Download Clinical study on eye metastasis in patients with breast cancer

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
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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
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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
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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
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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.
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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
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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
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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
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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,
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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
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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.
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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,
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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
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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. Jang RW reported that after active treatment
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a patient with an isolated choroidal metastasis from breast cancer still lived with
disease free survival 9.5 years follow-up64.
REFERENCES
1.Wiegel T, Kreusel KM, Bornfeld N, et al. Frequency of asymptomatic choroidal metastasis in patients with
disseminated breast cancer: results of a prospective screening programme. Br J Ophthalmol 1998;82:1159–1161.
2.Weiss L. Analysis of the incidence of intraocular metastasis. Br J Ophthalmol 1993; 77: 149–1151.
3.Albert DM, Rubenstein RA, Scheie HG .Tumor metastasis to the eye, part I. Incidence in 213 adult patients
with generalized malignancy. Am J Ophthalmol 1967; 63: 723–726.
4.Mewis L, Young SE. Breast carcinoma metastatic to the choroid analysis of 67 patients.Ophthalmology1982; 89:
147–151.
5.Merrill CF, Kaufman DI, Dimitrov NV. Breast cancer metastatic to the eye is a common entity. Cancer 1991; 68:
623–627.
6.Char DH, Miller T, Kroll S .Orbital metastases: diagnosis and course. Br J Ophthalmol 1997;81(5):386–390.
7.d’Abbadie I, Arriagada R, Spielmann M, Le MG. Choroidal metastases: clinical features and treatments in 123
patients. Cancer 2003; 98: 1232–1238.
8.Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with uveal metastases.
Ophthalmology1997;104 : 1265–1276.
9.Chong JT, Mick A. Choroidal metastasis: case reports and review of the literature. Optometry 2005;76(5):293–
301.
10.Fenton S, Kemp EG, Harnett AN.Screening for ophthalmic involvement in asymptomatic patients with
metastatic breast carcinoma. Eye2004;18(1):38–40.
11.Kanthan GL, Jayamohan J, Yip D, et al. Management of metastatic carcinoma of the uveal tract: an
evidence-based analysis. Clin Experiment Ophthalmol 2007; 35(6): 553-565.
12.Freedman MI, Folk JC. Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics.
Arch Ophthalmol, 1987, 105(9): 1215-1219.
13.Wang GL,Wang MY,Wei WB,Clinical features and treatment of choroidal metastasis.Chin J Ophthalmol
2009;45(3):229-230.
14Yan JH,Gao SH.Metastatic orbital tumors in southern china during an 18-year period.Graefes Arch Chin Exp
opthalmol 2011;249:1387-1393
15.Sasco AJ.Epidemiology of breast cancer: an environmental disease? APMIS 2001;109:321–332.
16.Hodgson NC, Button JH, Franceschi D, Moffat FL & Livingstone AS: Male breast cancer: is the incidence
increasing? Ann Surg Oncol2004;11: 751–755.
17.Dieing A, Schulz CO, Schmid P et al.:Orbital metastases in breast cancer: report of two cases and review of
the literature. J Cancer Res Clin Oncol12004;30: 745–748.
18.Horner F. Carcinoma der dura mater exophthalmus. Klin Monatsbl Augenheilkd 1864;2: 186–190.
19.Volpe NJ,Albert DM .Metastases to the uvea. In: Albert DM & Jakobiec FA (eds). Principles and Practice of
Ophthalmology. Philadelphia: WB Saunders 1994;3260–3270.
20.Ratanatharathorn V, Powers W, Grimm J, et al. Eye metastases from carcinoma of the breast: diagnosis,
radiation treatment and results. Cancer Treat Rev 1991; 18: 261–76.
21.Mejia-Novelo A, Varado-Miranda A, Mor-ales-Vazquez F,et al. Ocular meta-Acta Ophthalmologica
Scandinavica2007 141 stases from breast carcinoma. Med Oncol 2004;21: 217–221.
