Inflammatory Presentation of Orbital Metastasis Years after Bilateral Mastectomy for Breast Cancer: A Case Report and Literature Review.

Introduction
Orbital metastases from primary breast carcinoma are a rare but clinically significant aspect of ophthalmic oncology. While orbital metastases may account for only 1.5–3.3% of all orbital pathologies [1], orbital metastases may comprise 1.5–14.7% of all orbital tumors [2–4]. On computed tomography (CT), orbital metastases typically appear as a well-defined, contrast-enhancing mass affecting bones or musculature [5, 6]. Symptoms are often due to displacement of the globe or effects on extraocular muscles [1, 4]. Breast cancer comprises nearly half of orbital metastases, and is classically seen as an orbital mass on neuroimaging [1, 7]. Inflammatory presentations, occurring in approximately 4% of cases of orbital metastases from breast carcinoma, are notably rare and frequently misdiagnosed [1].
This report details a case of inflammatory orbital metastasis with no identifiable orbital mass from breast carcinoma in remission, occurring years after prior treatment with bilateral mastectomy and adjuvant therapy. This report is complemented by a review of available cases in the literature [8–13]. This report was conducted in accordance with the Health Insurance Portability and Accountability Act and in adherence to the Declaration of Helsinki. Consent was obtained from the patient. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550031).

Case Presentation
A 51-year-old African-American female reported 1 month of right upper and lower eyelid swelling. The patient had a medical history significant for invasive ductal carcinoma of the left breast treated initially with chemotherapy 3 years prior to the current presentation followed by ductal carcinoma in situ of the right breast treated with chemotherapy, double mastectomy, and radiation 2 years prior to the current presentation, with no history of metastasis, and regular monitoring via laboratory workup and imaging showing no disease recurrence.
Ophthalmic examination revealed visual acuity of 20/20 in each eye. Intraocular pressures were 18 mm Hg on the right and 17 mm Hg on the left. Pupils were equal and reactive without relative afferent pupillary defects, and extraocular motility was full. The external exam was remarkable for bilateral symmetric anatomic exophthalmos, right soft periorbital swelling causing pseudoptosis with compensatory left upper eyelid pseudo-retraction and bilateral lower eyelid retraction in the setting of a negative orbitomalar vector. Right-sided chemosis was noted in the slit lamp exam. There was no intraocular inflammation, and the fundus exam was within normal limits.
The patient’s symptoms and exam were suggestive of an orbital process, and additional evaluation was pursued. Laboratory studies were notable for an elevated erythrocyte sedimentation rate of 38 (normal <30 mm/h) and low angiotensin-converting enzyme of 4 (normal 8–52 U/L), and were negative for infectious causes or autoimmune disorders like thyroid eye disease and granulomatosis with polyangiitis. CT scan of the orbits (shown in Fig. 1a, b) demonstrated right-sided findings of periorbital and maxillary soft tissue swelling, intraorbital fat stranding, and enlargement of the extraocular muscles, most notably the lateral rectus muscle belly. Magnetic resonance imaging (MRI) (shown in Fig. 1c, d) showed significant orbital fat stranding and enlargement of the extraocular muscles in the right orbit. Neither the CT nor the MRI showed a mass lesion.
Given the initial clinical appearance of orbital inflammation with negative infectious testing, the patient began systemic steroid therapy at 1 mg/kg/day (which translated to 100 milligrams daily) with moderate improvement in symptoms and exam at higher doses of corticosteroids (but unable to taper below 40 milligrams daily). When neuroimaging showed marked inflammation without an obvious mass, this, coupled with improvement on systemic steroids, led to the choice to continue with steroids and not undergo early biopsy of the abnormal tissues. Despite a slow taper over 4 months, the patient was unable to tolerate tapering the steroids below 20 milligrams daily, at which point she felt the steroids were no longer helping, and she ceased taking them. Follow-up evaluation 1 month later revealed worsening of the right-sided periorbital swelling and orbital changes on CT (shown in Fig. 2a, b). The patient, therefore, underwent a biopsy of the right orbital tissues that appeared most atypical (orbital fat and the lateral rectus muscle), which revealed metastatic breast carcinoma. Figure 3 displays the patient’s external presentation initially, post-steroid treatment, and at the time of biopsy.
The patient was referred to oncology and was started on systemic chemotherapy with ribociclib, a CDK4/6 inhibitor, and fulvestrant, an estrogen receptor antagonist. She has also undergone orbital radiotherapy and has responded with dramatic improvement in her orbital disease.

