wet age - related macular degeneration ( amd ) is an ocular disorder that can be successfully treated with intravitreal antivascular endothelial growth factor ( vegf ) therapy . we report a case of incomplete response to intravitreal therapy associated with a clear cell renal cell carcinoma ( ccrcc ) . a 72-year - old male with wet amd responded poorly to intravitreal bevacizumab and ranibizumab injections . the removal of a ccrcc led to the spontaneous stabilization of the choroidal neovascular lesion . the renal carcinoma was examined for von hippel - lindau ( vhl ) gene alterations . immunohistochemical profiling of the hypoxia - inducible factor ( hif ) pathway addressing the marker hif-1 and its downstream targets vegf , glucose transporter 1 and carbonic anhydrase ix was performed . genotyping of the ccrcc revealed the presence of a truncating vhl mutation ( p.e134fs*25 ) . following tumour removal , the neovascular lesion remained stable for 6 months without any further anti - vegf therapy . the somatic vhl mutation correlates with persistent high levels of hif-1 pathway targets and vegf expression in the ccrcc . we postulate that this increased vegf in the tumour and subsequently in the plasma levels could have caused the incomplete response to intravitreal anti - vegf therapy . stabilization of the wet amd following tumour removal indicates that the angiogenic secreting tumour ( ccrcc ) abrogates the response to vegf inhibitor therapy . thus , in cases of poor response to intravitreal anti - vegf therapy , systemic evaluation including plasma levels of vegf and/or systemic screening for vegf - producing tumours should be considered . age - related macular degeneration ( amd ) is a leading cause of blindness in industrialized nations . in wet amd , subfoveal choroidal neovascularization ( cnv ) severely alters macular morphology and physiology , causing serious central vision loss . cnv is an angiogenic process in which vascular endothelial growth factor ( vegf ) plays an important role . both ranibizumab and bevacizumab have been shown to recover visual acuity and retinal morphology either with monthly treatments or with optical coherence tomography ( oct)-guided treatments [ 2 , 3 ] . in oct - guided treatments , patients are reinjected whenever oct b - scans show cnv activity , which is usually defined by the presence of intraretinal or subretinal fluid . increased levels of vegf have been demonstrated both in the aqueous and vitreous humour of patients with active cnv . however , the influence of persistent high levels of systemic vegf on the activity of amd has not been reported so far . we report a case of cnv secondary to wet amd who partially responded to monthly intravitreal anti - vegf therapy . following the removal of a vegf - producing clear cell renal cell carcinoma ( ccrcc ) , the ocular disease was controlled spontaneously . a 72-year - old male was referred to the retinal department after sudden visual loss in his left eye . at presentation , best - corrected visual acuity of his left eye was 20/200 . the aim was to employ an  as - needed treatment strategy , using any intraretinal or subretinal fluid on oct or presence of retinal haemorrhage as retreatment criteria . there was an immediate favourable response to treatment with an improved visual acuity of 20/40 and a significant reduction of the macular haemorrhage . however , subretinal fluid persisted despite monthly treatments . after 17 injections , bevacizumab was replaced by ranibizumab when the latter became available in our hospital . despite the change in medication nevertheless , visual acuity remained stable at 20/40 and subretinal fluid persisted on oct . at a routine systemic medical visit unrelated to the ophthalmologic treatments , the histological exam disclosed a ccrcc featuring an alveolar pattern with a network of thin - walled blood vessels , fuhrman grade 2 and focally grade 3 , cystic areas and necrosis . when he returned to the ophthalmology department 8 weeks after his last intravitreal injection of ranibizumab , his vision remained stable but oct did not show any subretinal fluid ( fig . the patient 's retina and visual acuity remained stable for 6 months without further anti - vegf treatment . molecular analysis of the ccrcc disclosed the presence of a frameshift mutation in the von hippel - lindau ( vhl ) gene ( p.e134fs*25 ) that leads to a predicted premature stop codon ( fig . vhl mutations are known to induce a pseudohypoxic state   with activation of the hypoxia - inducible factor ( hif ) pathway . thus , we decided to perform an