Choroidal Melanoma: from diagnosis to treatment Poster No.: R-025 Congress: RANZCR-AOCR 2012 Type: Educational Exhibit Authors: C. Mandel, N. Bergen, C. Phillips Keywords: Eyes, Oncology, Neuroradiology brain, MR, CT, Gamma knife, Staging, Stereotactic radiotherapy, Diagnostic procedure, Neoplasia, Multidisciplinary cancer care, Cancer DOI: 10.1594/ranzcraocr2012/R-025 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply RANZCR's endorsement, sponsorship or recommendation of the third party, information, product or service. RANZCR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold RANZCR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies,.ppt slideshows,.doc documents and any other multimedia files are not available in the pdf version of presentations. www.ranzcr.edu.au Page 1 of 6
Learning Objectives Although choroidal melanoma is a rare tumour, knowing about this disease is becoming more important for radiologists as newer eye-conserving treatments become commoner. This presentation will provide information about choroidal melanoma, from diagnosis to treatment, providing radiologists, and others, with a greater understanding of this rare disease and the role of radiology in managing patients with this diagnosis. Topics covered include: 1. 2.. 4. 5. 6. 7. 8. 9. 10. 11. 12. 1. Presentation: symptoms and signs Diagnosis and differential diagnosis Incidence Demographics Risk factors Investigation Staging Anatomy and embrology Pathology and genetics Clinical course Treatment Follow up Prognosis Images for this section: Page 2 of 6
Fig. 1: Axial T2W MRI image demonstrating a small melanoma in close proximity to the optic nerve Page of 6
Background Ocular tumours Uveal melanoma is the second commonest ocular tumour, metastases (most commonly breast and lung) being the commonest. More than 90% of uveal melanomas arise in the choroid. Ciliary melanoma accounts for just over 5% and iris melanoma for less than 5%. Rarer ocular tumours include lymphoma and adenocarcinoma. Presentation: symptoms and signs Choroidal melanoma usually presents in one of the following ways: incidental finding on ophthalmological examination (0-40%) painless loss of vision visual field defect visual symptoms including flashes and floaters Local complications of the tumour include retinal detachment, retinal perforation or local invasion, which can account for the presenting symptoms. Fig. 2 on page Page 4 of 6
Fig. 2: Oblique sagittal T2W MRI image showing a large retinal detachment Page 5 of 6
Fig. : Axial T1W MRI image showing a choroidal melanoma, retinal detachment and haemorrhage Diagnosis and differential diagnosis The diagnosis is usually clinical: this is at least 99% accurate in medium- and large-sized melanomas[1] on page Page 6 of 6
Fig. 4: Photograph of a choroidal melanoma The major clinical differential diagnosis is a benign naevus (1 in 10 ocular lesions). This is most likely to be a problem with smaller lesions Factors used to differentiate between melanoma and naevus include: naevus melanoma thickness <2mm (max mm) #2mm visual symptoms no maybe subretinal fluid no yes orange pigment no yes touching optic disc no yes drusen yes no Page 7 of 6
Documented enlargement of a lesion is also a sign that it is likely to be a melanoma. Pigmented lesions at greater risk of growth include: larger or thicker lesions orange pigment around the lesion no drusen retinal pigment epithelial changes next to the lesion Rarer ocular tumours include lymphoma and adenocarcinoma. These are usually able to be differentiated from choroidal melanoma on clinical grounds, including fundoscopy and fluorescein angiography. Amelanotic melanomas are more difficult to differentiate. These tumours should, however, be considered in the radiological differential diagnosis, as should metastases, the commonest type of intraocular tumour. Non-malignant tumours include adenoma, cysts, haemangioma and leiomyoma: all are rare. Incidence As this is a rare tumour accurate data are hard to find. In the United States of America the incidence is estimated to be six per million head of population In Victoria in 2009 there were 51 patients with eye tumours (all ages & eye tumours: Cancer Council Victoria[2] on page ). Eight patients died of ocular tumours. In the United Kingdom 400-450 eye tumours (all types) per year are reported In the USA there are 100-1800 uveal melanoma reported per year and approximately 270 deaths per year. Unlike skin melanoma, the incidence is not increasing. Demographics Most patients are over 50 years of age, with a mean age 55, and a peak age of 60. These tumours are rare in children and in those over 70 Uveal melanoma is commoner in people with: Page 8 of 6