22.Tamura M, Tada T, Tsuji H,et al. Clin-ical study on the metastasis to the eyes from breast cancer. Breast
Cancer;2004;11: 65–68.
23.Ferry AP. Metastatic carcinoma of the eye and ocular adnexa. Int Ophthalmol Clin1967;7: 615–658.
24.Demirci H, Shields CL, Chao A-N, Shields JA. Uveal metastasis from breast cancer in 264 patients. Am J
Ophthalmol 2003;136 : 264–271.
25.Kreusel KM, Wiegel T, Stange M, et al. Intraocular metastases of metastatic breast carcinoma in the woman.
Incidence, risk factors and therapy.Ophthalmologe 2000;97: 342–346.
26.Shields JA & Shields CL: Metastatic tumours to the intraocular structures. In:Shields JA & Shields CL (eds).
Intraocular Tumours. Philadelphia Saunders 1992;207–238
27Shields JA, Shields CL & Singh AD.Metastatic neoplasms in the optic disc: the 1999 Bjerrum Lecture. Part 2.
Arch Ophthalmol 2000;118: 217–224.
28.Jian HY, Shao HG, Metastatic orbital tumors in southern China during an 18-year period Graefes .Arch Clin
Exp Ophthalmol 2011; 249:1387– 1393.
29.Jacobson DM.Paraneoplastic disorders of neuroophthalmologic interest. Curr Opin Ophthalmol 1996;7: 30–
38.
30.Shams’ili S, Grefkens J, de Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with
- 15
antineuronal antibodies: analysis of 50 patients. Brain 2003;126 :1409–1418.
31.Guangyan Ji, Lei Xing, Jianbo Huang, et al. Progress in the study of cancer-associated retinopathy in breast
cancer patients. Chinese-German Journal of Clinical Oncology, 2012;11(10); 566-571.
32.Polans AS, Witkowska D, Haley TL. Recoverin, a photoreceptor-specific calcium-binding protein, is
expressed by the tumour of a patient with cancer-associated retinopathy. Proc Natl Acad Sci USA 1995;92: 9176–
9180.
33.Hortobagyi G: Adjuvant therapy for breast cancer. Annu Rev Med 2000;51: 377– 392.
34.Piccone MR, Maguire AM, Fox KD, et al. Choroidal meastases. Case 1: breast cancer. J Clin Oncol 1999;17:
3356–3358.
35.Kosmas C, Malamos NA, Antonopoulos M. Complete regression of choroidal metastases from breast cancer
after docetaxel based systemic chemotherapy. Med Paediatr Oncol 2000; 34: 229–230.
36.Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39—
51..
37.Munzone E, Nole F, Sanna G, et al. Response of bilateral choroidal metastases of breast cancer to therapy with
trastuzumab. Breast. 2005;14(5):380—383.
38.Wong ZW, Phillips SJ , Ellis MJ . Dramatic response of choroidal metastases from breast cancer to a
combination of trastuzumab and vinorelbine. Breast J 2004;10(1):54-56.
39.Manquez ME, Brown MM, Shields CL, et al. Management of choroidal metastases from breast carcinomas
using aromatase inhibitors. Curr Opin Ophthalmol 2006;17(3): 251—256.
40.Goirin MB,Day R, Costantino JP, et al.longterm tamoxifen citrate use and potential ocular toxicity. Am J
ophthalmol1998;125:493-501.
41.Biswal BM. Restoration of vision following combination chemotherapy of nasopharyngeal carcinoma
choroidal metastases. Med Pediatr Oncol. 2001;37(5):484.
42.Stephens RF, Shields JA. Diagnosis and management of cancer metastatic to the uvea: a study of 70 cases.
Ophthalmology1979;86(7):1336-1349.
43.Wiegel T, Bottke D, Kreusel KM ,et al. External beam radiotherapy of choroidal metastases – final results
of a prospective study of the German Cancer Society (ARO 95–08). Radiother Oncol2002;64:13–18.
44.Rosset A, Zografos L, Coucke P, et al. Radiotherapy of choroidal metastases. Radiother Oncol1998;46(3):
263-268.
