Ocular involvement in metastatic and systemic malignancies is not rare

Abstract Background Metastatic disease to the eye most commonly involves choroid followed by orbit leading to varied ocular manifestations. By comparison, it is relatively rarer than primary malignancies of eye as well as metastasis in other parts of the body. Aim The aim of this study is to evaluate the common eye and orbital structures involved in secondary ocular and metastatic disease, to describe its clinical manifestations and outline the management done. Methods A retrospective study of newly diagnosed cases of ocular metastasis in last 2 years conducted in our recently established department of ocular oncology at a tertiary eye care hospital in Nepal. Demography, age and sex distribution were noted. The patients were segregated into those with secondary or metastatic ocular malignancies. Detail study on the metastatic disease to eye was made in regards to presenting symptoms, signs, primary site of cancer, and the treatment done. Details of the investigations done, like biopsy and imaging were also recorded. Results There were a total of 28 patients, whose age group ranged from 9 years to 69 years with median age of 43 years. Females constituted 46% of total patients. Both the eyes were involved in 9 patients (32%). Eye was secondarily involved by paranasal sinus tumors and Non Hodgkin lymphoma (7 patients each). Ocular metastasis was commonly seen from broncogenic carcinoma in four and breast carcinoma in three patients. Simultaneous metastasis to other parts of the body was also seen in 61% of our patients. Diminution of vision in 49% was the most common presenting feature followed by proptosis in 16% and palpable mass in 14% of patients. Orbit in 43% cases is the commonest ocular structure involved. Histopathologic diagnosis was done in 32% only while rest was based on imaging alone. The most common treatment done was chemotherapy in 57% patients. Conclusion Ocular metastasis can display a wide variety of clinical and imaging features and therefore a high degree of suspicion is required. It is often associated with simultaneous metastasis to other parts of the body as well, hence the importance of earlier diagnosis and metastatic workup.


| INTRODUCTION
Secondary ocular malignancies are not uncommon. Ocular malignancy is the least discussed topic in oncology forum; much less is reported in oncology journals. However the scenario is more griever that it appears. Ocular oncologists and other ophthalmologists frequently encounter lesions suspicious of eye cancer; most are primary malignancies arising from different parts of eye and orbit within the age group ranging from neonates to old age. In children retinoblastoma is common primary malignancy and in adults, squamous cell carcinoma of conjunctiva, melanoma, and adenocarcinomas are common. However secondary malignancies from adjacent structures like paranasal sinuses, infiltration from systemic cancers like leukemia, and even distant metastasis from other parts of the body are also frequently encountered by ocular oncologist.
Metastatic disease to the eye most commonly involves the choroid followed by orbit. 1 By comparison, it is relatively uncommon accounting for less than 5% 2 of all orbital tumors and occurring in about 7% of all cancers of body. 3 The common primary sites in adults being lung in males and breast in females and they account for 50% of all orbital metastases. 4 In approximately 20% of patients however, orbital metastasis is the initial manifestation of systemic malignancy. 5 Therefore, ocular manifestation of systemic malignancies should be known to both medical oncologist as well as ophthalmologist.
However, due to infrequent nature of carcinomas metastatic to orbit, most articles are in the form of case report rather than research papers. Our objective is to evaluate and describe the clinical manifestations and its management of secondary as well as metastatic carcinomas invading the eye and orbital structures.

| Methodology
This is a retrospective, noncomparative, and descriptive study conducted from October 2017 to September 2019 in the department of ocular oncology at a tertiary care eye hospital in Nepal. Institutional review board approval has been obtained. The data was collected from our comprehensive electronic medical record files. Clinical photographs, fundus photographs, and imaging films were collected where indicated, after obtaining a written informed consent from the patients.
Demographic data recorded included age, gender, race, laterality, and eye involved. The presenting ocular symptoms and positive finding on detail examination of eye was recorded. Best corrected visual acuity at presentation was noted. History of presenting illness if known like, malignancy elsewhere in body was noted. Intraocular distribution of metastatic tumors was also studied. All the patients were also seen by a medical oncologist. Diagnosis and investigations obtained from their records as well. The patients were segregated into those with primary malignancy, invasion from adjacent structures outside orbit, infiltration from systemic cancers, and ocular metastasis from distant tumors. Primary ocular malignancies were excluded and the rest were included in the study. Diagnosis was based on histopathology wherever possible; if not it was made from detailed ocular examination and imaging like CT scan and MRI. If the patient was a known case of carcinoma elsewhere, it was taken as a distant metastasis based on imaging alone.
The clinical data were recorded and analyzed with regards to common age group affected by secondary tumors; it is presenting clinical features, anatomic site of eye involved, vision affected, and common primary malignancy secondarily affecting the eye. Treatment done in the form of medical, surgical or both was also recorded.

