Retinl Hemngioms: Understnding Clinicl Fetures, Imging, nd Therpies Severl different vsculr tumors cn occur in the retin, ech with its own fetures nd findings. Y CROL L. SHIELDS, MD; LEXZNDR DOUGLSS, S; TIMOTHY HIGGINS, S; WSIM. SMR, MD; nd JERRY. SHIELDS, MD Severl types of benign nd mlignnt tumors cn rise in the retin, originting from neurl (retinoblstom), vsculr (hemngiom/hemngioblstom), nd glil (strocytic hmrtom nd cquired strocytom) elements. The vrious retinl vsculr tumors re benign, nd ech hs distinct funduscopic nd imging fetures. Relted systemic findings nd tumor mngement depend on the specific type of hemngiom. Some of these retinl vsculr tumors cn be ssocited with the oculoneurocutneous syndromes (phkomtoses). This rticle reviews four such tumors nd describes their clinicl findings nd imging fetures on fluorescein ngiogrphy (F), ultrsonogrphy, opticl coherence tomogrphy (OCT), nd other studies. RETINL HEMNGIOLSTOM The retinl hemngioblstom, previously termed retinl cpillry hemngiom, is vsculr hmrtom tht generlly hs clinicl onset in the first 2 decdes of life. ilterl or multiple retinl hemngioblstoms re ssocited with von Hippel-Lindu (VHL) syndrome, nd ptients should be evluted for this condition using brin nd renl imging s well s genetic testing (Tble 1). Solitry retinl hemngioblstoms my lso be ssocited with VHL syndrome. Clinicl Fetures Retinl hemngioblstom ppers ophthlmoscopiclly s reddish-ornge mss, nd it cn be locted in the peripherl retin or ner the mculr region or optic disc. 1-5 This tumor displys dilted retinl vessels feeding nd drining the tumor. Erly on, the tumor my not be cliniclly visible nd my be seen only on F (Figure 1). s it enlrges, the vessels become more dilted nd tortuous (Figure 1). This tumor cn produce subretinl fluid, subretinl nd intrretinl exudtion, nd vitreoretinl fibrosis. The exudtion hs tendency to ccumulte selectively in the mculr re s mculr str. In some instnces, the tumors remin pinpoint nd re detected only by observtion of dilted vessels, confirmed lter by hyperfluorescence on F. When retinl hemngioblstom is locted t the optic disc, the mss cn msquerde t Glnce There re numerous types of retinl vsculr tumors, nd ech hs distinct clinicl fetures, imging findings, genetic ltertions, nd mngement strtegies. Retinl hemngioblstom ppers s reddishornge mss nd cn be locted in the peripherl retin or ner the mculr region or optic disc. Cvernous hemngiom does not hve feeding rtery like retinl hemngioblstom nd is usully locted long the course of retinl vein. cquired vsoprolifertive tumor cn produce findings of intrretinl nd subretinl exudtion, subretinl fluid, remote epiretinl membrne, cystoid mculr edem, retinl hemorrhge, nd vitreous hemorrhge. JULY/UGUST 2015 RETIN TODY 61
TLE 1. CRITERI FOR THE DIGNOSIS OF VON HIPPEL-LINDU SYNDROME If fmily history is: Positive Negtive Feture for ny one of the following: retinl hemngioblstom brin hemngioblstom viscerl lesion for ny one of the following: two or more retinl hemngioblstoms two or more brin hemngioblstoms single retinl or brin hemngioblstom with viscerl lesion Viscerl lesions include renl cysts, renl crcinom, pheochromocytom, pncretic cysts, islet cell tumors, epididyml cystdenom, nd endolymphtic sc tumor. s ppillitis, nd the feeder vessels re often not visible. Regrdless of tumor loction, ccumultion of subretinl fluid with exudtion cn led to profound visul loss. C E D F Genetics nd Pthogenesis In VHL syndrome, the stroml cells hve muttion on chromosome 3p25-26, which leds to dysfunctionl VHL protein. 6,7 These cells cnnot degrde hypoxi-inducible fctor 1 (HIF-1), so this fctor ccumultes nd cuses production of VEGF, pltelet-derived growth fctor (PDGF), erythropoietin, nd trnsforming growth fctor-lph, ll of which led to prolifertion nd vsculriztion of the tumor. 