fair skin red or fair hair blue eyes There is no difference in incidence between males and females. Risk Factors Most patients do not have any risk factors. Known risk factors include: naevus of Ota (ocular or oculo-dermal melanocytosis) ocular naevi dysplastic naevus syndrome neurofibromatosis Sunlight and chemical exposure are of questionable risk with no proof of an increased incidence with increased exposure. Although agricultural and laundry workers have been said to be at increased risk this is also unproven. Investigation local Radiological techniques used to diagnose and stage choroidal melanoma include ultrasound, usually performed by an ophthalmologist, computed tomography (CT) and magnetic resonance imaging (MRI) with the latter two most useful in planning treatment. Other local investigations can include fluorescein angiography fundus photography and, increasingly, fine needle aspiration cytology. systemic Systemic staging investigations, if necessary, include liver function tests, liver imaging (CT, ultrasound or MRI) or more extensive staging with CT or positron emission tomography. For small lesions imaging is often not performed as the risk of metastases is so low. Gene expression profiling is becoming more common as more is learned about the genetics of ocular melanoma and effect of these mutations on prognosis. Staging Page 9 of 6
TNM staging is based primarily on the size of the melanoma. The secondary staging criterion is the anatomical extent, namely involvement of the ciliary body and/or extrascleral tissues[] on page. This table illustrates the T stage (T1-4) as determined by the tumour thickness and basal diameter. Thickness >15.0 (mm) 4 4 4 4 4 4 4 12.1-15.0 4 4 9.1-12.0 4 6.1-9.0 2 2 2 2 4.1-6.0 1 1 1 2 2 4 #.0 1 1 1 1 2 2 4 #.0.1-6.0 6.1-9.0 9.1-12.0 12.1-15.015.1-18.0>18.0 Largest basal dimension The T stages are further categorised according to involvement of adjacent tissues: a no involvement of ciliary body nor extra-ocular extension b ciliary body involvement c extra-ocular extension # 5 mm; no involvement of ciliary body d extra-ocular extension # 5 mm; and involvement of ciliary body e extra-ocular extension # 5 mm. The N stages are: N0 no nodal metastases N1 nodal metastases There are two M stages: M0 no distant metastases M1 distant metastases M1 is further divided according to the size of the largest metastasis M1a # cm M1b # cm, but # 8 cm M1c >8 cm Page 10 of 6
From the TNM classification the following stages are derived: Stage T N M I T1a N0 M0 IIA T1b-d or T2a N0 M0 IIB T2b or Ta N0 M0 IIIA T2c-d, Tb-c or T4a N0 M0 IIIB Td or T4b-c N0 M0 IIIC T4d-e N0 M0 IV any N1 M0 any M1 Anatomy and embryology The choroid is the middle layer of the globe, located between the sclera on the outside and the retina on the inside. It contains blood vessels and stroma that supports the retina. There are no lymphatics, an important factor when determining where to look for metastases. The melanocytes, from which melanomas arise, originate in the neural crest from which the globe develops. Pathology and genetics Tumours with monosomy are almost all fatal whereas fewer than 5% of those without chromosome deletion are fatal. There is an increased risk of metastasis in patients with: BAP1 (BRCA-1 associated protein) mutation (84%) GNA11 (guanine nucleotide binding protein alpha 11) mutation (50%) The histological characteristics[4] on page the pathology grade: of the tumour are used to determine Page 11 of 6
