The Case of the Middle-Aged Woman With Sudden Unilateral Vision Loss

A 38-year-old woman presents to an ophthalmologist complaining of vision loss in her left eye over the last week. She denies having any eye pain, tearing, or discharge. She has no previous ocular medical history and denies experiencing any associated trauma. An external examination of the affected eye (not shown) is unremarkable, and both eyes demonstrate normal extraocular movements.

What is the most common cause of transient monocular vision loss?
A. Optic neuropathy
B. Migraine
C. Ischemia
D. Papilledema

Image courtesy of Wikimedia Commons.

Answer: C. Ischemia is the most common cause of transient monocular vision loss.^[1]

The patient's vision in the unaffected right eye is 20/20, but it is only 20/80 in the affected left eye. The funduscopic examination is abnormal, revealing a yellowish dome-shaped abnormality (shown).

What is the most likely diagnosis?
A. Ocular tuberculosis
B. Retinal detachment
C. Retinoblastoma
D. Uveal melanoma

Image courtesy of Medscape.

Answer: D. Uveal melanoma is the most likely diagnosis.

Uveal melanoma is the most common primary malignant intraocular tumor.^[2] Uveal melanomas may be classified as anterior (if they involve the iris) or posterior (if they involve the choroid, as in this patient, or the ciliary body). Indirect ophthalmoscopy is the most reliable means of diagnosis, usually revealing a brown or yellow mass deep to the retina without any feeder vessels. Ultrasonography is a great method for evaluating any posterior segment masses. Use of this imaging modality in ocular melanoma can help to establish the diagnosis, reveal extraocular extension, evaluate for associated retinal detachment (shown), and evaluate for tumor size.

Image courtesy of Thomas M. Aaberg Jr, MD.

Other imaging modalities can also be helpful for establishing the diagnosis of ocular melanoma, including fluorescein angiography, indocyanine green angiography, optical coherence tomography, and autofluorescence. Fluorescein and indocyanine green angiography do not have specific pathognomonic findings, but they may help point to the diagnosis. An early fluorescein angiogram is shown demonstrating the intrinsic vascularity of a choroidal melanoma, a finding that may also be found with choroidal nevi.

True or false? Computed tomography (CT) scanning and magnetic resonance imaging (MRI) have equal sensitivity for the diagnosis of uveal melanoma as ultrasonography but at increased costs.

Image courtesy of Medscape.

Answer: False. CT scanning and MRI are less sensitive than ultrasonography for the diagnosis of uveal melanoma.

CT scanning and MRI may be very useful, however, in evaluating extraocular tumor extension. CT scans with contrast will reveal enhancement of the lesions. Unlike other tumors (eg, choroidal osteoma) uveal melanoma will not calcify. MRI can help to differentiate surrounding fluid from tumor tissue. The T2-weighted MRI shown reveals a small anterior choroidal melanoma (arrow).

What is the most widely used current therapy for posterior uveal melanoma?
A. Enucleation
B. Brachytherapy
C. Local resection
D. Photocoagulation

Image courtesy of Medscape.

Answer: B. Brachytherapy

Multiple therapeutic options exist for uveal melanoma, including watchful waiting, brachytherapy, enucleation, photocoagulation, thermotherapy, and local resection, but brachytherapy is the most commonly performed for choroidal and ciliary body melanoma.^[2] For some patients with choroidal melanoma, early treatment rather than watchful waiting may better prevent metastatic death.^[3,4] Brachytherapy is especially useful for medium-sized choroidal melanomas; the procedure involves placement of a plaque with one of several radioactive isotopes (shown). The radioactive plaque is generally left in place for 3-7 days. Radiation emitted from the plaque kills the cancer cells. Laser photocoagulation and thermotherapy are typically reserved for small tumors.

Image courtesy of Medscape.

