Breast carcinoma is the most common cancer in females. An estimated 2.3 million new cases of breast carcinoma are diagnosed annually worldwide.1 These patients have potential risks of ocular complications not only from the secondaries in the eye but also due to the side effects of medications such as corticosteroids and cytotoxic drugs used to treat breast cancers. Metastases from the primary tumour to the eye can affect almost every structure of the eye and adnexa, affecting vision and ocular motility from the involvement of the extra-ocular muscles. The ocular findings are sometimes the first indication of the disease involving the breast.2 Ocular manifestations develop in 5–30% of the patients suffering from breast carcinoma. The uveal tissue of the eye has the highest metastatic efficiency index among all tissues in the human body due to its microenvironment and vascular factors, leading to an increased propensity for its involvement.3
Demerci et al. presented a retrospective review of 264 patients having uveal metastasis from breast cancer. They found that uveal metastasis was the initial manifestation of carcinoma of the breast in seven (3%) patients. They also reported that the uvea was the first systemic site to be involved in metastatic disease in 43 (16%) patients with previously diagnosed breast cancer.4
Shields et al. reported on the occurrence of uveal metastases in 520 eyes of 420 consecutive patients. A history of primary cancer was present in 278 (66%) patients, while there was no oncological history in 142 (34%) patients. Out of the 420 patients with uveal metastases, the primary tumour was most commonly localized in the breast and seen in 196 (47%) cases. In the 142 patients among whom ocular malignancy was detected without a previous history of cancer, the second most common primary site was ultimately found in the breast (10 patients, 7%).5
The most accurate method of analysing the incidence of ocular metastasis requires histopathologic studies of the eyes of individuals with autopsy-proven systemic carcinoma. The first such study was reported by Guther et al. However, their study was limited to the posterior segment of the eye. They found four cases of ocular metastases among 853 patients who had died of systemic carcinoma (0.5%).6
Patients with advanced breast carcinoma and metastatic disease have uveal metastases in up to 10% of asymptomatic cases, and 37% of patients dying from complications of breast carcinoma have microscopic uveal metastases. This has raised the question of the role of ophthalmologists in the routine screening of patients with advanced disease. However, at present, routine screening remains controversial, and any future results would be useful in guiding the management of such cases.7
Glaucoma can occur through diverse mechanisms in patients having metastatic breast cancer. However, only a limited number of case reports and studies are available to understand the association between the two conditions. Glaucoma and breast carcinoma are two commonly prevalent and serious conditions affecting the morbidity and mortality of a large group of the population. Therefore, it would be useful clinically, epidemiologically and for resource allocation purposes to assess the extent of association between these two conditions.
Methods
A literature search for the terms ‘breast carcinoma’ and/or ‘glaucoma’ was done on search engines such as PubMed, the Cochrane Library, PLoS One and Google Scholar. Due to the paucity of articles in English, the search was not limited to any language. If required, language translation was done, and the required data were extracted and incorporated into this article.
Discussion
Types of glaucoma
Glaucoma is a potentially blinding diverse group of conditions, characterized by the loss of retinal ganglion cells and optic nerve axons. According to Shields, ‘The term glaucoma should be used only in reference to the entire group of disorders, just as the term cancer is used to refer to another discipline of medicine that encompasses many diverse clinical entities with certain common denominators’.8
Glaucomas have traditionally been classified into primary and secondary types. Primary glaucoma is one in which the apparent abnormality, open- or closed-angle, is limited to the anterior chamber angle with no other contributing factors. Secondary glaucomas are those which have some specific aetiology to account for their occurrence.8
Secondary glaucomas can occur from diverse causes such as trauma, lens-induced or drug-induced inflammation following surgery, elevated episcleral venous pressure and exudative retinal detachment. Several malignancies are directly or indirectly associated with secondary glaucomas. The primary cancers of the eye, such as primary uveal melanomas and retinoblastoma, orbital tumours with raised episcleral venous pressure and carcinomas arising from distant metastasis, can lead to raised intraocular pressure (IOP) and secondary glaucoma. Among the malignancies with metastasis to the eye, and associated with glaucoma, the most common causes are breast and lung carcinomas.2
Breast carcinoma
Breast carcinomas can metastasize to the ciliary body and iris. Studies have found that the most common cause of metastases to the ocular structures is breast carcinoma.3,5,9–12 The primary tumour in up to 80–90% of all female patients is breast carcinoma.10 Although metastases to the ciliary body account for only 2% of the total uveal metastases, they are occasionally difficult to identify as they may masquerade as chronic uveitis or secondary glaucoma by invading the iris root and trabecular meshwork. Metastatic tumours infiltrating the peripheral iris or trabecular meshwork may also produce a similar clinical picture. Mass effects of the tumours can cause shallowing of the anterior chamber, mimicking acute angle closure glaucoma.13 Occasionally, the metastases are diagnosed after postmortem studies.14
