Rectus Muscle Metastasis from Primary Uveal Melanoma: A Case Series and Literature Review

Abstract

Introduction

We aim to describe 2 patients with metastatic uveal melanoma who developed metastases to the contralateral rectus muscles and review the literature on this rare presentation.

Case Presentations

Patient 1 was a woman in her 60s with a history of cirrhosis who presented with a medium-sized choroidal melanoma in the right eye that was treated with plaque brachytherapy. She underwent regular hepatic imaging for surveillance post-treatment. Two-and-a-half years later, she developed diplopia, and a left medial rectus muscle lesion was found on MRI imaging. Biopsy was consistent with metastatic uveal melanoma. Systemic therapy with tebentafusp was initiated. The lesion slowly progressed over 2 years. The patient passed away from complications from her cirrhosis. Patient 2 was a man in his 70s with a large choroidal melanoma in the left eye treated with enucleation. He had metastatic disease at the time of diagnosis that was treated with multiple systemic therapies. Metastases to the right superior and lateral rectus muscles were noted on MRI imaging and were initially observed. He developed painful proptosis and was found to have acute enlargement of the lesions. Treatment with 30 Gy external beam radiation to the right orbit was performed with good local response. He passed away from tumor progression.

Conclusion

Metastasis to rectus muscles from uveal melanoma has historically been exceedingly rare. These cases highlight new challenges in treating symptomatic intraorbital metastasis as surgical outcomes and survival improve in patients due to advances in systemic therapy.

Introduction

Most orbital metastases originate from breast, prostate, and lung cancer, with melanoma representing only a small proportion of tumors metastatic to the orbit [1]. Metastasis to the contralateral eye and orbit from primary uveal melanoma is exceedingly uncommon, and metastasis specifically to the contralateral rectus muscles in patients with uveal melanoma is even more rare, with only a few cases reported in the literature [2–5].

These metastatic tumors are particularly challenging to manage given the potential for visual morbidity in the patient’s only remaining or only seeing eye in the setting of treated uveal melanoma in the fellow eye. Furthermore, there are limited data on effective management of rectus muscle metastasis as many of the reported cases have been in patients with disseminated metastatic disease with short survival [3].

With therapeutic advances in metastatic uveal melanoma, such as the drug tebentafusp (a bispecific protein that binds gp100 on melanoma cells to CD3 receptors on T cells) and novel liver-directed therapies, patients are surviving longer with metastatic disease [6]. Management of more rare sites of metastasis involves balancing patient quality of life as patients live longer with their disease. Here, we describe the presentation and management of 2 cases of patients with uveal melanoma metastatic to the contralateral extraocular muscles and review the literature on this topic.

Report of Cases

Patient 1

A woman in her 60s with a history of hepatic cirrhosis due to chronic hepatitis C presented for evaluation after a choroidal nevus in the right eye that had been followed by an outlying retina specialist and was noted to have increased in size with worsening subretinal fluid. Presenting acuity was 20/100 in the right eye due to subfoveal subretinal fluid from the lesion and 20/20 in the left eye. The anterior segment was normal in both eyes with the exception of age-appropriate cataracts. A dilated funduscopic exam revealed a 14 × 14 × 3.2 mm pigmented choroidal lesion centered above the superotemporal arcade in the right eye. Multimodal imaging showed a dome-shaped choroidal lesion on B-scan echography with overlying subretinal fluid on optical coherence tomography over the lesion (Fig. 1). The patient was diagnosed with a medium-sized choroidal melanoma and the primary ocular tumor was treated with I-125 plaque brachytherapy. Prognostic biopsy of the tumor was deferred per patient preference.

Fig. 1.

Patient 1 at presentation. a Color fundus photograph showing a pigmented choroidal melanoma centered above the superotemporal arcade. b B-scan echo (T11PE) showing a domed-shaped choroidal lesion measuring 3.2 mm in thickness. c Optical coherence tomography (OCT) of the macula demonstrating extensive subretinal fluid tracking from the lesion into macula.