Grade Cell type (percentage of Percentage of all tumours that cell type in total cell population) G1 Spindle cell >90% 9% G2 Mixed i.e. 86% >10% epithelioid, <90% spindle G Epithelioid >90% 5% Local invasion is noted in 81% of pathological specimens Rupture Bruch's membrane 88% Invasion of retina 49% Tumour cells in vitreous 25% Invasion into emissary veins 55% Vortex vein invasion 9% Tumour vessel invasion 14% Scleral invasion is noted in 56 % and extra-scleral invasion in 8% of tumours [5] on page. Clinical Course Between 1% and 4% of patients have metastatic disease at the time of diagnosis. One quarter of small tumours have metastatic potential. Tumour genetics are important in determining the metastatic potential of tumours so there is now increasing interest in obtaining tissue prior to treatment. This is usually a fine needle aspirate performed by the ophthalmologist. Local spread Melanomas typically grow through Bruch's membrane into the subretinal space, retina and vitreous. Growth through the sclera is uncommon as the sclera is very tough but can occur and is an important imaging finding. In this situation tumour can spread into the orbit or conjunctiva depending on its location within the globe. Spread along the optic nerve is rare. Page 12 of 6
Distal spread is via direct invasion (through the sclera) or haematogenous. Nodal spread Local nodal involvement only occurs if the sclera is breached. In this situation the regional nodes are the pre-auricular, submandibular and then the cervical nodes. Metastases Patients with tumours that are thicker, have a larger basal diameter, or extra-scleral extension are at greater risk of metastases. Metastases are most commonly found in the liver (9%). Other sites include lungs (24%), bone (16%), and rarely in the subcutaneous tissues and brain[5] on page. Other sites are extremely rare. Fig. 5: Contrast-enhanced, axial CT image of the liver demonstrating several small liver metastases Page 1 of 6
Fig. 6: Contrast-enhanced, axial CT image of the lungs showing a pulmonary metastasis Page 14 of 6
Fig. 7: Axial CT-PET image showing increased uptake in an ischial metastasis Page 15 of 6
Fig. 8: Axial CT-PET image showing increased uptake in a subcutaneous metastasis Page 16 of 6
Fig. 9: Axial T1W, contrast-enhanced MRI image showing a dural metastasis overlying the left parietal lobe Page 17 of 6
Fig. 10: Axial T1W, contrast-enhanced MRI image of the head showing a metastasis in the right frontal lobe Page 18 of 6
Treatment The aims of treatment are to prevent metastases (preserve life) and, where possible, preserve vision. Traditionally tumour resection was considered to be life-saving. There is little evidence to link any type of treatment of the primary with prolongation of survival. Modern management encompasses a range of treatment options which include surveillance, surgery, radiotherapy, laser and photodynamic therapy. The suitability of the various treatments is determined by the size and location of the tumour, in particular proximity to the optic nerve and macula; the effects of treatment on vision and importance of this to the patient; the presence of metastases; and patient factors such as other illnesses and patient preferences. Observation Observation may be used in small lesions that are not growing or if the tumour is in the only functioning eye. This is not an option in larger tumours or those with monosomy. Now that non-surgical treatments are available, observation is used less often. Surgery There is now a range of operations used to treat choroidal melanoma. Eye-preserving operations are trans-retinal or transcleral resection, suitable for tumours confined to the globe. Enucleation is the operation of choice if there is little likelihood of preserving useful vision; there is a high risk of complications; optic nerve invasion is present; or if the tumour is very large. The globe is replaced by a ball implant, often made of coral, and the extraocular muscles attached to it. A custom-made eye prosthesis (a 'glass eye') is attached to the implant once the wound has healed. The cosmetic result is often very good as the artificial eye is able to move in a reasonably normal fashion. Page 19 of 6
Fig. 11: Axial CT image of the orbits, soft tissue window, showing a coral implant and attached prosthetic eye after enucleation Page 20 of 6
Page 21 of 6