7 There re three types of muttion in the VHL gene: type 1, with deletion or nonsense muttion nd mnifesting minly hemngioblstoms only; type 2, with missense muttion t risk for hemngioblstoms nd pheochromocytoms (type 2), dditionl renl cell crcinom (type 2), or only pheochromocytom (type 2C); nd type 3, with risk for polycythemi. 8 The best test for the detection nd confirmtion of retinl hemngioblstom is F becuse it shows rpid filling of the feeding rtery, then the tumor, followed by rpid exit through the drining vein. Subclinicl pinpoint tumors cn be detected on ngiogrphy before they become symptomtic (Figure 1). Smll to lrge tumors cn disply fluorescein dye lekge from the mss into the djcent retin nd vitreous cvity, feture tht cn led to remote mculr edem nd epiretinl membrne (ERM). Ultrsonogrphy depicts the introculr mss s Figure 1. Young child with fmily history of von Hippel-Lindu syndrome, t risk for retinl hemngioblstoms. No tumors were visible in the right () or left () eyes, but retinl hemngioblstoms were clerly seen on F in the right eye (C) temporl to the mcul nd in the left eye (D) s pinpoint dots superior to the mcul (two sites). lrge retinl hemngioblstom (E) with prominent dilted, tortuous feeder vessels (F) tht required plque rdiotherpy cn be seen. cousticlly solid with surrounding subretinl fluid. OCT cn show the intrretinl, opticlly dense tumor occupying full-thickness retin with relted subretinl fluid, intrretinl/ subretinl dense exudtion, intrretinl edem, nd ERM. 9 OCT is lso importnt in judging tretment response. 2,9 Mgnetic resonnce imging (MRI) nd computed tomogrphy (CT) cn expose n enhncing retinl mss in eyes with extensive retinl detchment. These scns re lso essentil for detecting ssocited centrl nervous system nd bdominl neoplsms in VHL syndrome (Tble 2). Severl protocols re used for the evlution of VHL systemic fetures, with vritions depending on whether the geneticlly positive ptient or t-risk reltive is being exmined (Tble 3). Keep in mind tht retinl hemngioblstom could be the first finding of VHL syndrome, nd it generlly presents between the ges 12 nd 25 yers (Tble 2). Other VHL-relted tumors, 62 RETIN TODY JULY/UGUST 2015
Tumor TLE 2. TUMORS IN VON HIPPEL-LINDU SYNDROME Hed nd Neck Most Common ge t Frequency of Tumor Retinl Hemngioblstom 12-25 yers 25-60% Cerebellr Hemngioblstom rinstem Hemngioblstom Spinl cord Hemngioblstom 18-25 yers 44-72% 24-35 yers 10-25% 24-35 yers 13-50% Endolymphtic Sc Tumor 16-28 yers 11-16% Trunk Renl Cell Crcinom/Cyst 25-50 yers 25-60% Pheochromocytom 12-25 yers 10-20% Pncretic Tumor/Cyst 24-35 yers 35-70% Epididyml Cystdenom 14-40 yers 25-60% mles rod Ligment Cystdenom 16-46 yers 10% femles Dt compiled from survey of literture from 1976-2004, including dt from the VHL Fmily llince nd dpted from the VHL Fmily llince Hndbook. VHL Fmily llince: www.vhl.org/ such s pheochromocytom, epididyml cystdenom, nd endolymphtic sc tumor, tend to occur t similr young ge. Others, such s brin hemngioblstom nd renl cell crcinom, occur lter (Tble 2). Mngement nd Course Mngement of retinl hemngioblstom should include both systemic nd oculr evlution. The systemic evlution should be performed by qulified tem of specilists including clinicins nd rdiology experts looking for relted VHL tumors such s cerebellr hemngioblstom, pheochromocytom, renl cell crcinom, nd other ssocited neoplsms nd cysts (Tble 2). rin nd bdominl MRI or CT should be performed periodiclly in ffected ptients. The eye evlution should include complete dilted funduscopic exmintion nd F, s per the Cmbridge protocol (Tble 3). This is importnt for the detection of subclinicl retinl tumors tht might Test TLE 3. THE CMRIDGE PROTOCOL FOR SCREENING PTIENTS WITH VON HIPPEL- LINDU SYNDROME OR T-RISK RELTIVES Frequency ffected symptomtic Ptient Physicl exmintion Retinl exmintion b F Renl ultrsound rin MRI/CT bdomen MRI/CT 24 hour urine for VM Every 3 yers until ge 50 yers, then every 5 yers Every 3 yers t-risk Reltives: Sme Protocol s bove but With ge Limits Retinl exmintion b F rin MRI/CT