One year following treatment, the treated tumor was involuting appropriately with thickness reduced to 2 mm, and the subretinal fluid resolved with acuity in the right eye returning to 20/40. Two years following treatment, the tumor had decreased to 1.7 mm, and the visual acuity was 20/30 due to mild early radiation retinopathy (Fig. 2). She was followed with routine hepatic surveillance imaging that showed evidence of chronic cirrhosis but no intrahepatic mass lesion.

Fig. 2.

Patient 1, 2 years following treatment. a Color fundus photograph showing treated melanoma with surrounding retinal pigment epithelial changes. b B-scan echo showing domed-shaped lesion with reduction in thickness to 1.7 mm (T11PE). c OCT of the macula showing resolved subretinal fluid. OCT, optical coherence tomography.

Two-and-a-half years following treatment of the primary tumor, hepatic surveillance ultrasound showed new sub-centimeter lesions in the liver. While awaiting confirmatory imaging, she presented acutely with a new headache and diplopia and was found to have a 2.2 × 1.4 cm left medial rectus mass on MRI imaging (Fig. 3a). Abdominal MRI showed features of cirrhosis with multiple dysplastic nodules and LI-RADS 3 lesions (lesions that are indeterminate for hepatocellular carcinoma), versus metastatic nodules in both lobes of the liver, in addition to signs of portal hypertension.

Fig. 3.

MRI brain and orbits patient 1. a Axial T1 MRI brain and orbits post contrast shows a 2.2 × 1.4 cm left medial rectus mass (white arrow). b Histopathology medial rectus biopsy patient 1: H and E stain (200x) shows aggregates of pigmented cells with spindle and occasional epithelioid morphology.

Given her underlying hepatic disease and concern that she could have a second hepatocellular primary tumor, biopsies of both the hepatic lesion and the left medial rectus mass were considered. Due to her thrombocytopenia from the underlying hepatic disease and bleeding risk associated with hepatic biopsy, the patient elected to undergo biopsy of the left medial rectus mass, which was consistent with metastatic choroidal melanoma (Fig. 3b). Genetic mutational analysis of the biopsy specimen showed variants in the SF3B1 (c. 1874G>A) and GNAQ (c.626A>C) genes.

The patient underwent HLA haplotype testing and was HLA-A*02:01 positive. She began systemic therapy with weekly tebentafusp infusions. She initially had stable disease with no new hepatic lesions while on therapy. Subsequently, there was slight growth of one of the liver lesions on MRI that was radiographically felt to be most consistent with a separate focus of hepatocellular carcinoma, and this was treated with CT-guided microwave ablation with a good response. She remained on tebentafusp infusions for the following 2 years. During that time, she developed mild enlargement of the medial rectus mass on MRI imaging. She developed mild pain with abduction and diplopia in extreme gaze. She was evaluated by the neuro-ophthalmology service without signs of compressive optic neuropathy. Options of radiation to the left orbit, surgical excision of the tumor, and observation were reviewed with the patient given her symptoms. At that time, the visual acuity was 20/40 in the right eye due to radiation retinopathy and 20/20 in the left eye. She opted for continued careful observation of the left medial rectus lesion unless there was marked progression, given the risks for radiation-related sequelae, hemorrhage, and increased diplopia with surgical intervention to the left orbit. She developed progressive decline from liver failure from her underlying hepatic cirrhosis and passed away 4 years and 7 months following the time of her initial diagnosis.