| RESULTS
A total of 28 patients with secondary ocular malignancy were enrolled in the study. Their age group ranged from 9 years to 69 years with mean age of 42.6 years mode of 50 years median age being 43 years. Females constituted 46% of patients and rest of 54% were males. Both the eyes were involved in nine patients (32%), rest had unilateral involvement.
Diminution of vision in 13 patients (49%) was the most common presenting feature. Four patients (11%) had NPL (no perception of light which is equivalent to complete loss of vision) while it was less than 3/60 in 14 patients (38%) as shown in Table 1 Tables 3 and 4.
On further investigation, 17 of our patients (61%) also had simultaneous metastasis to other sites like brain in nine patients, liver in four, lungs in two, spine in one, and pananasal sinus in one patient.

F I G U R E 3 Ocular structures involved in secondary tumors
Choroid is followed by orbit as the next common site of metastatic cancers. Various studies reports 1-13% of metastasis occurring in orbit. [9][10][11][12][13][14][15] Researches also show that these lesions account for about 1% to 13% of all orbital tumors. [16][17][18][19] In our study due to inclusion of both secondary and metastatic cancers, orbit is found to be the commonest site in 43%, followed by choroid in 39%. Other rare sites are conjunctiva and eyelid.  There was a slight male preponderance (54%) in our study as well as in other studies. [20][21][22] However, Shields et al in their two studies of orbital and choroidal metastasis had 64% female patients, where they mention that breast cancer, which is the commonest primary site for choroidal metastasis is more common in females and therefore more females presenting with metastasis. 5,23 Breast carcinoma as the most common source of ocular metastasis ranging from 29% to 53% of cases in various studies. 5,6,8,22,[24][25][26][27][28] It was followed by lungs in around 8% cases while it was the commonest cause in 21% cases in a study done by Shields et al. 8,21,[25][26][27] In our study also lung carcinoma was the commonest tumor metastasizing the eye (in 14%) which was followed by breast carcinoma (in 11%).
However in our study due to inclusion of all types of secondary carcinomas including local invasion and hamatogenic malignancies, Non-Hodgkin lymphoma, and local orbital invasion from sinonasal carcinoma (25% each) were the commonest type of primary malignancies secondarily invading ocular structures. A similar study done by Yan et al from China also reported nasopharangeal carcinoma as the commonest primary tumor invading ocular structures (in 30% cases). 21 Other primary sites mentioned in various studies were gastrointestinal carcinomas, liver, renal cell carcinoma, prostrate carcinoma, and skin melanoma. 5,8,22,23,25,26 It is generally thought believed that metastatic tumors which is spread by hamatogenic route should involve bilateral eyes, but to out assurance, it is not the case. In our study, only 32% had bilateral disease while various studies reports 0%.4%,5%, and 18% only. 5,20,21,23 However, ocular metastasis usually signifies increased morbidity and mortality among the patients because it is frequently associated with simultaneous metastasis to other organs as well. In our study, 61% of patients had metastasis to other sites as well, the most common one being brain followed by liver and lungs. Arepalli

ACKNOWLEDGEMENT
The authors would like to thank the medical and radiation onclologists for referring the their patients to us and managing our patients as well.

CONFLICT OF INTEREST
The authors have no conflict of interest.

AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsi- Supervision, R.S.; Funding Acquisition, R.S.

ETHICAL STATEMENT
Approval was obtained for this retrospective study from the Institutional Review Board of Tilganga Institute of Ophthalmology, Kathmandu, Nepal.

INFORMED CONSENT
Written informed consent was obtained from the patients for photographs and imaging documentations.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.