bdomen MRI/CT, beginning t ge 5 yers, from ge 10-60 yers Every 3 yers from ge 15-40 yers, then every 5 yers until ge 60 yers Every 3 yers from ge 20-65 yers Symptomtic ptients should be investigted urgently nd mnged ccording to their findings. b We believe tht retinl exmintion should be performed t lest twice yerly in symptomtic ptients nd t-risk reltives. bbrevitions: F, fluorescein ngiogrphy; MRI, mgnetic resonnce imging; CT, computed tomogrphy; VM, vnillylmndelic cid be seen only on F (Figure 1). We perform F under nesthesi nnully in VHL-documented ptients 5 yers of ge nd younger, erlier thn suggested by the Cmbridge protocol, to detect pinpoint tumors nd llow prompt tretment. The tretment of retinl hemngioblstom vries with the clinicl sitution. 4,10-13 Tumors ssocited with VHL syndrome tend to be more ggressive; therefore, nerly ll retinl hemngioblstoms must be considered for tretment. If lesions re smll (<3 mm) in size, lser photocogultion or photodynmic therpy (PDT) cn be used; if medium (3-6 mm), PDT or cryotherpy cn be used; nd if lrge (>6 mm), PDT, plque rdiotherpy, or internl resection by prs pln vitrectomy route cn be employed. Tumors not ssocited with VHL syndrome tht re smll nd hve symptomtic lesions without JULY/UGUST 2015 RETIN TODY 63
subretinl fluid cn be cutiously observed, prticulrly if they re in the mculr, perimculr, or juxtppillry region, where tretment could be detrimentl to vision. Tretment is wrrnted if lekge ensues. Criteri for tretment re similr to those listed bove. Lser photocogultion nd PDT re useful for smll- to medium-sized tumors locted posterior to the equtor nd cryotherpy for those nterior to the equtor. Plque rdiotherpy is reserved for lrger tumors, nd surgicl repir of secondry ERM or trction retinl detchment is occsionlly necessry. In the cse of n ggressive juxtppillry tumor tht does not respond to conventionl tretment, externl bem rdiotherpy or plque rdiotherpy cn be considered. Some necdotl cses hve reportedly responded to orl proprnolol, orl cetzolmide, nd orl prednisone, but lrge studies hve not been conducted. Orl nd intrvitrel nti-vegf gents hve not been successful in effecting tumor regression, but intrvitrel nti-vegf cn be useful for reducing mculr edem nd occsionlly subretinl fluid. Wong nd Chew reviewed the role of nti-vegf gents nd emerging therpies for retinl hemngioblstom. 4 Histopthology Histopthologiclly, retinl hemngioblstom consists of prolifertion of retinl cpillries tht usully replces the full thickness of the neurosensory retin. On light microscopy, there is benign prolifertion of endothelil cells, pericytes, nd stroml cells. In the end stge, totl retinl detchment with mssive retinl gliosis, ctrct, nd phthisis bulbi cn occur. RETINL CVERNOUS HEMNGIOM Retinl cvernous hemngiom is often ssocited with similr skin nd centrl nervous system lesions nd therefore should be clssified with the oculoneurocutneous syndromes, or phkomtoses. Clinicl Fetures Ophthlmoscopiclly, retinl cvernous hemngiom usully ppers s cluster of drk intrretinl venous neurysms, sometimes described s bunch of concord grpes (Figure 2). 1,2,14-20 This tumor is usully without symptoms but cn be ssocited with visul impirment from vitreous hemorrhge, secondry retinl trction, or mculr scrring. Unlike retinl hemngioblstom, the cvernous hemngiom does not hve feeding rtery nd is typiclly locted long the course of retinl vein. Occsionlly, this lesion is on the optic disc. Rrely is there exudtion, but commonly there is overlying, white, fibroglil tissue on the tumor surfce, suggesting previous vitreous or preretinl C Figure 2. Mculr retinl cvernous hemngiom () with lte onset prtil fluorescence () nd n OCT scn showing multiloculted cvernous spces (C) within the retin. hemorrhge. Retinl cvernous hemngioms re usully nonprogressive but cn show miniml enlrgement over time. Vitreous hemorrhge is the most commonly reported compliction. Genetics Retinl cvernous hemngiom cn occur with cerebrl cvernous mlformtion (CCM) s spordic or fmilil utosoml dominnt disorder with incomplete penetrnce. Three genes cuse CCM: CCM1/KRIT1, CCM2/ MGC4607, nd CCM3/PDCD10. 