视网膜母细胞瘤Rb

Dr. Shuan Dai 关于视网膜母细胞瘤的专家讲座 Shuan Dai,MB BS,MSc.,FRANZCO Consultant of Peadiatric Ophthalmology & Strabismus & Neuro-Ophthalmology Dept. of Ophthalmology Auckland Hospital Auckland University School of Medicine Grafton Road Auckland 1 New Zealand 第一部分: 讲座内容 Shuan Dai医生的英文版讲稿： Retinoblastoma –diagnosis & treatment Shuan Dai, MB BS, Msc., FRANZCO What is retinoblastoma (RB, I will use this abbreviation through out my talk) and how big is the problem ? Retinoblastoma is the commonest malignant ocular tumour of childhood, Its’incidence is about one in 15000-20,000 live births. So, there would be a large number of new cases in China each year. (over 1000 cases/year ?) The tumor arises from primitive retinal cells so the majority of cases occur in children under the age of 4 years, with most of the cases diagnosed between 1-2 years old. Female and males are equally affected. 50% RB is hereditary and 50% is non hereditary. Untreated, the tumor is almost uniformly fatal, but with modern methods of treatment the survival rate is over 90%. Effective treatment requires team work from ophthalmology,oncology,radiology & pediatrics. This is critical to increase the overall success rate. How does RB occur – the basic genetics of RB RB 1 gene is a tumor suppressor gene. It regulates normal cell growth cycles. Mutation of both copies of the gene will cause Retinoblastoma (RB) This is the so called “two-hit" hypothesis proposed by Knudson. If the mutation occurred in the germ line cells, all cells in the body will be affected and this leads to the development of “hereditary RB”. if the mutation only occurred in the developing retinal cells (retinoblast) only this will lead to the “non hereditary” RB. All hereditary RB are bilateral or multifocal, 15% of unilateral RB is hereditable (due to germ line mutation) and 85% of unilateral RB is non hereditable. Only about 20% of the RB patient has positive family history, the reason for this is that many new RB patients developed RB from “new” mutations as the hereditary RB patients all have one bad copy of RB gene already and “second” mutation can easily results in new tumor formation. RB is autosomal dominant with penetrance rate being 90%( if you have the mutated gene, 90% you will manifest the disease), if the bilateral RB patient has child in the future, the child has 50% chance to inherit the mutated RB gene and 45%(50%x90%) chance to have the disease. Both girls and boys are equally effected 50%. For unilateral RB patient, the risk for their future children would be 7.5% (50% of 15%) risk of inherit the mutated RB gene and 6.75% (7.5%x90%). For healthy parent with a RB child, the risk for the next child is: 50% risk of inherit the mutated RB gene and 45% risk of having RB if the effected child had bilateral or multifocal RB, if the effected child has unilateral RB the risk of the next child having RB is 6.75% (non germ line mutation) or 45%( if germ line mutation). So genetic testing plays a critical role for better prediction of the risk. This information is very useful for you counseling the parents. The diagnosis of the RB In a typical RB case, you would see white elevated lesion on the retina, often has blood vessels growing over the surface of tumor. But this vascular pattern may not be present in early stages. Intratumor calcification is characteristic for RB. In some advanced cases, you would see “vitreous seeding” of tumor cells and this is pathognomonic for RB. However, many cases present later and often complicated by retinal detachment due to delayed recognition . You can still see the tumor mass under the detached retina in most cases of RB. Many RB in the early phase do not look like this and high index of suspicion and thorough examination is the only way to reach the diagnosis. RB part2 As a rule, dilated fundus examination under general anesthesia (EUA) is essential to ascertain the nature of the mass lesion and the number of the tumors, especially to see the peripheral retina. Fundus picture showed be taken for documentation when you can. (The fundus pictures here all taken with RETCAM). CT scan of orbit and head and followed by MRI scan to assess the extent of the tumor to see any extraocular extension of the tumor, relation to the optic nerve and if there is any metastasis or concurrent intracranial midline tumors (trilateral RB, more details to follow). Imaging study for RB B Scan: Often seen dome shaped, low to medium reflectivity of the tumors and some high reflectivity within the tumor representing calcification from tumor necrosis. The following web link will lead you to an excellent article on B scan image for ocular tumors and I highly recommend to you and others who interested to know more on this. http://www.emedicine.com/oph/topic757.htm#target17 