Necrotic Uveal Melanoma Mimics Orbital Cellulitis: A Review

Uveal melanoma is the most common primary intraocular malignancy, accounting for 85% of intraocular malignancies and affecting 2–8 people per million population [1, 2]. Uveal melanoma develops from uveal melanocytes of neural crest origin, most commonly from the choroid or ciliary body (98%) [1-3]. Patients have varying presentations with blurry vision being the most commonly reported symptom (37.8%), followed by an asymptomatic presentation in 30.2%, photopsia in 8.6%,floaters in 7%, visual field loss in 6.1%, and pain in 2.4% [4].

Orbital inflammation can be a rare manifestation of uveal melanoma. We report a patient with necrotic uveal melanoma presenting with acute painful vision loss, proptosis, and orbital inflammation. In addition, we detail a review of published cases of necrotic uveal melanoma presenting with orbital cellulitis.

A 64-year-old Caucasian male presented to the Emergency Department with a 3-day history of acute vision loss of the right eye with associated periorbital edema, pain radiating to the forehead, and subjective fever and chills. He had no past medical history. On examination, he was afebrile. Visual acuity was no light perception in the right eye and 20/20 in the left eye. A right relative afferent pupillary defect was present. There was mild right-sided proptosis. The intraocular pressure of the right eye was elevated to 88 mm Hg. The right upper and lower eyelids were tender to palpation, edematous, and erythematous (shown in Fig. 1a). Anterior segment examination demonstrated diffuse severe conjunctival chemosis and a total hyphema obscuring visualization of the posterior segment (shown in Fig. 1b, c). B-scan ultrasonography demonstrated vitreous hemorrhage but no retinal detachment or visible mass. The left eye was unremarkable. MRI of the orbits demonstrated proptosis and diffuse orbital inflammation; however, there was no evidence of sinusitis, foreign body, or abscess. There was enhancement of an intraocular lesion in the right eye (shown in Fig. 2). Though the imaging was suspicious for malignancy, an intraocular tumor could not be definitively distinguished from intravitreal hemorrhage. There was no improvement in symptoms despite intravenous vancomycin and ceftriaxone. Laboratory testing, including a complete blood count, coagulation panel, hypercoagulability panel, and sickle cell screen, was all within normal limits. Magnetic resonance venogram was negative for thrombosis or fistula. Though definitive diagnosis could not be made by imaging, the patient was clinically diagnosed with an intraocular tumor. Enucleation of the blind and painful eye was performed. Histopathology demonstrated a pigmented mass of necrotic spindled and epithelioid cells in the posterior segment (shown in Fig. 3a–c). There was corneal stromal neovascularization and loss of endothelial cells. The iris, ciliary body, and neurosensory retina were necrotic. Due to the extent of the necrosis, the presence of iris neovascularization and angle closure could not be excluded. The choroid was still viable and showed a reactive inflammatory process to the necrotic mass. There was no viable tumor or extrascleral extension. The sclera was edematous. Immunohistochemistry staining with Sox10 was unsuccessful as the necrotic cells did not stain. However, Fontana-Masson staining confirmed that the pigment present within the necrotic cells and within the macrophages was melanin. Systemic surveillance with MRI of the abdomen and pelvis demonstrated a 0.9-cm enhancing right hepatic lobe mass. Follow-up imaging demonstrated additional hepatic metastases. Core needle biopsy of the hepatic mass stained positive for Melan-A and SOX10, consistent with metastatic uveal melanoma. The patient was treated with immune checkpoint inhibitors, nivolumab 1 mg/kg and ipilimumab 3 mg/kg, which was followed by microwave ablation of the hepatic lesions. Subsequent surveillance imaging of the chest, abdomen, and pelvis demonstrated progression of metastatic lesions in all segments of the liver and multiple lung nodules of indeterminate significance. Surveillance imaging of the brain remained negative. The patient is alive at 17 months from the initial presentation, 13 months after enucleation.

A comprehensive review of the relevant literature with a tabulation of previously reported cases of necrotic uveal melanoma presenting as orbital cellulitis was conducted (Table 1). Scopus and PubMed were searched for cases of spontaneous necrotic uveal melanoma that presented with orbital inflammation. Cases were included if they presented with orbital inflammation and symptoms of orbital cellulitis including proptosis and restriction of extraocular movements, or if they were described as presenting with “orbital cellulitis” or “pseudocellulitis,” and if they were later diagnosed as necrotic uveal melanoma by histopathology. Cases were excluded if symptoms presented after treatment or if there was no histopathologic confirmation of diagnosis.

Our review found 44 published reports and series of spontaneously necrotic uveal melanoma involving 55 patients. Of the 55 patients with necrotic uveal melanoma, 26 patients (47%) presented with orbital inflammation. Cases 1–26 are shown in Table 1. The mean age of presentation was 64 years (range 24–89 years), and 69.2% of patients were male. Presenting symptoms included proptosis (82.8%), pain (80.7%), vision loss (61.5%), and restricted extraocular movements (46.2%). Of those presenting with vision loss, 50% presented with chronic (>1 month) gradual visual loss. The fundoscopic view to the choroid was obscured in 58% of cases due to hyphema, corneal edema, intravitreal hemorrhage, or a dense cataract. Nineteen patients (73.1%) received a B-scan ultrasound, 16 patients (61.5%) received a CT scan, and 4 (15.3%) received an MRI. Eighteen (94.7%) of the B-scan ultrasounds, all of the CT scans, and 3 (75%) of the MRIs demonstrated evidence of a mass. The uveal melanoma involved the choroid in 80.8%, ciliary body in 7.7%, and was unspecified in 11.5% of cases. Histologically, 42.3% had a mixed epithelioid and spindle cell morphology, 23.1% had a spindle cell morphology, 11.5% had an epithelioid morphology, and 23% had an unknown or unreported morphology.

