1. Introduction

2. Orbital Metastases

Surgical tumor resection significantly increased symptom relief and survival compared to biopsy-only. While orbital radiotherapy may effectively prevent tumor progression in the long term, the role of advanced systemic therapies requires further evaluation.

Although some differences in primary tumors have been reported between studies, probably mirroring the underlying geographic variations of cancer rates, breast cancer (36.3%), melanoma (10.1%) and prostate cancer (8.5%) were the most frequent [3,4,5]. Similar prevalence rates have been reported for patients with uveal metastases, likely suggesting common routes of tumoral hematogenous spread and organotrophic seeding to both ocular and orbital structures [21,22,23,24]. The true incidence of orbital metastases from primary tumors may be difficult to ascertain only from clinical series of patients with histopathology reports, paving the way to a detection bias in the data collection for this paper. Cancers with more aggressive disease courses may rapidly metastasize to multiple major organs besides the orbit, severely debilitating patient functional status and thus making histological confirmation of suspected orbital metastases unnecessary. This likely explains the lower rates of primary lung cancers (5.6%) compared to other tumors such as carcinoid (6.6%). Indeed, carcinoids are less common malignancies, but they often show better prognoses and slower disease courses, with rare concurrent systemic metastases [5,8]. The median time interval between primary tumor diagnosis and the onset of orbital metastases was 12 months, further reflecting the long-lasting process of metastatic seeding into the orbit. In line with the literature on patients with choroidal metastases, the detection of orbital lesions preceded the primary tumor diagnosis in 30.1% of patients, with 37 cases of CUPs (4.2%). CUPs represent metastatic carcinomas with no primary neoplasms identified at diagnostic workup and mostly deriving from older case series [3,25,26,27,28,29]. More recently, upfront whole-body PET/CT scans are frequently recommended in patients with no history of cancer and clinical suspicion of orbital or intraocular metastases to expedite management and systemic treatments [6,30,31].

As opposed to benign orbital tumors, orbital metastases frequently manifest clinically with an abrupt onset of rapidly progressive symptoms [1,32]. Most metastases occurred unilaterally and diffusely infiltrated intra/extraconal orbital soft tissues, causing globe displacement with proptosis, diplopia and impaired eye motility [3,4,5]. The direct compression of the optic nerve, commonly at the orbital apex, additionally led to RAPD and vision decline, with a serious impact on patients’ functional status [33,34]. Less frequently, paradoxical enophthalmos of the affected eye resulted from the infiltration of neoplastic cells into the extraocular muscles and retro-bulbar stromal tissues causing desmoplasia, fibrosis and globe retraction [35,36,37]. Some ocular symptoms, such as visual impairments and periocular pain, may share similarities between orbital and choroidal metastases, thus requiring further assessment with orbital imaging [7,38].

This is especially the case in patients with no evident orbital or ocular masses. Some primary cancers tend to infiltrate specific orbital tissues, such as breast cancers localizing within the orbital fat pad due to the local hormonal patterns, and melanomas invading and enlarging the extraocular muscles as seen clearly on MRI scans [39,40]. Similarly, prostate and liver cancers commonly infiltrate the orbital bony structures inducing osteoblastic or osteoclastic reactions, and this is better identified on CT scans [7,41].

Both incisional and fine-needle aspiration biopsy showed no benefits in clinical and survival outcomes but were chosen over tumor resection in most patients. On par with choroidal metastases, biopsy of suspected orbital metastases is often required for differential diagnosis in patients with no cancer history or for histomolecular characterization when biopsy of other metastatic sites is less viable [6,42]. When surgery is not deemed feasible, biopsy represents a safe alternative advantageous to initiate systemic therapy; however, tumor resection should be preferred in eligible patients. Indeed, tumor debulking, regardless of the extent-of-resection, led to significant clinical (p = 0.005), radiological (p = 0.007), and survival (p = 0.004) improvement when compared to biopsy. The mechanism for this result may likely be the prompt decompression with relief of mass effect and decrease in tumor burden with increased effectiveness of complementary therapies [14,39,43]. 

Regarding orbital exenteration, there is no survival benefit compared to patients undergoing orbital-preserving complete tumor resection (p = 0.153). Such a finding substantiates once again that survival is more likely affected by systemic disease control than metastasis-directed local therapy. Orbital exenteration is often considered for treating aggressive craniofacial malignancies with orbital infiltration and perineural invasion, effectively reducing rates of local recurrences and re-operations [44,45]. In orbital metastases, the limited benefit of orbital exenteration is likely due to the underlying systemic spreading of tumor cells and related poor prognoses [46,47]. Hence, orbital exenteration may be unnecessary for treating orbital metastases in patients with systemic malignancies, and thus surgery should be intended to preserve acceptable quality of life while avoiding highly disfiguring procedures. However, orbital exenteration may play a role in providing relief of severe orbital pain in patients with already poor or absent pre-operative vision function [3,4,39].

In some cases, orbital metastases may extend intracranially into the anterior and middle cranial fossa, similarly to other craniofacial malignancies such as nasopharyngeal carcinomas. Still, a more in-depth evaluation of specific tumor microenvironments is highly encouraged to identify favorable therapeutic targets and support less-invasive treatment strategies specifically for patients with cranio-orbital metastases.

Radiotherapy is a well-established palliative therapeutic option for benign and malignant orbital lesions, as well as for periocular ones [11,12,32,51,52,53]. In line with previous reports on choroidal metastases, radiotherapy significantly ameliorates clinical and functional status in patients with orbital metastases (p = 0.032), favoring nonsurgical lesion shrinkage and relief of mass effect [22,54]. Although some cases of radiation-induced cataracts have been reported in earlier studies [55], modern image-guided radiotherapy planning allows the delivery of maximal doses to selected targets [56,57], sparing critical orbital structures and preventing the onset of severe adverse events [55,58,59,60]. Thus, radiotherapy appears to be safe and effective in the treatment of orbital metastases similarly to choroidal metastases, but the severity of radiation-induced complications might differ due to the unfortunate proximity of choroidal metastases to the macula and lens [54,61]. The usefulness of particle therapy, a type of radiotherapy characterized by a peculiarly beneficial dose distribution to the target (Bragg peak), to maximize the sparing of critical ocular structures with respect to the photon-based radiotherapy needs to be further investigated to evaluate its cost effectiveness [62,63]. However, particle therapy has not a widespread distribution, and classic radiotherapy could be more easily accessible. In such critical anatomical sites, safely delivering a high ablative dose in those tumor layers more distantly located from organs at risk while gradually underdosing the successive ones might have a radiobiological rationale in addition to a potentially successful effect. This approach with partial tumor irradiation or with spatially fractionation of the radiation dose is just a hypothesis because it has been effectively tested only for treatment of bulky tumors at different body sites from those examined here [64,65].

The prognosis of patients with orbital metastases is poor with one-year survival rates, (40%) lower than patients with choroidal metastases (52%) and comparable to patients with brain metastases (39–46%), implying that their occurrence is more frequent at the very advanced disease stages, which call for an effective improvement in current systemic therapeutic strategies [22,50,70,71].

This entry is adapted from the peer-reviewed paper 10.3390/cancers14010094