18 CCM3 is relted to higher risk for cerebrl hemorrhge in childhood. In most instnces, retinl cvernous hemngiom hs typicl ophthlmoscopic ppernce. F is the most helpful dignostic ncillry test becuse it produces nerly pthognomonic findings of rteril phse hypofluorescence with slow fluorescein ppernce within the venous neurysms. Within the neurysml spce, the red blood cells deposit in the inferior portion nd plsm deposits in the superior region, without lekge of dye. This is clled the fluorescein-erythrocyte interfce, chrcteristic feture of cvernous hemngiom. Vitreous hemorrhge cn occur with lrge retinl cvernous hemngioms, obscuring the tumor nd cusing it to be detectble only by ultrsonogrphy. On -scn ultrsonogrphy, there is high initil spike nd high internl reflectivity; on b-scn, the lesion shows n irregulr but well-defined surfce, coustic solidity, nd no choroidl excvtion. OCT demonstrtes mrkedly irregulr retinl surfce, with numerous cvernous spces within the retin. In generl, the retinl ntomy is disorgnized from tumor compression. 64 RETIN TODY JULY/UGUST 2015
Figure 3. dvnced rcemose hemngiom () in the perippillry region showing prominence on F (). Mngement nd Course Most cses of retinl cvernous hemngiom require no tretment becuse these tumors rrely progress or produce visul symptoms. Vitreous hemorrhge cn occur nd cn be mnged with observtion or vitrectomy. For repetitive hemorrhge, the tumor cn be sclerosed with plque rdiotherpy, PDT, or cryotherpy. It is importnt to perform brin MRI to evlute for relted cerebrl cvernoms, nd genetic testing for the CCM genes is dvised, especilly if there is fmily history of cvernoms or the ptient shows multiple cvernoms. Histopthology Histopthologiclly, retinl cvernous hemngiom ppers s mss of lrge-cliber vsculr spces in the inner retin nd ll lyers of the retin. This tumor is lined by endothelium interconnected by nrrow chnnels. 20 There cn be extensive cystic nd fibrous degenertion of the retin. RETINL RCEMOSE HEMNGIOM Retinl rcemose hemngiom is not true neoplsm but rther simple or complex rteriovenous communiction. It cn occur s solitry unilterl lesion, or it cn be prt of Wyburn-Mson syndrome (WMS; lso clled onnet-dechume-lnc syndrome), which is ntomiclly termed retinoencephlofcil ngiomtosis. This rteriovenous mlformtion cn ffect the retin, visul pthwys, midbrin, nd fcil bones, including the mndible nd mxill. There is no hereditry tendency. Clinicl Fetures Cliniclly, the retinl rcemose hemngiom mnifests s lrge, dilted, tortuous retinl rtery tht psses from the optic disc for some distnce into the fundus, communicting directly with dilted retinl vein nd then bck to the optic disc (Figure 3). In some cses, the vsculr nomly displys complex rry of blood TLE 4. RCHER CLSSIFICTION FOR WYURN-MSON SYNDROME Group Feture Comments I II III bnorml cpillry plexus between the mjor vessels of the rteriovenous mlformtions. rteriovenous mlformtions lck ny intervening cpillry bed between the rtery nd vein. Extensive rteriovenous mlformtions with dilted nd tortuous vessels nd no distinction between rtery nd vein. Such lesions tend to be smll, ptients symptomtic, nd intrcrnil involvement uncommon. Risk of retinl decompenstion resulting in retinl edem, hemorrhge, nd vision loss. Low risk for intrcrnil rteriovenous mlformtions. High risk for visul loss due to retinl decompenstion or retinl compression of nerve fiber lyer, optic nerve, or other vessels. High risk for intrcrnil rteriovenous mlformtions. dpted from rcher DM, Deutmn, Ernest JT, Krill E. rteriovenous communictions of the retin. m J Ophthlmol. 1973;75(2):224-241. vessels. This retinl mlformtion does not usully produce exudtion or hemorrhge. rcher clssifiction is used to ctegorize the ffected eye ccording to size nd loction of the vsculr mlformtion (Tble 4). 