Fig. 12: Axial T1W, contrast-enhanced MRI image after enucleation with coral implant and prosthetic eye in situ There is a risk of local recurrence with local excision. This is not a risk with enucleation unless there is extra-ocular extension. Treatment may, therefore, be combined with other treatments such as radiotherapy. Exenteration is rarely performed, usually for local invasion not treatable by other means. A custom-made prosthesis is required for cosmesis. Ocular conservation is attempted in 70% of patients and is successful in 90%. Radiotherapy Radiotherapy can be either brachytherapy or external beam. Brachytherapy requires a general anaesthetic and is performed by a team of an ophthalmologist, a medical physicist and, in some centres, a radiation oncologist. The treatment is delivered via a surgically-applied plaque. This is left in situ for between 1 and 7 days, is saucer-shaped with the radiation source on the concave surface and a shield on the outer, convex surface. Ruthenium is used for thinner tumours and iodine for thicker tumours. Almost half of these patients have significant visual impairment at three years[6] on page. This is more common in patients with diabetes mellitus, thicker tumours or retinal detachment. The location of the tumour within the eye and the radiation dose are also factors that affect the long-term risk of loss of vision. Proton beam can be used but is not widely available. It requires an operation to suture tantalum markers to the globe. The treatment is administered over five days. Stereotactic radiotherapy can be single ('radiosurgery') or fractionated treatment. The radiation is administered as a focussed high dose from multiple projections giving a high dose to the tumour and relatively lower dose to surrounding structures. At Peter MacCallum Cancer Centre we offer stereotactic radiotherapy to patients where preservation of the eye and binocular vision are sought although, in the long term, visual loss is common. Most of our patients have juxtapapillary lesions, with the tumour located Page 22 of 6
near the optic nerve, which means that application of a brachytherapy plaque is difficult, or will result in undertreatment of part, or all, of the tumour. Stereotactic radiotherapy has adopted the dose fractionation regimen from proton beam therapy: 50 to 70 Gy in 5 fractions. Fig. 1: Scout image from CT showing patient in a head frame used for planning stereotactic radiotherapy Page 2 of 6
Fig. 14: Images from stereotactic radiotherapy planning software showing isodose lines Late side-effects or radiotherapy include retinopathy and complications thereof (vitreous haemorrhage and glaucoma) optic neuritis, cataract and dry eye. Loss of vision is a longer-term risk: this can be the result of radiation retinopathy, optic neuropathy or neovascular glaucoma. Rarely, the globe may need to be enucleated secondary to radiotherapy late effects. Other treatments Infrared laser can be used on small lesions, a treatment known as transpupillary thermotherapy. Local failure occurs in 40% of patients. Photodynamic therapy is a combination of infrared laser and intravenous verteporfin, the laser being used to activate the verteporfin. Page 24 of 6
Combined treatment Some publications suggest that preoperative radiotherapy, before enucleation, can result in a small increase in 5 year survival (from 57% to 62%) and reduce local recurrence[7] on page Laser thermotherapy may also be used in conjunction with radiotherapy Systemic therapy There are no specific systemic therapies for prevention or treatment of metastases in uveal melanoma. In Australia typical treatments are local resection, enucleation, laser or plaque brachytherapy performed by ophthalmologists or stereotactic radiotherapy or proton therapy, the latter requires the patient to be treated abroad as this technology is not available here. Follow up Post-treatment follow up consists of regular clincial review, with particular interest in findings that may be due to local recurrence, local treatment complications or distal metastases. After enucleation, close attention is paid to the operative site for three years. Magnetic resonance imaging of the head and orbits, using the same, or an abbreviated version, of the protocol used for staging. If there are contra-indications to MRI then CT would be substituted. Local recurrence and signs of radiation toxicity are the main indications. Systemic monitoring consists of biochemistry, such as liver function tests. Body CT, chest radiography, ultrasound and and PET may have a role[8] on page but in practice these tests are only useful if there are clinical findings of concern. Recurrence Local recurrence is usually treated with exenteration or enucleation. Page 25 of 6