Discussion
This report describes a rare case of a purely inflammatory presentation of a metastatic orbital tumor originating from a primary breast carcinoma 2 years into disease remission. A review of the published literature specifically focused on inflammatory presentations of orbital metastasis from breast carcinoma without an accompanying mass yielded six case reports over the last 43 years (shown in Table 1) [8–13].
Most commonly, breast carcinoma metastasis in the orbit presents as a mass with symptoms due to mass effect and displacement of the globe [1, 4]. A mere 4% of patients with breast carcinoma metastatic to the orbit will present with a strictly inflammatory picture, which typically includes ocular pain, chemosis, injection, pain in eye movement, erythema, and eyelid swelling in the absence of an identifiable mass [1]. Among the published patients with an inflammatory presentation, and including our patient, clinical manifestations included eyelid swelling (5/7), pain (3/7), diplopia (3/7), proptosis (2/7), and ptosis (2/7) [8–13]. Unfortunately, the broad range of signs and symptoms of metastatic orbital disease overlaps with numerous other common orbital pathologies, including thyroid eye disease, idiopathic orbital inflammation or orbital myositis, granulomatosis with polyangiitis, bacterial cellulitis, and endophthalmitis [1]. Thus, even though an inflammatory presentation of metastatic orbital disease may be accepted knowledge for orbit specialists, evaluation of these patients must include a thorough history, possible laboratory studies, and neuroimaging.
Neuroimaging can often be diagnostic for metastatic breast cancer when a classic history and orbital mass are observed. Unfortunately, neuroimaging can also cloud the picture with findings that mimic non-oncologic disease processes, particularly in the absence of an identifiable mass, and patients may be initially misdiagnosed. In inflammatory presentations of metastatic orbital disease, CT and MRI may show thickening of the extraocular muscle(s) and fat stranding, and this may lead providers to inadvertently prioritize autoimmune inflammatory disease over other possible diagnoses [4]. Furthermore, most breast carcinoma orbital metastases present as visible masses on imaging [1], leading physicians to possibly overlook metastasis in their absence. Imaging of metastatic breast carcinoma typically shows discrete masses that are isodense to muscle on non-contrast CT scans, with slight enhancement on contrast administration [1, 14], and MRI findings show discrete lesions appearing hypointense to fat on T1-weighted images and hyperintense on T2-weighted images [14, 15]. Among seven cases, including our patient, all showed some level of inflammation and generalized enhancement of the extraocular muscles and/or the surrounding orbital tissue, without a discrete orbital mass [8–13]. The authors suspect the metastatic disease in these cases was purely infiltrative as opposed to forming a focal mass.
In this case, improvement with steroids – “the deception of a corticosteroid trial” – and the absence of a clear mass on imaging led to deferring a biopsy [16]. In addition, it is important to recognize that steroids may also decrease the diagnostic utility of a biopsy in the setting of malignancy (such as primary central nervous system lymphoma) [17]. The authors thus recommend: In cases of inflammatory orbital disease with failure to resolve on expected therapy, and certainly in patients with a history of malignancy, healthcare providers should have a low threshold for early biopsy of the involved orbital tissue. Biopsy is crucial for definitive diagnosis, particularly in inflammatory presentations where imaging can be non-specific. If steroids were used, these should ideally be stopped several weeks before biopsy [16]. Tissue biopsies in 7 patients, including our patient, confirmed metastatic breast carcinoma [8–13]. While most patients are diagnosed with breast cancer 3–5 years prior to presentation of the orbital metastasis [4, 14, 18–20], it has been estimated that in 26% of cases of breast carcinoma with metastasis to the orbit, the orbital lesion precedes the diagnosis of the primary breast cancer [1, 14]. Therefore, an inflammatory presentation can easily be misdiagnosed and may delay the discovery of the underlying cancer [1, 14]. Among the patients reviewed herein, two did not have a prior diagnosis of primary breast carcinoma [8–13]. Among the 5 patients with prior primary breast carcinoma diagnoses, the mean time to orbital metastasis diagnosis was 4.4 years after primary breast carcinoma diagnosis [8–10, 13]. While our patient experienced a shorter time from primary breast cancer diagnosis and treatment to orbital metastasis, years of tumor-free survival after diagnosis and treatment of the primary breast cancer should not lull the ophthalmologist into a false sense of security; rather, any patient with a history of breast cancer presenting with orbital pathology should prompt a high suspicion for metastatic disease.
In summary, this report details a case of inflammatory presentation of metastatic breast carcinoma to the orbit without an identifiable orbital mass occurring 2 years into remission after bilateral mastectomy, along with findings from a literature review of similar cases. This inflammatory type of presentation is uncommon among metastatic orbital tumors and is susceptible to being misdiagnosed. It is crucial to keep this diagnosis in mind for patients who present with similar symptoms, especially those with a known history of primary breast carcinoma. However, it should also be considered in patients without any previously identified primary tumor.

Statement of Ethics
This study was performed in accordance with the Declaration of Helsinki. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement
The authors have no conflicts of interest to declare.

Funding Sources
This study was not supported by any sponsor or funder.

Author Contributions
R.A., M.K.W., and D.M. contributed to manuscript writing, editing, and conceptualization. B.A.S. contributed to idea formation, conceptualization, manuscript editing, and supervision.