Patient 2

A man in his 70s presented to an outlying facility with weakness, nausea, and loss of appetite. Abdominal imaging demonstrated multiple hypodense hepatic lesions and pulmonary nodules. Biopsy of a hepatic mass was consistent with metastatic melanoma positive for a GNAQ mutation (Guardant 360 Panel, Guardant Health, Palo Alto, CA). An MRI of the brain demonstrated a mass in the left eye, and an ophthalmologic exam showed a large left primary cilio-choroidal melanoma. He was started on treatment with immune checkpoint inhibitors nivolumab and ipilumab but developed progression of disease. He then received nivolumab-relatimab-rmbw. His left eye became blind and painful. Enucleation of the left eye was performed and demonstrated a 20 × 20 × 14 mm large ciliochoroidal melanoma. Pathology from the enucleation specimen showed a large ciliochoroidal melanoma with predominantly necrotic cells. Cells were mostly spindle-shaped with rare epithelioid cells. BAP1 immunohistochemistry was indeterminate due to the predominantly necrotic nature of the tumor. He developed continued progression of his disease, and treatment was changed to chemo-immunotherapy with carboplatin/paclitaxel/pembrolizumab. He developed continued disease progression and underwent palliative radiation to metastatic lesions in the mediastinum and back. He also developed a right frontotemporal brain mass with other enhancing lesions in both cerebral hemispheres. He underwent resection of the right frontotemporal mass with pathology consistent with metastatic melanoma. He underwent stereotactic radiation to the remaining CNS lesions.

He was then referred to our center for further evaluation given the continued systemic disease progression. HLA-A*02:01 haplotype testing was negative, and he was not eligible for tebentafusp. Palliative management with a trial of temozolomide was recommended. He developed mild pain with eye movements in the right eye, and MRI imaging demonstrated right superior and lateral rectus muscle metastatic lesions. He was examined in the eye clinic, at which time vision in the right eye was 20/20 and the optic nerve was healthy in appearance without findings suggestive of compressive optic neuropathy. Given his mild symptoms with extreme gaze, he elected to initially observe the lesions metastatic to the rectus muscles. However, he presented acutely to the emergency department 1 week later with right upper eyelid swelling, new proptosis, and chemosis (Fig. 4a). MRI at that time showed increased enhancement of the right superior rectus muscle and lateral rectus muscle (Fig. 4b) along with significant proptosis. He underwent external beam radiation to the right orbit (30 Gy/10 fractions) and treatment with oral steroids. Two months following completion of radiation to the right orbit, the vision in the right eye remained 20/20, and the chemosis and proptosis were markedly improved. He passed away 2 months later in the setting of progressive disease (2.5 years since his initial diagnosis).

Fig. 4.

External photo patient 2. a External photograph of patient 2 at the time of acute presentation with marked chemosis and conjunctival injection (note fluorescein dye instilled for exam). b MRI orbit axial T1 MRI post contrast shows enhancing mass involving the lateral rectus muscle (white arrows indicating the lesion, note similar lesion on MRI of superior rectus muscle).

Discussion

Metastasis to the orbit from uveal melanoma is exceedingly rare, and metastasis specifically to the rectus muscles in the contralateral eye is even less common [3–5]. A large study of melanoma patients showed that only 13/13,000 patients developed metastasis to the contralateral orbit, and of these, only 3 patients had involvement of the rectus muscles (two had metastases near the lateral rectus) muscle [5]. Management of these patients is challenging, considering that most have limited vision in the eye treated for primary uveal melanoma and have additional complications from metastatic tumor progression or side effects of systemic therapy. Our cases add to the literature on the presentation and management of this rare occurrence.