Metastatic disease may be treated with a range of chemotherapeutic agents, such as dacarbazine or sunitinib. Local treatment, such as embolisation of liver metastases may also be helpful. There is ongoing investigation of new therapies such as targetted therapy immunotherapy, vaccines, monoclonal antibodies other chemotherapeutic agents. Prognosis The outlook for patients with small choroidal melanomas is good, the 5-year survival being 85%. The overall 10 year survival is 77%[9] on page Fifty per cent of patients will have metastases 15 years after diagnosis. More specifically, patients with stage I tumours have 88% ten year survival whilst patients with a stage IV tumour have 0% ten year survival. Median survival of patients with metastases ranges from 17 months for stage M1a to 4.5 months for patients with stage M1c tumours. When interpreting survival statistics for small tumours it is important to bear in mind lead time bias as many of these tumours grow very slowly. Imaging Findings OR Procedure Details Ultrasound Ultrasound is typically the first imaging performed, often by the ophthalmologist in his/ her rooms. It has the advantage of being able to 'see' through opaque vitreous (such after haemorrhage). Its uses include measuring the thickness and diameter of the tumour and detecting extra-scleral spread, all important factors in determining prognosis and treatment. Ultrasound, when compared with histology, is able to determine the diameter, (+/- 2mm) of tumours with an accuracy of 90%[10] on page. It is less accurate in thicker tumours and those located anteriorly in the globe. Page 26 of 6
Fig. 15: Ultrasound image of the globe showing a small choroidal melanoma with measurements of thickness and basal diameter As the globe is small and superficial, high frequency, 'small parts' probes should be used if the machine does not have a dedicated ophthalmology probe. Page 27 of 6
Computed tomography Computed tomography is useful for radiotherapy planning. In order to be effective, the images need to be thin-section and high-resolution. We use intravenous contrast medium and reconstruct a volume acquisition in three planes (axial, coronal and oblique sagittal along the plane of the optic nerve). We also create a set of images the radiotherapyplanning plane as this makes fusion in the radiotherapy planning software more accurate. Fig. 16: Unenhanced, axial CT image of the right orbit showing a choroidal melanoma Magnetic resonance imaging Magnetic resonance imaging is essential for radiotherapy planning, particularly in the smaller tumours that may not be so well seen on CT. We acquire thin-section, highresolution images of the orbit and also acquire some whole-head sequences for radiotherapy planning purposes. Page 28 of 6
Fig. 17: oblique sagittal T2W image showing small melanoma Typical sequences and parameters on our Tesla magnet include: head Name/ Sequence Slice thickplane ness (mm) Interslice gap TE TR Matrix Slices Field of view (mm) Acquisition time (min) (mm) T2W axial TSE 5 2 92 700 512 x 24 286 240 1.2 T1W D MPRAGE1 1 2.8 1900 256 x Slab 256 176 256.2 Page 29 of 6
Contrastenhanced Orbit Name/ Sequence Slice Interthick- slice plane ness gap (mm) (mm) TE T2W TSE TR TI Matrix Slices Field of view (mm) Acquisition time 84 x 4 20 180 1.50 256 x 64 218 220 5.28 (min) 0.6 91 200 0.9 0 196 80 T1W TSE coronal 0.6 11 900 20 x 4 240 180 2.7 T2W TSE oblique sagittal 0. 90 000 448 x 1 270 120 2.20 T1W axial TSE 0. 1 962 20 x 18 240 180 1.58 T2W axial TSE 0. 91 200 84 x 18 20 180 1.58 T1W TSE coronal 0.6 11 540 20 x 4 240 180 2.7 0. 11 855 20 x 18 240 180 1.58 Coronal T2W STIR SPACE 160 D Contrastenhanced T1W TSE axial contrastenhanced These images provide us with the best data-set to define the extent of the tumour for radiotherapy planning purposes, the location of nearby radiosensitive structures, also important for planning radiotherapy, a cross-check with ophthalmologist-performed Page 0 of 6