The patient was not considered a suitable candidate for brachytherapy and underwent enucleation instead. Enucleation was previously the classic treatment of choice for primary choroidal melanoma; it remains the preferred therapeutic option for large tumors (shown).^[2] Data from the Collaborative Ocular Melanoma Study (COMS) did not reveal any significant difference in mortality between brachytherapy and enucleation for up to 12 years after treatment.^[5,6]

What is the 5-year survival rate for patients with choroidal melanomas (>8 mm)?
A. <20%
B. 20%-40%
C. 40%-60%
D. 60%-80%

Image courtesy of Medscape.

Answer: C. 40%-60%

The 5-year survival rate in patients with uveal melanoma is dependent on the size at presentation.^[2,4] The 5-year survival rate of patients with tumors less than 3 mm is 84%; it is 68% for those with lesions measuring 3-8 mm; and it is 47% for those with tumors larger than 8 mm.^[4] The patient in this case did well following enucleation, and she returned to routine outpatient follow-up. The histologic image of an enucleated eye reveals a choroidal melanoma with an associated exudative retinal detachment.

Image courtesy of Medscape.

The patient is subsequently lost to follow-up but returns 8 years later to her primary care physician complaining of the gradual onset of a headache in the right half of her head. She reports experiencing frequent, repetitive, nonprojectile vomiting over the last 3-4 months as well as having cognitive defects. The patient's vital signs are within normal limits, and her physical examination findings are nonfocal. Her initial laboratory results are shown. Her physician fears a recurrence of her uveal melanoma.

What is the most common location of uveal melanoma metastases?
A. Liver
B. Brain
C. Lungs
D. Bone

Answer: A. Liver

Ocular melanoma has a high recurrence rate (about 50%),^[7,8] with the liver as the most common site of recurrence (≤90%).^[9-11] The reported median survival time is less than 6 months from when the metastasis is detected^[9]; the COMS investigators noted a 1-year survival rate of 20%.^[12] Order liver function tests if there is concern about newly diagnosed or recurrent uveal melanoma. The most sensitive tests are alkaline phosphatase (AP), glutamic-oxaloacetic transaminase (AST, GOT), lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (GGT).

Given the patient's nonspecific symptoms, what imaging study would most likely aid in making the diagnosis?
A. Whole body positron emission tomography (PET) scanning
B. CT scanning of the chest, abdomen, and pelvis
C. MRI of the brain
D. Ultrasonography of the enucleation bed

CT scan of multiple unresectable liver metastases in a patient previously treated for uveal melanoma courtesy of Brasiuniene et al.^[13]

Answer: C. MRI of the brain

The patient's symptoms point toward a neurologic etiology. Although the liver is the most common metastatic location, other common locations include the brain, lung, bone, skin, and subcutaneous sites.^[2,8,10,11] Direct extension into the brain is also possible. Although a contrast-enhanced CT scan of the brain would provide a lower-cost alternative to MRI, this imaging modality would be less likely to differentiate between recurrent melanoma and another primary central nervous system (CNS) malignancy. In general, MRI is reserved for patients who are symptomatic. The T1-weighted MRI reveals a hyperintense lesion in the superficial cortex of the posterior frontal lobe with surrounding edema, which is a typical finding in CNS melanoma.

Image courtesy of Medscape/Prasenjit Das, MB BS, MD.

On MRI, melanoma may appear hyperintense on T1-weighted scans and hypointense on T2-weighted scans (shown) due to the melanin content of the tumor. PET scanning; CT scanning of the chest, abdomen, and pelvis; and radionuclide bone scanning are all important adjuncts to evaluate the extent of disease. Any patient with a history of melanoma with neurologic symptoms should undergo an MRI of the brain for evaluation of potential brain metastasis. In clinical studies, intracranial melanomas are seen in 10%-40% of cases of cutaneous or visceral melanoma,^[14-16] and cerebral metastases are found in 50%-75%^[14,15] (possibly as high as 90%^[16]) of melanoma patients at autopsy.

Image courtesy of Medscape/Prasenjit Das, MB BS, MD.