There are only a few existing reports describing the presentation of patients with uveal melanoma metastatic to the rectus muscles, and they are summarized in Table 1. Massy et al. [2] described a patient with cilio-choroidal melanoma who underwent enucleation. Eight years later, he presented with exophthalmos and a pigmented conjunctival lesion [2]. He was found to have focal intramuscular lesions in the superior rectus of the enucleated eye as well as in the superior and inferior rectus of the contralateral eye in the setting of metastatic disease to the liver and pancreas [2]. He was treated with palliative cobalt radiotherapy that resulted in slight regression of exophthalmos [2]. The patient passed away 5 months later [2]. Krema et al. [3] described a patient with a medium-sized choroidal melanoma in the right eye who was treated with plaque brachytherapy and developed metastatic disease 2 years following the initial diagnosis. The patient was enrolled in a clinical trial of the tyrosine kinase inhibitor sorafenib and also underwent stereotactic radiation to hepatic lesions [3]. Her disease was controlled for a period of 2 years until she developed progression and presented acutely with bilateral conjunctival hyperemia, chemosis, and proptosis more similar to the unilateral presentation of patient 2 in our series, who had been enucleated in the left eye [3]. The patient was treated with external beam radiation to the orbits with good response [3]. Another report by McElnea et al. [4] described a woman in her 70s who had been treated 12 years prior with left exenteration and postoperative external beam radiation to the left orbit for choroidal melanoma with extraocular extension. She presented acutely with right eye pain that worsened with abduction [4]. MRI demonstrated a medial rectus lesion, and biopsy was consistent with metastatic uveal melanoma [4]. She was treated with ipilumab and nivolumab [4]. There was continued progression of the disease in the right orbit, and she was treated with 36 Gy of stereotactic radiation to the right orbit, which resulted in stabilization of the orbital metastasis 16 months following the diagnosis of the orbital metastases [4]. Three additional patients with rectus muscle metastasis to the medial, superior, and inferior rectus muscles were also identified as part of a large retrospective study and were treated with excision and stereotactic radiation [5].

Table 1.

Summary of published cases of rectus muscle metastasis from metastatic uveal melanoma

Study	Primary tumor location and treatment	Time from primary treatment to rectus metastasis, years	Known metastatic disease at diagnosis (yes/no)	Presentation of rectus metastasis (symptoms)	Muscles involved	Imaging findings (diffuse vs. focal lesions)	Management	Response to treatment	Patient outcome
Massy et al. [2], (1998)	Cilio-choroidal melanoma of the right eye, enucleation	8	Yes	Exophthalmos causing limitation of motility; conjunctival pigmented lesion	Right superior rectus; left superior and inferior rectus	Three well-circumscribed intramuscular masses (focal)	Cobalt photon radiotherapy to left orbit (∼47.5 Gy in 23 fractions)	Slight regression of exophthalmos with radiotherapy	Death after 5 months
Krema et al. [3], (2013)	Right eye choroidal melanoma treated with iodine-125 plaque brachytherapy	4.5	Yes	Bilateral eyelid swelling, proptosis, exotropia, limitation of ocular motility	Right medial rectus; left medial and lateral rectus	Bilateral multiple localized non-uniform thickenings of muscle bellies with tendon sparing (multifocal)	Orbital external beam radiotherapy (20 Gy in 5 fractions)	Marked reduction of proptosis with radiotherapy	Transitioned to palliative care
McElnea et al. [4], (2019)	Left eye choroidal melanoma with extrascleral extension treated by orbital exenteration and radiotherapy	12	Yes	Retro-orbital pain	Right medial rectus	Homogeneous fusiform enlargement of medial rectus involving its tendon (diffuse)	Stereotactic orbital radiotherapy (∼36 Gy)	Persistent medial rectus lesion without regression	Alive at time of reporting (16 months post diagnosis)
Masoomian et al. [5],a (2015)	3 patients with metastasis to the contralateral rectus muscles from UM (part of larger series of 13 patients with metastases to the contralateral eye/periocular structures)	a	12/13 patients in the series had metastatic disease	Proptosis, periocular pain, and limitation of eye motility	Medial (1), superior (1), inferior (1)	Solitary masses in a rectus muscle (focal)	a	a	a
Kapoor et al. – patient 1 (present series)	Right eye medium-sized choroidal melanoma treated with I-125 plaque brachytherapy	2.5	Yes	Acute headache and diplopia	Left medial rectus	Solitary 2.2 × 1.4 cm intramuscular mass involving the left medial rectus muscle (focal)	Observation	Slow enlargement of the medial rectus mass	Death from progressive liver failure after 2 years
Kapoor et al. – patient 2 (present series)	Left eye large cilio-choroidal melanoma enucleated	2	Yes	Mild pain with eye movement; acute right upper eyelid swelling, proptosis, and chemosis	Right superior and lateral rectus muscles	Focal masses	External beam radiation to the right orbit (30 Gy in 10 fractions)	Resolution of proptosis and chemosis	Death 2 months later

UM, uveal melanoma.

