of seeding tumour cells at the time of surgery, safer biopsy techniques (including fine needle aspiration biopsy, open biopsy and trans pars plana approach) to minimize the risk of tumour spread have been reported. PROGNOSIS Overall, the prognosis for patients with eye metastases remains poor. For these patients life expectancy is reported to be 0.2–48 months (median 6–9 months)63.In other words, uveal metastases occur relatively late during the course of carcinoma. The median survival time (MST) following choroidal metastasis for all stages of breast cancer was 314 days. The MST after choroidal metastasis patients thought to have stage I or II breast cancer , prior to diagnosis of the metastasis , was longer than that of patients with stage III or IV cancer(873 /139) days. Older patients with metastatic breast cancer have a longer MST than younger patients. According to one report, the survival rate in patients with uveal metastases from beast cancer is 65% at 1-year, 34% at 3-year and 24% at 5-year follow-up24. However, with recent improvement in treatment methods, an increasing proportion of patients with metastatic disease, especially those patients with breast cancer are living prolonged periods with their disease under control. 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