Association of breast carcinoma and glaucoma
The exact prevalence of breast carcinoma and associated glaucoma is not known. A presentation by Barte et al. at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting in 2012 has shown that females with a history of breast cancer were approximately three times more likely to have a diagnosis of primary open-angle glaucoma (POAG) compared with females without a history of breast cancer (odds ratio 2.71, 95% CI [confidence interval] 1.07–6.87). In their study, among female patients diagnosed with POAG, 14% (n=18/130) had a history of breast cancer compared with only 5% (n=7/138) of females in the control group (p<0.05).15 Patients with invasive breast carcinoma may have ocular metastases in 5–30% of the cases, which may rarely cause elevated IOP.16
In a study conducted by Jung et al., based on the Korean National Health Insurance Database, the risk of cancer among patients with glaucoma was analysed. Among 52,915 responders, 2,220 females had cancer, out of which 278 had breast cancer. In these patients with breast cancer, 324 eyes had glaucoma. The researchers reported the hazard ratio (95% CI) ranging from 1.167 (0.995–1.37) to 1.169 (0.996–1.372), depending on the hazard model. The study concluded that individuals with glaucoma have a higher risk of overall cancer and a higher risk of specific cancers than those without glaucoma.17
A postmortem study of 230 patients with autopsy-proven cancer by Bloch et al. found 28 (12%) cases having metastatic foci in ocular tissues. In the study, the most common metastatic tumour to the eye was breast carcinoma. Over one-third of the 52 patients with breast cancer had ocular metastases. The most common site of the metastases was the choroid, but multiple sites of implantation were often present. Since most patients with cancer are too sick to be seen by ophthalmologists, they ignore their eye symptoms or rarely have postmortem examination of their eyes; hence, it is not possible to get accurate rates of incidence of ocular involvement from breast cancer metastases.11
In a study by Ferry and Font, out of 219 cases of carcinoma metastatic to the eye, the primary site accounting for the most cases was the breast (40%). Out of these, 12 (5.5%) respondents had secondary glaucoma.18 In a follow-up study, the same authors reviewed a series of 227 patients with metastatic carcinoma of the eye. They reported that breast carcinoma was the second most primary cause (9 out of 26 patients) of anterior segment involvement. In that study, while decreased vision was the most common symptom (80% of patients), 56% of patients were diagnosed with glaucoma. Both open and closed mechanisms of glaucoma were found in the autopsy studies. In open-angle types, the trabecular meshwork was covered with sheet-like plaques of tumour cells, producing what the authors called a ‘malignant epithelialization’ of the anterior chamber angle. Another clinic-pathologic finding in some patients was the infiltration of the trabecular meshwork and emissary vessels with neoplastic cells, producing open-angle glaucoma. The mechanism of the closed-angle type of glaucoma was the occlusion of the chamber angle by lobules of the tumour breaking through the limits of the uvea into the angle or by the development of peripheral anterior synechiae.19
A retrospective, case–control study by Lin et al. used the Taiwan National Health Insurance Research Database to study the association of POAG with systemic comorbidities. The study group had 76,673 patients with POAG, while 2,30,019 subjects comprised the control group. Among patients with glaucoma, 230 (0.3%) patients had metastatic cancers, excluding lymphomas. Conversely, 690 (0.3%) individuals had metastatic cancers in the comparison group. The p-value was insignificant (0.212). This study showed no difference between patients with and without POAG in the rates of metastatic cancer.20
There have been a few case reports showing an association between glaucoma and breast cancer. A case report by Senthilkumar et al. showed the occurrence of iris metastasis from breast cancer, leading to unilateral neovascular glaucoma.21 Mejía-Novelo et al., in their analysis of 16 patients with ocular metastases from breast cancer, reported one patient with glaucoma.22 Swampillai et al. reported a 54-year-old patient who complained of seeing a dark patch in the peripheral field of the right eye and flashes of light in the left eye. She had received treatment for invasive ductal breast carcinoma 4 years back with a diagnosis of systemic metastases 1 month before the development of the ocular problems. Tonometry showed the IOP to be 65 mmHg in the right eye and 35 mmHg in the left eye. On examination, she was found to have a large posterior iris lesion in the right eye and a localized ciliary body mass causing anterior displacement of the iris in the left eye. She underwent cyclo-diode treatment in the right eye and external beam radiotherapy in both eyes. Subsequently, the IOP came down to 8 mmHg.2
Osorio-Cabarcas et al. reported a 60-year-old female patient who had recurrent unilateral anterior uveitis on initial presentation. After a few months, segmental iris atrophy in the affected eye was noted. Subsequently, she was diagnosed with invasive ductal breast carcinoma without systemic metastasis. Later, she developed neovascular glaucoma in one eye and underwent glaucoma-filtering surgery. The recurrent uveitis and glaucoma were suspected to be secondary to paraneoplastic syndrome associated with breast carcinoma.23 Paraneoplastic effects are remote effects that occur not from metastases but are immunological responses against tumour antigens expressed by normal cells.13