ultrasound as to any extra-scleral spread of tumour and a baseline set of images for comparison with follow-up imaging. The volume acquisitions are particularly important as we reconstruct images in the same plane, and at the same slice thickness, as is used for the radiotherapy planning CT images. This provides optimum fusion of images and, therefore, optimum radiotherapy planning and treatment. Imaging findings Like skin and mucosal melanomas, the appearance of choroidal melanoma is variable. Most are dark on T2W imaging, intermediate or bright on T1W imaging and enhance brightly after administration of intravenous contrast medium. Other imaging findings to note are: complications of the melanoma, namely retinal detachment, exudate or haemorrhage. These problems are diagnosed clinically but are potentially confusing on imaging unless the radiologist is alert to their presence. Extra-scleral extension. The presence of extra-scleral tumour affects the choice of treatment so its detection is critical Page 1 of 6
Fig. 18: Axial T1W unenhanced MRI image of the orbits showing a very small, high signal intensity choroidal melanoma Page 2 of 6
Fig. 19: axial T1W, contrast-enhancedmri image showing a small melanoma near the optic nerve Page of 6
Fig. 1: Axial T2W MRI image demonstrating a small melanoma in close proximity to the optic nerve Conclusion Page 4 of 6
Although tumours of the globe are rare, melanoma is the commonest primary tumour at this site. Given the small size of the lesions, meticulous attention to detail is essential in order to obtain accurate information so that patients receive optimal treatment. Whilst ultrasound is often the initial imaging technique, MRI is the most important in patient work-up for radiotherapy and for post-treatment follow-up. CT has a role, especially in planning radiotherapy. Knowledge of the anatomy of the globe and the pathology of uveal melanoma is important for understanding the appearances of melanoma and the patterns of spread. Small tumours are capable of metastasising and knowledge of the tumour genetics can detect high risk tumours. Radiologists have an important role in the management of these patients, from diagnosis to treatment and on-going follow-up. Personal Information References [1] Accuracy of Diagnosis of Choroidal Melanomas in the Collaborative Ocular Melanoma Study. The Collaborative Ocular Melanoma Study Group Arch Ophthalmol. 1990;108(9):1268-127 [2] Canstat: cancer in Victoria 2009. Cancer Council of Victoria, cancer epidemiology centre, Melbourne 2011 [] AJCC Staging Manual 7th Edition. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, rotti A (eds) American Joint Committee on Cancer. Springer Verlag, New York. 2010 [4] Histopathologic characteristics of uveal melanomas in eyes enucleated from the collaborative ocular melanoma study COMS study group American Journal of Ophthalmology 1998 125: 745-766 Page 5 of 6
[5] Assessment of Metastatic Disease Status at Death in 45 Patients With Large Choroidal Melanoma in the Collaborative Ocular Melanoma Study (COMS) The Collaborative Ocular Melanoma Study Group Arch Ophthalmol. 2001;119:670-676 [6] Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma Ophthalmology 2001. 108:48-66 [7] The Collaborative Ocular Melanoma Study (COMS) randomized trial of preenucleation radiation of large choroidal melanoma II: initial mortality findings American Journal of Ophthalmology 1998. 125:779-796 [8] Screening for Metastasis From Choroidal Melanoma: The Collaborative Ocular Melanoma Study Group J Clinical oncology2004. 22:248-2444 [9] Mortality in Patients With Small Choroidal Melanoma The Collaborative Ocular Melanoma Study Group Arch Ophthalmol. 1997;115(7):886-89 [10] Comparison of Clinical, Echographic, and Histopathological Measurements From Eyes With Medium-Sized Choroidal Melanoma in the Collaborative Ocular Melanoma Study Arch Ophthalmol. 200;121:116-1171 Page 6 of 6