45.Rudoler SB, Corn BW, Shields CL, et al. External beam irradiation for choroid metastases: identification of
factors predisposing to long-term sequelae. Int J Radiat Oncol Biol Phys. 1997;38(2):251—256.
46.Amer R, Peer J, Chowers I. Treatment options in the management of choroidal metastases. Ophthalmologica
2004;218 : 372–327.
47.shields CL, Shields JA, Potter PD. Plaque radiotherapy for the management of uveal metastases. Arch
Ophthalmol1997;115:203–209.
48.Tsina EK, Lane AM, Zacks DN, Munzenrider JE, Collier M,Gragoudas ES. Treatment of metastatic tumours
of the choroid with proton beam irradiation.Ophthalmology2005; 112 : 337–343.
49.Miller K, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus
bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the
Eastern Cooperative Oncology Group (E2100). N Engl J Med 2007;357: 2666–2676.
50.Amselem L, Cervera E, Dı´az-Llopis M, et al. Intravitreal bevacizumab (Avastin) for choroidal metastasis
secondary to breast carcinoma: short-term follow-up. Eye 2007;21: 566–567.
51.Yao HY, Horng CT, Chen JT, et al. Regression of choroidal metastasis secondary to breast carcinoma with
adjuvant intravitreal injection of bevacizumab. Acta Ophthalmol. 2010;88(7):282—3
52.Isola V, Pece A, Pierro L. Photodynamic therapy with verteporfin of choroidal malignancy from breast cancer.
Am J Ophthalmol2006;142(5):885-887.
53.Soucek P, Cihelkova I. Photodynamic therapy with verteporfin in subfoveal choroidal metastasis of breast
carcinoma (a controlled case). Neuro Endocrinol Lett2006;27(6):725-728.
54.Levinger S, Merin S, Seigal R, et al. Laser therapy in the management of choroidal breast tumor metastases.
Oph-thalmic Surg Lasers2001;32(4):294-249.
55.Kiratli H, Bilgic S. Transpupillary thermotherapy in the management of choroidal metastases. Eur J
Ophthalmol2004;14(5):423-429.
56.Kanthan GL, Jayamohan J, Yip D, et al. Management of metastatic carcinoma of the uveal tract: an
evidence-based analysis. Clin Experiment Ophthalmol 2007;35(6):553—565.
57.Coffee RE, Jain A, McCannel TA Ultra wide-field imaging of choroidal metastasis secondary to primary breast
cancer. Semin Ophthalmol2009;24(1):34-36.
58.Natesh S, Chin KJ, Finger PT. Choroidal metastases fundus autofluorescence imaging: correlation to clinical,
OCT, and fluorescein angiographic findings. Ophthalmic Surg Lasers Imaging2010;41(4):406-412.
59.Raj C，Leber G .The escape artist:Detecting choroidal metastases in the setting of breast cancer N Z Med
J2008;121(1279):100-2,
60.Smith JA, Gragoudas ES, Dreyer EB. Uveal metastases. Int Ophthalmol Clin 1997; 37: 183–199.
61.Moll AC, Hoekstra OS, Imhof SM, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET)
- 16
to detect vitreal retinoblastoma in the eye: Preliminary experience. Ophthalmic Genet2004;25:315.
62.Solav S, Bhandari R, Sowani A, et al. Choroidal metastasis from carcinoma of breast detected on F18-FDG
PET CT scan: A case report and review of literature[J]. Indian J Nucl Med2010;25(4): 160-163.
63.Ratanatharathorn V, Powers W, Grimm J et al. Eye metastases from carcinoma of the breast: diagnosis,
radiation treatment and results. Cancer Treat Rev 1991; 18: 261–276
64.Raymond W Jang, Mary Doherty, J Jill Hopkins ,et al. A case of prolonged disease-free survival in a patient
with choroidal metastasis from breast cancer. nature clinical practice ONCOLOGY february 2009 vol 6 no
2 ;181-121.
- 17