The above pictures showed large calcified tumor mass in the vitreous cavity. This tumor calcification is well demonstrated in the coronal and axial CT scans. The CT scan showed no spread of tumor to the orbit. CT Scan or MRI Considered by most as a useful initial imaging study for RB: Because It will show the typical calcifications seen in RB. Extent of the tumor in relation to the optic nerve, extraocular spread and intracranial tumors better delineated by MRI. For both image methods, you need to tell the radiologist what you are looking for and give suggestion such as using fine cut (1-2mm) instead of 4-5mm which could miss intraocular tumors. Carefully looking at pine region, or suprasellar region for intracranial tumors (this is not metastasis but primary tumors—the trilateral RBs). CT scan carries small risk of trigger mutations in those with know germ line RB gene mutation and this may have increased the risk of new tumors in RB patients or new secondary tumors else where in the body such as osteoarcoma etc. So, we only use CT for initial work up diagnosis and RB patient follow-up is done by MRI scan annually for selective high risk patients for the first 5 years. Trilateral Retinoblastoma: (A) Trilateral retinoblastoma with a large suprasellar and hypothalamic mass in a 2 months-old-baby girl shown on MRI. She presented poor fixation, no light perception and rowing eye movements since birth. (B, C) RetCam® images showing bilateral involvement with 2 tumors in each eye. The intracranial mass could not be resected because of its location surrounding both carotids arteries, nor could craniospinal radiation be used because of her young age, the baby received 7 cycles of CVE-CSA, with intratecal and intra-Omaya Topotecan and Cytarabine. She was found to be heterozygous 196 bp into intron 7 deletion that is expected to cause mis-plicing exon 8, leading in a non-functional pRB protein. (E) Dramatic resolution of the tumor to a small dense focus, with recovery of fixation and visual function. (F, G) All tumors responded to systemic chemotherapy and focal laser. The tumor near the optic nerve in the left eye requires more laser treatment until it is a flat scar. (Images Shuan Dai and Carmelina Trimboli) Role of FFA: ( A:The above picture showes tumor after laser treatment. It is hard to be certain of tumor activity. B:FFA showed intratumor vascularization suggestive of active tumor.) So, fluorecein angigraphy is a very useful tool to identify residual active tumors after laser or cryotherapy where the fundus picture alone may miss the active tumor. UBM (ultrasound biomicroscope): High frequency two-dimensional ultrasound gives excellent picture of the anterior segments of the eye. Very valuable for detecting tumors near Ora Serrata and excellent For identifying vitreous seeding in patients with medium opacity . (Retcam picture of the fundus showed vitreous seeding (white balls in the central of vitreous and tumors involving the ora serrata. The UBM picture in the lower left corner showed the tumor adjacent to Ora Serrata and ciliary body). Differential diagnosis of RB It is absolutely essential to reach the correct diagnosis before the right treatment can be given. This is very true in dealing with retinoblastoma, which is universally fatal if left untreated and today’s success is around 90% to save the patient’s life and eye, in many retain useful vision. Of the many mimic conditions, I list here the most common ones. PHPV (persistent hyperplasia of primary vitreous): This is the most common disease to cause confusion. It presents with leukocoria and presents at birth or soon afterwards. Microophthalmia is present in all affected eye and almost always unilateral (there has been reported cases of bilateral and this is extremely rare) and there is a dense retrolental mass which may be vascularized. The ciliary processes are often prominent and drawn towards the centre of the pupil. RB often occurs in normal sized eye. The typical tumor calcification in B scan and CT scan is not seen in PHPV. (See the following picture of leukocoria & post lenticular stalk) C C: Coats disease A & B: 24 months old child with PHPV:Picture of leukocoria & post Coates disease: Coats' disease is almost always unilateral and most commonly affects boys. Early Coats' disease may present with loss of vision or with a white pupillary reflex due to accumulation of exudates at the macula. The tortuous, dilated, leaking vessels may be in the far periphery and hard to see without EUA. Later stages of Coats' disease show exudative detachment with tortuous dilated telangiectatic vessels, subretinal lipid and cholesterol crystals. The yellow color of the leukocoria may be the first clue to the diagnosis. In Coat's disease it is yellow whereas