21-26 Genetics There is evidence tht genetic or developmentl fctors tht occur erly in gesttion led to dysgenesis of the embryologic vsculr plexus. 26 The time of insult determines the loction nd extent of mnifesttions. The tumor is estblished with ophthlmoscopy nd confirmed with F, which shows rpid filling of the ffected dilted rtery nd vein, usully with no intervening cpillry chnnels nd typiclly without lekge into surrounding tissues. Mngement nd Course The mngement of ptient with this vsculr tumor consists of systemic nd ophthlmic monitoring. Furthermore, the ptient should be evluted for WMS with imging studies for similr vsculr bnormlities in the brin nd fcil bones. The retinl lesion usully remins stble, nd tretment is rrely needed. JULY/UGUST 2015 RETIN TODY 65
TLE 5. OCULR CONDITIONS SSOCITED WITH SECONDRY VSOPROLIFERTIVE TUMOR ssocited Oculr Condition Retinitis pigmentos 10 (18) Prs plnitis 11 (20) Cots disese 11 (20) Previous retinl detchment repir 8 (14) Idiopthic peripherl retinl vsculitis 3 (5) Fmilil exudtive vitreoretinopthy 3 (5) Toxoplsmosis 3 (5) niridi 1 (2) Congenitl hypertrophy of retinl pigment epithelium Secondry VPT n = 56 ptients n (%) 2 (4) Idiopthic choroiditis 1 (2) Retinopthy of premturity 2 (4) Histoplsmosis 1 (2) Totl 56 Dt dpted from Shields CL, Kliki S, l-dmsh S, et l. Retinl vsoprolifertive tumors. Comprtive clinicl fetures of primry versus secondry tumors in 334 cses. JM Ophthlmol. 2013;131(3):328-334. bbrevitions: VPT, vsoprolifertive retinl tumor Histopthology Little histopthologic informtion hs been published on retinl rcemose hemngiom. The lrge, dilted retinl vessels pper to hve n cellulr dventitil covering, nd the retin is thin nd cn show extensive degenertion. CQUIRED VSOPROLIFERTIVE TUMOR cquired vsoprolifertive tumor of the oculr fundus is vsculr mss tht cn occur s primry or secondry condition from predisposing intermedite uveitis, retinitis pigmentos, Cots disese, or chronic retinl detchment (Tble 5). 27-34 Clinicl Fetures Ophthlmoscopiclly, cquired vsoprolifertive tumor ppers s n elevted sessile or dome-shped mss tht is typiclly locted in the equtoril inferotemporl region (Figure 4). The mss cn be circumscribed or quite ill-defined. Minimlly dilted retinl feeding rtery nd drining vein cn be found, but not s mrkedly dilted or tortuous s seen with retinl C Figure 4. Subtle, ill-defined peripherl retinl vsoprolifertive tumor () documented with telngiectsi, nonperfusion, nd lekge on F (), nd showing remote epiretinl membrne in the fove on OCT (C). hemngioblstom. The tumor cn produce findings of intrretinl nd subretinl exudtion, subretinl fluid, remote ERM, cystoid mculr edem, retinl hemorrhge, nd vitreous hemorrhge. The retinl exudtion generlly begins t the tumor mrgin nd grdully mrches posteriorly into the mcul, with ensuing visul loss. Genetics No genetic bnormlities hve been ssocited with this condition, but ptients with secondry tumors should be evluted for underlying retinl conditions. Rrely, this lesion is ssocited with neurofibromtosis type 1. 30 F demonstrtes filling of the mss through slightly dilted nd minimlly tortuous retinl rtery nd drining vein. There is frequently lekge from the vsoprolifertive tumor into the surrounding retin nd vitreous cvity. Remote mculr edem or ERM cn be seen on F nd confirmed on OCT; OCT cn lso demonstrte relted remote ERM. Mngement nd Course Smll, peripherl tumors cn be cutiously observed if there is no lekge, but it is importnt to relize tht they cn progress slowly nd potentilly led to profound visul loss. This progression might be nticipted nd hlted with erly tretment. Tumors with ctive lekge require therpy, which cn include lser photocogultion, thermotherpy, indocynine green-enhnced thermobltion, PDT, cryotherpy, or plque rdiotherpy. 28-33 Cryotherpy often leds to tumor control nd hs been reported to induce relese of the ERM in 63% of cses. 32 Intrvitrel injection of n nti-vegf gent cn ssist in 66 RETIN TODY JULY/UGUST 2015