In a case report published by Vale et al., a 72-year-old female presented with uniocular pain and visual loss. She was diagnosed with neovascular glaucoma secondary to iris metastasis from unilateral breast carcinoma. Within a week after a single intravitreal injection of bevacizumab, iris neovascularization was resolved, IOP was reduced and ocular pain was relieved.24 A similar case of a 47-year-old patient having metastatic breast cancer and presenting with pain, uniocular visual loss and multiple iris nodules was reported by Seidman et al. The patient was diagnosed with neovascular glaucoma and responded to three monthly intravitreal injections of bevacizumab.25
An unusual case of a patient with breast carcinoma developing POAG following taxane chemotherapy was reported from France. The patient developed open-angle glaucoma apparently from fluid retention induced by the chemotherapeutic agent. The IOP went as high as 44 mmHg every time the patient was given that agent, forcing the physicians to avoid using taxanes for chemotherapy in that patient.26 Another case reported by Özcura et al. involved a 50-year-old female who was diagnosed with unilateral non-metastatic breast cancer and was started on tamoxifen therapy. It was a known case of POAG, where she had undergone trabeculectomy in one eye and her IOP was controlled with timolol and dorzolamide eyedrops in both eyes. One year after starting tamoxifen therapy, she was found to have elevated IOP in both eyes. The IOP returned to normal after stopping tamoxifen.27
Male breast cancer (MBC) accounts for less than 1% of the total neoplastic cases occurring in that sex. Among all breast cancer cases, MBC forms only 1% of the cases.3 Ocular metastases from MBC are infrequently reported.28–33 This is attributed to the low prevalence of the disease. However, once MBC occurs, the course is more aggressive than in females, and mortality occurs within a few months of diagnosis.31 Our literature search found only one case of MBC with elevated IOP.33 Teodoru et al. reported a 65-year-old male who was diagnosed with stage-IV breast cancer previously. He presented with orbital metastases. He had proptosis, and the IOP was elevated to 40 mmHg. After starting him on maximal antiglaucoma medications, the IOP returned to normal levels after 3 weeks of treatment.
Treatment of glaucoma in patients with breast carcinoma
Treatment of glaucoma is currently limited to the control of IOP. The options for that include pharmacological treatment and laser or surgical techniques. Patients with glaucoma secondary to systemic metastasis present a clinical challenge due to the often refractory nature of glaucoma, the priority of systemic treatment and the side effects of systemic therapies that can aggravate or cause increased IOP. Pharmacological treatment of IOP is unpredictable, and the options are limited due to the relative contra-indications for prostaglandin analogues and pilocarpine. Prostaglandin analogues increase the non-conventional uveoscleral outflow, while pilocarpine increases conventional trabecular outflow, which can cause further systemic metastasis of the malignancy. Filtration surgery also has a potential for orbital spread. Moreover, the bleb and drainage device tubes can get blocked from the tumour deposits. Therefore, ciliary body destructive surgery is a better option to reduce IOP in a controlled manner.2
It is also important to undertake local management of the metastatic eye disease. Unless the ocular metastases are not treated, it would be difficult for the ophthalmologist to control glaucoma. The options for local management of the metastases include external beam radiation, proton beam radiotherapy, systemic chemotherapy and hormonal therapy, transpupillary thermotherapy, photodynamic therapy and, finally, enucleation of the eye, which might be required for patients with intolerable pain from secondary glaucoma.3 In cases of neovascular glaucoma, there are reports of effective response to anti-vascular endothelial growth factor injections.3,24,25
An important aspect of the pharmacological treatment of glaucoma is compliance with the prescribed regimen. However, a study investigating medication adherence by patients with glaucoma who also suffered from carcinoma reported lower compliance with the treatment protocol after the detection of carcinoma. In the study, the medication possession ratio (MPR) measured using 1-year intervals decreased by 17.4% after cancer diagnosis (p<0.001). MPR measured using 2-year and 2-year-average intervals decreased by 10.4% (p<0.001) and 9.21% (p<0.001), respectively.34
Limitations
The limitation of this article is the absence of a significant number of studies involving a large patient database, despite the common occurrence of breast cancer and glaucoma in the general population.
Conclusion
In conclusion, patients presenting with unusual forms of glaucoma should be evaluated for the possibility of malignancies, especially breast carcinoma in female patients. Occasionally, ocular features can be a presenting feature of the systemic disease. Although the studies so far point to the rarity of the association between glaucoma and breast carcinoma, such a combination can have devastating consequences for the patients. With the increasing reports of MBC, the association with glaucoma should not be overlooked in male patients as well. Therefore, an effort should be made to rule out breast carcinoma in all suspicious cases as it is the most common type of malignancy associated with secondary glaucomas.