in retinoblastoma it is white. Intraocular calcification is rare in Coats' disease. Ultrasonography shows a diffuse uniform increase in opacity of the vitreous with no mass evident on contrast enhancement. Ocular toxocariasis: Ocular inflammation due to toxocariasis presents either as a chronic endophthalmitis with a a, in the posterior or peripheral retina of an o es help to differentiate this condition from re st se to tr fu su R S o n opaque vitreous, or a solitary granulom therwise healthy child. Several featur tinoblastoma. Toxocariasis may show marked vitreous inflammation, with yellow-grey rands extending into the vitreous from the chorioretinal lesions. Such findings are rarely en in retinoblastoma. CT scan shows calcification in retinoblastoma but not in xocariasis. Solitary granulomas may resemble retinoblastoma but often show a small anslucent centre. If there is doubt about the diagnosis, a period of observation with regular ndus examination may be indicated. A positive serological test for toxocariasis is pportive, but not diagnostic, since exposure to the organism is common. etinopathy of prematurity (ROP): tage 4 & 5 ROP can be easily confused with RB. History of premature birth would point ne to the diagnosis and ROP almost always bilateral. B scan and CT will not show calcifications as you would see in RB. Stage 4 ROP Retinal dysplasia: Retinal dysplasia presents as bilateral retrolental masses at birth or soon afterwards, unrelated to prematurity or oxygen use. Retinal dysplasia in patients with trisomy 13 occurs in association with a variety of other serious systemic abnormalities. A similar ocular condition is seen in Norrie's disease, incontinentia pigmenti, and Warburg syndrome, but it may also occur as an isolated finding in an otherwise normal child. Examination under anaesthesia will reveal a shallow anterior chamber, clear lens, and a relatively avascular retrolental mass without any inflammatory signs. There is no calcification on ultrasonography or CT scan. 第 5 部分 ———————————————————————————————— Rentrolental mass in retinal dysplasia Homogenous mass without calcification Staging the RB: International intraocular retinoblastoma classification (IIRC) Proper staging is key to an optimal treatment plan. The International Intraocular Retinoblastoma Classification (IIRC) scores for intraocular disease and the Tumor-Node-Metastasis (TNM). Reese-Ellsworth Classification still in use in some RB centers in the USA. The IIRC is the latest and best describes the disease severity and extent with better prognostic value, therefore should be used. Classification Schema for Retinoblastoma International Intraocular Retinoblastoma Classification (IIRC) TNM Clinical Classification Group A: Small intraretinal tumors away from fovea (macula) and optic disc (optic nerve) T1a: Tumor confined to the retina • All tumors 3 mm (2 disc diameter, DD), or smaller, in greatest dimension, confined to the retina and • All tumors located further than 3 mm from the fovea and 1.5 mm from the optic disc • ≤ 3mm height • further than 1.5 mm from fovea or optic nerve Group B: All remaining discrete tumors confined to the retina T1b: Tumor confined to the retina • All tumors confined to the retina not in IIRC Group A • Any tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding • > 3 mm height • up to half volume of eye Group C: Discrete local disease with minimal subretinal or vitreous seeding T2a: Contiguous spread to adjacent tissues • Tumor or tumors that are discrete • Subretinal fluid, present or past, without subretinal seeding, involving up to a quarter of the retina • Local subretinal seeding, present or past, less than 3 mm from the tumor. • Local fine vitreous seeding close to discrete tumor • minimal tumor spread to vitreous and/or subretinal space Group D: Diffuse disease with significant vitreous or subretinal seeding T2b,c Continguous spread to adjacent tissues • Tumor or tumors may be massive or diffuse • Subretinal fluid, present or past, without subretinal seeding, causing total retinal detachment • Diffuse subretinal seeding, present or past, may include subretinal plaques or tumor nodules • Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses • (T2b) massive tumor spread to vitreous and/or subretinal space • (T2c) 2/3 eye volume • (T2c) angle closure glaucoma Group E: Presence of any one or more of these Poor-prognosis features T2c Unsalvageable intraocular disease • Tumor touching the lens • Neovascular glaucoma • Tumor anterior to the anterior vitreous face involving ciliary body or anterior segment • Diffuse infiltrating retinoblastoma • Opaque media from hemorrhage • Tumor necrosis with aseptic orbital cellulitis • Phthisis bulbi • Suspicion of optic nerve involvement on imaging • Suspicion