The patient underwent a biopsy to confirm the suspicion of a metastatic recurrent melanoma. The characteristic histopathology of sheets of spindled-to-polygonal cells with frequent mitotic activity and dense cytoplasmic collections of brownish-black melanin pigment (arrows) confirmed the diagnosis.

True or false? Metastatic melanoma to the CNS is practically incurable.

Image courtesy of Medscape/Prasenjit Das, MB BS, MD.

Answer: True. Metastatic melanoma to the CNS is practically incurable.

As noted previously, recurrence and metastasis from uveal melanoma has a very poor prognosis.^[11,12,17] Key prognostic factors include the size and number of lesions, performance status, comorbid conditions, as well as clinical, molecular, and histopathologic features.^[2,17,18] The treatment of CNS melanoma is individualized and involves symptomatic relief; surgical tumor debulking, with or without whole brain radiation therapy (WBRT), is first-line therapy. Systemic treatments that include newer agents are also available, but the data are limited on their use. Steroids are indicated for perilesional edema to reduce intracranial pressure and mass effect.^[16] Survival data for various prognostic criteria from the Radiation Therapy Oncology Group is shown.^[19]

Table adapted from Buchsbaum JC, Suh JH, Lee SY, et al. Cancer. 2002;94(8):2265-72. PMID: 12001126.^[19]

When possible, surgery is the most effective treatment option for metastatic melanoma to the brain. Patients with a solitary, relatively accessible lesion are most likely to benefit. The addition of postoperative WBRT has proven to be more successful than surgery alone, with the goal of killing small occult lesions that are not identifiable on imaging studies or that were not removed with the surgical procedure.

Image courtesy of Goulart CR, Mattei TA, Ramina R. ISRN Surg. 2011;2011:276908. PMID: 22084751.^[16]

Stereotactic radiosurgery involves delivering high doses of radiation to the tumor in one or multiple sessions, with relative sparing of the surrounding tissues. It is useful for single metastases that are inaccessible to surgery or for multiple metastases.^[17,18] Patients with single lesions have a better outcome.^[20,21] In general, the tumors should be smaller than 4 cm.^[18] Local tumor control rates at 1 year are reported to be 63%-75%.^[22] Survival rates for patients with solitary metastases have been quoted as high as 17.7-22 months, and 4.6-7.5 months for multiple metastases.^[23,24]

Image courtesy of the National Cancer Institute/Daniel Sone.

Melanoma is relatively resistant to chemotherapy and drugs must be able to penetrate the blood-brain barrier (BBB). The National Cancer Institute notes that there is no effective method of systemic treatment for metastatic ocular melanoma,^[2] and chemotherapy is notoriously ineffective for metastatic CNS melanoma. Systemic therapy for CNS melanoma should be managed at institutions with experienced personnel and the resources to closely monitor patients.^[25] Approved systemic agents include ipilimumab (monoclonal antibody), vemurafenib (BRAF inhibitor), dabrafenib with/without trametinib (BRAF inhibitors), trametinib, high-dose interleukin-2 (IL-2) (in select patients), dacarbazine (alkylating agent), temozolomide (alkylating agent), and paclitaxel (antimicrotubule agent).^[25] High-dose IL-2 should only be administered by clinicians experienced in its use; it should not used for patients with inadequate organ reserve, poor performance status, or untreated/active brain metastases.^[25]

Images courtesy of Wikimedia Commons/Armin Kübelbeck (needle) and Sam Shlomo Spaeth (vial).

Given the solitary, relatively superficial location of the metastatic melanoma in this patient, she underwent excision and postoperative WBRT. A postoperative noncontrast CT scan of the head (shown) demonstrated no evidence of residual tumor, with mild cerebral edema. The patient's neurologic symptoms resolved with surgery, and she remained symptom-free at 1-year follow up.

Image courtesy of Medscape/Prasenjit Das, MB BS, MD.