^aSpecific data for these individual patients not reported given part of larger series with aggregate data.

These reports, along with our series, highlight that patients with uveal melanoma metastatic to the contralateral rectus muscles can present either in the setting of known disseminated metastatic disease or with rectus metastasis as the first manifestation of metastases. It is important to note that these patients can present with orbital signs that mimic other disease entities such as thyroid eye disease, and the index of suspicion for metastatic disease should be high in patients with a diagnosis of uveal melanoma [3]. As highlighted by Table 1, involvement of the rectus muscles can be either focal or diffuse. Both diagnosis and management can be challenging, and our patients highlight the need to obtain prompt orbital imaging in patients with uveal melanoma who present with new orbital symptoms in their contralateral eye. Our first patient’s underlying hepatic disease and concern for a second primary hepatocellular primary tumor warranted biopsy of the lesion. However, biopsy of these lesions can have morbidity, and the need for orbital biopsy should be decided on a case-by-case basis as it may not be necessary in patients who have biopsy-proven metastatic disease in other organ systems. The possibility of a second primary tumor should always be considered in these cases. We elected to defer biopsy in patient 2’s case given the biopsy confirmation of metastatic uveal melanoma in two other organ systems and the known large ciliochoroidal melanoma. It is unknown whether specific tumor genetic mutations may predispose to different sites of metastasis.

The role and timing of treatment for metastatic disease to the rectus muscles also requires further study. In the cases described, these patients developed continued progression of their orbital disease while on systemic therapy, and based upon this limited literature, it appears that systemic therapy often does not adequately treat the orbital metastatic lesions [3, 4]. Surgical resection is often limited by the inability to fully resect the lesion, potential for rapid regrowth, and risk for hemorrhage with rapid regrowth. External beam radiation appears to control the orbital lesions but carries the risk for radiation retinopathy and optic neuropathy, ocular surface dryness, and cataract progression that can be visually significant. Judicious use of radiation in the context of the patient’s vision and predicted survival can be considered part of a multidisciplinary approach to their metastatic disease.

Survival after diagnosis of metastatic uveal melanoma has historically been extremely poor, with most patients succumbing to their disease within 6 months of diagnosis of metastasis [7]. With novel advancements in therapy, patients are now living longer with metastatic uveal melanoma [6]. Ocular oncologists should be aware of these late manifestations of metastatic disease as we manage patients and balance quality of life for patients with metastatic uveal melanoma.

Conclusion

Metastatic uveal melanoma to the rectus muscles is an extremely rare phenomenon. Patients can present with varying degrees of orbital signs as the first presentation of disseminated metastatic disease or in the context of known metastases. Optimal management of these patients requires further study, and decisions should be made on a case-by-case basis considering the patient’s vision, status of systemic disease, and anticipated survival.

Statement of Ethics

This work was reviewed by the Institutional Review Board at the University of Iowa and was determined to be non-human subjects research as an isolated case series. Written informed consent was obtained from the next of kin for each patient.

Conflict of Interest Statement

Elaine Binkley was a member of the journal’s Editorial Board at the time of submission. The other authors have no conflicts of interest to declare.

Funding Sources

No funding was obtained for this project.

Author Contributions

Conception/design of work, data acquisition, analysis, and interpretation: S.K., E.B., N.S., J.M., E.S., and A.J. Drafting and critically reviewing work: S.K., E.B., H.C.B., C.K., and J.Y. Final approval of the published version: S.K., E.B., N.S., E.S., A.J., J.M., H.C.B., C.K., and J.Y.

Funding Statement

No funding was obtained for this project.

Data Availability Statement

All data obtained for this study are contained within the manuscript. Further inquiries can be directed to the corresponding author.