of choroid or sclera involvement on imaging • Suspicion of orbital involvement on imaging • > 2/3 volume of eye • any glaucoma • anterior segment • hyphema • massive vitreous hemorrhage • tumor in contact with lens • orbital cellulitis The extraocular classification is completed after enucleation of the RB affected eye and based on pathology report and MRI of brain and body if indicated. Classification for extraocular retinoblastoma Clinical Pathological T3 Invasion of optic nerve or optic coats pT3 Invasion of optic nerve or optic coats • pT3a tumor through lamina cribosa but not to line of resection • pT3b massive choroidal invasion • pT3c tumor beyond lamina cribosa but not to line of resection AND massive choroidal invasion T4 Extraocular tumor pT4 Extraocular tumor • optic nerve invasion to line of resection • invasion of orbit through sclera • anterior and posterior orbital extension • brain extension • subarachnoid space of optic nerve • to apex of orbit • to, but not through, chiasm • into brain beyond chiasm N pN Regional Lymph Nodes M PM Distant Metastases pM1 distant metastases pM1a bone marrow metastases pM1b other sites Genetic testing in RB & gene therapy Genetic testing provides the most accurate diagnosis and the base for prediction of risk to offspring. However, as you pointed out, 90% or more can be diagnosed clinically and the quickest gene testing Lab for mutation would take 2-4 weeks or even longer and the sensitivity of the testing remains a problem form many RB centers. Many molecular Labs can do genetic testing for mutations of disease causing gene. But the sensitivity is crucial (detect rate of 90 is quite different from detect rate of 60-70%). As far as I know that Professor Brenda Gallie’s Lab in Toronto has the highest accuracy and sensitivity. They use many of the available DNA testing techniques therefore yield best result. Bilateral RB (92% sensitivity over last 120 families) and unilateral RB (91% sensitivity) with tumor tissue (fresh or frozen) or positive family history. These are the tests they use: Methods: Deletion/duplication analysis, Heterozygosity testing, Linkage analysis, Methylation analysis, Mutation scanning, Sequencing of RNA, Sequencing of entire coding region, Sequencing of select exons, Targeted mutation analysis. Additional Testing Offered: Clinical confirmation of mutations identified in a research lab, Prenatal diagnosis. Gene therapy: As far as I am aware that there has been research going on but nothing is available so far. I am pretty sure the time will come when we can replace the damaged gene segment with a healthy one. But this is complex, you have to do this pretty early to be effective , to many with family history of RB this should been done before the child birth. The critical question is what are we going to do with those new mutations (far more common than inherited mutations). The safety of such genetic therapy (to make sure not causing other cancers, or interfering normal cell cycles etc… so there is a long way to go before we can reach this goal. For patients at present time, gene therapy for RB is not realistic Their contact details: http://www.retinoblastomasolutions.org Treatment of RB Enucleation: Indications: ¾ Unilateral cases: removing a retinoblastoma-containing eye is recommended since it is an excellent way to cure the disease confined within the eye; indicated for Group C, D and E eyes. For bilateral cases: ¾ Enucleation is advisable for a Group D eye when the fellow eye is Group A, which can be cured with focal therapy, avoiding the morbidity of systemic chemotherapy. ¾ Enucleation is indicated for all Group E eyes to avoid a trial of chemotherapy or radiation that can create a false sense of security by obscuring adverse risk factors that predispose to difficult-to-treat and poor-prognosis systemic metastasis. A futile trial of radiation therapy may predispose to fatal second primary tumor development in the long term. ¾ Exceptional circumstances: bilateral primary enucleation is needed when both eyes present with Group E disease. Attempts to save such eyes may put the child’s life in jeopardy from systemic metastasis. Only rarely can these eyes be cured; visual potential is extremely poor in such severely compromised eyes. ¾ Enucleation is also indicated for recurrent tumors when all the other treatment modalities have failed, or when complications (retinal detachments, media opacities, hypheama) prevent evaluation and treatment of progressive disease. Focal therapy: Cryotherapy ¾ Treatment of small peripheral retinoblastoma primarily, or after other therapy. ¾ Cutting-cryotherapy for posterior retinoblastoma refractory to laser focal therapy. ¾ Prechemotherapy cryotherapy 24-48 hours before chemotherapy. Clinical significance: 1