Orbital Metastases: Comparison
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Orbital metastases may significantly worsen the functional status of oncological patients, leading to debilitating visual impairments. Surgical resection, orbital exenteration, and complementary therapies may result in heterogeneous clinical outcomes. Most orbital metastases occur at later stages after primary tumors, frequently showing diffuse location within the orbit and rarely invading intracranial structures. Biopsy-only techniques were more frequently preferred in view of the less invasive approaches, but surgical resection and orbital radiotherapy were related to improved clinical outcomes. Although patients with primary breast cancer and patients undergoing resection showed superior prognoses, overall survival rates were generally poor, suggesting the need to better understand orbital metastases’ microenvironments for devising optimal systemic treatment strategies.

  • orbital exenteration
  • orbital metastases
  • radiation oncology
  • skull base oncology

1. Introduction

Orbital metastases represent 1–13% of all orbital neoplasms and affect approximately 2–5% of patients with systemic malignancies [1,2,3][1][2][3]. Breast, melanoma, and prostate cancers comprise the prevalent primary tumors, and their incidence is increasing due to improved surveillance, systemic disease control and management of oncological patients [3,4,5][3][4][5]. Orbital metastases can often be detected in those with no previous history of cancer due to their common presenting of symptoms of visual disturbance, thus preceding the diagnosis of primary tumors [4,6][4][6]. Common presenting symptoms include diplopia, ocular pain, and vision loss, coupled with globe displacement and palpable orbital masses [7,8][7][8]. Metastases frequently appear on imaging as irregular and contrast-enhancing lesions in the anterior orbit involving bones and extraocular muscles [8,9,10][8][9][10].
Treatment strategies depend on the clinical presentation and primary tumor pathology; however, a gold standard for treatment has yet to be defined [3,11][3][11]. In poor surgical candidates, orbital irradiation can be utilized to facilitate reduction in tumor volume and symptom relief [12]. Surgical debulking is effective in decreasing mass-effect and improving symptoms but can also lead to serious complications such as permanent visual deficits [13]. Chemotherapy, hormonal therapy, and/or targeted therapy have the benefit of simultaneous control of primary and metastatic lesions [7,9][7][9].
There is a limited number of individual studies on orbital metastases, and feasible therapeutic options are still debated [14,15][14][15].

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][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][16][17][18][19]. 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][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][3][20][21][22][23][24]. 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][6][25][26].

As opposed to benign orbital tumors, orbital metastases frequently manifest clinically with an abrupt onset of rapidly progressive symptoms [1,32][1][27]. 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][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][28][29]. 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][30][31][32]. 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][7][33].

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][34][35]. 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][7][36].

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][6][37]. 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][14][34][38]. 

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][39][40]. 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][41][42]. 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][3][4][34].

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][11][12][27][43][44][45]. 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][17][46]. Although some cases of radiation-induced cataracts have been reported in earlier studies [55][47], modern image-guided radiotherapy planning allows the delivery of maximal doses to selected targets [56[48][49],57], sparing critical orbital structures and preventing the onset of severe adverse events [55,58,59,60][47][50][51][52]. 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][46][53]. 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][54][55]. 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][56][57].

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][17][58][59][60].

3. Conclusions

Orbital metastases are rare, debilitating lesions in oncological patients. Histopathological examination is recommended to guide complementary therapeutic protocols, but surgery is often challenging. Tumor resection, regardless of its extent, showed improved clinical and survival outcomes over biopsy, but the impact of underlying clinical and tumor characteristics should be still considered on a case-by-case basis before planning surgical strategies. Orbital exenteration appears less useful when used in addition to complete tumor resection because no survival benefit was found. Furthermore, the positive clinical impact of orbital radiotherapy may favor its implementation in patients not eligible to undergo surgery or who underwent a subtotal resection. Future prospective studies are required to better understand the role of multimodal systemic therapeutic strategies in the management of orbital metastases based on primary tumor histopathology.

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