Enucleation was performed in 19 patients (73.1%), exenteration in 5 patients (19.2%), and evisceration in 2 patients (7.7%). All 5 patients who were managed by exenteration had extraocular extension of the uveal melanoma. While there were 2 reported cases, evisceration is usually avoided in patients with a vague clinical history and without adequate visualization of the fundus in an effort to decrease tumor seeding. Of the 2 cases reported by Eagle et al. [5] who underwent evisceration, 1 patient had subsequent surgery to remove the scleral shell; however, there was no evidence of residual tumor (case 1). The second patient (case 19) was found to have extrascleral extension; however, there was no follow-up data regarding further management or outcome. Extraocular extension was present in 10 patients (38.4%). Of these patients, treatment included exenteration in 5 patients (cases #3, 9, 13, 15, and 17), enucleation with lateral orbitotomy in 2 patients (cases 11 and 14), enucleation with posterior tenonectomy in 1 patient (case #24), standard enucleation in 1 patient (case# 25), and evisceration in 1 patient (case #19). Two patients with extraocular extension received adjuvant external beam radiation therapy (cases # 11 and 13). Only 2 patients were reported to have metastatic disease and both received adjuvant treatment consisting of cytarabine (case #3) and immune checkpoint inhibitors, nivolumab and ipilimumab (case #26). Three other patients were deceased within 1 year, indicating possible metastatic disease. Only 16 reports (61%) included follow-up information.

The first published case of necrotic uveal melanoma presenting with orbital inflammation was by Kline et al. [6] in 1977. Since then, there have been an additional 22 case reports or series, encompassing an additional 25 patients, reporting necrotic uveal melanoma presenting with symptoms mimicking orbital cellulitis [5-26]. The cause for the necrosis is not fully understood; however, it is likely that the orbital inflammation in these patients is caused by an inflammatory process triggered by the tumor necrosis. Through the release of inflammatory mediators and cytokines, such as tumor necrosis factor and IL-6, necrotic tissue is capable of inciting uveitis, episcleritis, and panophthalmitis [24]. Inflammation has been attributed to the cytotoxic effects of released cellular debris after a spontaneous infarction [27].

Several potential mechanisms of tumor autoinfarction have been proposed. Reese et al. [27] proposed that lymphocytic activation of endothelial cells leads to thromboses and vessel occlusion, leading to spontaneous infarction and subsequent necrosis. Others have proposed that the rapidly expanding tumor infarcts as it outgrows its blood supply [13, 21, 23].

A proinflammatory phenotype of uveal melanoma has been described in association with increased HLA class 1 and class 2 expression and increased infiltration by macrophages and lymphocytes [28]. Though increased immune infiltration is a positive prognostic factor in other cancers, it is associated with a negative prognosis in uveal melanoma [28]. Several studies have demonstrated the presence of a lymphocytic infiltrate in a high percentage of necrotic uveal melanomas [27, 29, 30]. Of the reviewed cases, 53.8% contained epithelioid cells, which are also associated with increased cellular infiltrate and higher HLA class 1 and 2 expression [31, 32]. Based on the previously reported association between necrotic uveal melanoma and increased inflammatory infiltrate, it is possible that patients with necrotic uveal melanoma have a predilection towards the inflammatory phenotype, with subsequent vascular damage and autoinfarction [27-32]. Alternatively, posterior segment tumors can induce neovascularization of the iris, possibly also through an inflammatory mechanism [33, 34]. This can result in necrosis secondary to acute angle closure.

In our case, histopathologic examination revealed extensive necrosis of the iris, ciliary body, and neurosensory retina. There was a reactive inflammatory process to the necrotic mass, with numerous melanin-laden macrophages infiltrating the darkly pigmented mass of necrotic spindle and epithelioid cells. The tumor size could not be determined because the exact transition between the necrotic tumor and the necrotic response to the tumor was unclear. Our case is only the second case where no viable tumor cells were identified on histopathology [10].

Orbital inflammation is a rare manifestation of uveal melanoma. Autoinfarction and tumor necrosis leads to a proinflammatory state which may lead to orbital inflammation, even in the absence of extrascleral extension of the tumor. Necrotic tumors may not be visible, thus an occult tumor must always be considered and ruled out in patients with severe ocular inflammation where the view to the fundus is obscured.

This study did not require review by our Institutional Review Board. We report a case of necrotic uveal melanoma presenting with orbital inflammation mimicking orbital cellulitis and present a comprehensive review of the literature and tabulation of reported cases. Written consent was obtained from the patient to publish medical history and clinical photographs.

The authors have no conflicts of interest to declare.

The authors have no funding sources to declare.

Ahmad Abdel-Aty prepared the manuscript and conducted the literature review. Wendy L. Linderman contributed to the preparation of the manuscript and in the development of inclusion/exclusion criteria for reviewed articles. Ninani Kombo evaluated clinical data and contributed to the preparation of the manuscript. John Sinard provided interpretation of the histopathology and contributed to the preparation of the manuscript. Renelle Pointdujour-Lim evaluated clinical data and contributed to the preparation of the manuscript.