reducing remote mculr edem, nd sub Tenon fsci injection of trimcinolone cn minimize inflmmtory response t tretment. Histopthology Histopthology of cquired vsoprolifertive tumor in the erly phses when the tumor is mostly vsculr hs not been clerly estblished. It is believed to represent prolifertion of blood vessels, glil tissue, nd retinl pigment epithelium, often in response to previous insult from intermedite uveitis, retinitis pigmentos, Cots disese, or other conditions. Lter, s the tumor becomes cliniclly fibrotic, more rective strocytic ppernce cn be documented. 34,35 CONCLUSION There re number of vsculr tumors of the retin, nd ech hs distinct clinicl fetures, imging findings, genetic ltertions, nd mngement strtegies. It is importnt to remember tht severl of these tumors could potentilly crry genetic muttions tht imply systemic disese nd relted brin lesions, so genetic testing nd MRI cn be instrumentl in mngement. We hve found n informtive website (www.genetests.org) for oculr genetic testing tht is helpful in directing clinicins towrd relevnt lbortories tht cn provide genetic evlution. s of pril 2015, this website hd logged 44 003 tests on 4176 disorders with 4747 genes from 649 lbortories. n lexzndr Douglss, S, is postbcclurete resercher t the Oculr Oncology Service, Wills Eye Hospitl, Thoms Jefferson University, in Phildelphi, Pennsylvni. Timothy Higgins, S, is postbcclurete resercher t the Oculr Oncology Service, Wills Eye Hospitl, Thoms Jefferson University, in Phildelphi, Pennsylvni. Wsim. Smr, MD, is postdoctorl resercher t the Oculr Oncology Service, Wills Eye Hospitl, Thoms Jefferson University, in Phildelphi, Pennsylvni. Jerry. Shields, MD, is director of the Oculr Oncology Service t the Oculr Oncology Service, Wills Eye Hospitl, Thoms Jefferson University, in Phildelphi, Pennsylvni. Crol L. Shields, MD, is the co-director of the Oculr Oncology Service, Wills Eye Hospitl, Thoms Jefferson University, in Phildelphi, Pennsylvni. She is member of the Retin Tody Editoril ord. Dr. Shields my be reched t crolshields@gmil.com. Support provided by the Eye Tumor Reserch Foundtion, Phildelphi, Pennsylvni (CLS), nd Lucille Weidmn Fund for Peditric Eye Cncer, Phildelphi, Pennsylvni (JS, CLS). 1. Shields J, Shields CL. Vsculr tumors of the retin nd the optic disc. In: Shields J, Shields CL, eds. Introculr Tumors. n tls nd Textbook. Phildelphi: W Sunders; 2016:389-426. 2. Shields CL, Mnlc J, Ds C, Sktnste J, Shields J. Review of spectrl domin enhnced depth imging opticl coherence tomogrphy (EDI-OCT) of tumors of the retin nd retinl pigment epithelium in children nd dults. Ind J Ophthlmol. 2015;63(2):128-132. 3. Singh D, Shields CL, Shields J. Von Hippel-Lindu disese. Surv Ophthlmol. 2001;46(2):117-142. 4. Wong WT, Chew EY. Oculr von Hippel-Lindu disese: clinicl updte nd emerging tretments. Curr Opin Ophthlmol. 2008;19(3):213-217. 5. Mher ER, Neumnn HP, Richrd S. Von Hippel-Lindu disese: clinicl nd scientific review. Eur J Hum Genet. 2011;19(6):617-623. 6. Chn CC, Vortmeyer O, Chew EY, et l. VHL gene deletion nd enhnced VEGF gene expression detected in the stroml cells of retinl ngiom. rch Ophthlmol. 1999;117(5):625-630. 7. Kelin WG. Von Hippel-Lindu ssocited mlignncies: Mechnisms nd therpeutic opportunities. Drug Discovery Tody: Disese Mechnisms. 2005;2(2):225-231. 8. Clzd MJ. Von Hippel-Lindu syndrome: moleculr mechnisms of the disese. Clin Trnsl Oncol. 2010;12(3):160-165. 9. Shields CL, Pellegrini M, Ferenczy SR, Shields J. Enhnced depth imging opticl coherence tomogrphy (EDI-OCT) of introculr tumors. From plcid to sesick to rock nd rolling topogrphy. The 2013 Frncesco Orzlesi Lecture. Retin. 2014;34(8):1495-1512. 10. Singh D, Nouri M, Shields CL, et l. Tretment of retinl cpillry hemngiom. 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