immunophenotypical analysis of the hif-1 protein and its pathway downstream targets vegf , glucose transporter 1 ( glut-1 ) and carbonic anhydrase ix ( ca - ix ) . evaluation of the immunophenotype of the tumour cells revealed nuclear staining of hif-1 and increased expression of glut-1 , ca - ix and vegf when compared to normal adjacent tissue ( fig one year after surgery , the patient remains without evidence of any tumour ( local / distant ) recurrence . reactivation of cnv occurred 6 months later but it was controlled with 2 injections of bevacizumab . wet amd is characterized by the development of pathologic cnv that is highly dependent on vegf . increased ocular levels of vegf have been described in the aqueous and vitreous humour of affected patients . intravitreal vegf inhibition with either bevacizumab or ranibizumab has shown significant visual and anatomical results . we report a case of a wet amd patient showing partial response to intravitreal anti - vegf therapy . however , despite successive monthly injections , subretinal fluid persisted , indicating persistent exudation from the neovascular complex . even though the patient was proposed for an  as - needed treatment strategy , however , following the detection and removal of the ccrcc , cnv regressed and stabilized without further treatment . thus , we hypothesized that the tumour was producing growth factors that interfered with anti - vegf therapy . the vhl mutation detected led to increased vegf expression in the tumour cells , which may have led to an increase in circulating vegf levels . the choroid is a highly vascularized tissue . when high levels of circulating vegf are present , the continuous supply of this growth factor may abrogate the effectiveness of anti - vegf therapy in controlling cnv activity . removal of the ccrcc , and a putative consequent decrease in plasma vegf levels allowed better control of the disease . the patient remained injection - free for another 4-month spell . in the natural history of treated cnv lesions , the reactivation can be attributed to the ocular pathology and is not related to recurrence of the ccrcc or increased systemic vegf levels . after cnv reactivation , the response to treatment was distinct from that before removal of the ccrcc . this supports our claim that the tumour was producing systemic factors that abrogated response to treatment , and that tumour removal allowed a more predictable response to cnv . vhl loss can be due to gene mutations , promoter hypermethylation or chromosome 3 losses , and is reported to occur in up to 91% of the sporadic ccrccs [ 8 , 9 ] . the case herein reported was consistent with the vhl - mutated ccrcc spectrum : we detected a frameshift mutation that leads to a predicted truncated protein . we excluded the possibility of a germline mutation by genotyping the normal adjacent tissue that did not disclose vhl mutations . it is worth mentioning that vhl loss affected the tumour but was not a systemic alteration , which is consistent with the observed improvement in the subsequent evolution of the wet amd condition after removal of the ccrcc . we then sought to determine how vhl loss could be involved in the objective clinical benefit detected in our wet amd patient . the protein product of vhl , pvhl , holds multiple functions ; a pivotal one relates to its ability to target hif-1 for polyubiquitination and its proteasomal degradation . such imbalance in this mechanism , as observed in our pvhl - defective ccrcc case , fits with the expression of proteins under the transcriptional control of hif-1 . 3b ) that may sustain a pseudohypoxic state featuring higher glut-1 and ca - ix expression than in normal tissue ( fig . 3c and d ) . in accordance with our hypothesis that a tumour factor could restrain anti - vegf therapy response , we claim that vegf secreted from ccrcc tumour cells played a role in abrogating the response to vegf inhibitor therapy for the wet amd of this patient . so far , this is the first report describing a wet amd patient with an incomplete response to anti - vegf therapy probably due to a ccrcc secreting proangiogenic factors . indeed , a study   addressing circulating vegf detection in cancer patients found that vegf could only be substantially increased in rcc cancer patients , and this was due to a genetic defect ( vhl alterations ) that leads to increased vegf production . in the same report , vegf plasma levels were four and five times higher than in non - rcc cancer patients and normal controls , respectively , which is in accordance with our observations . unfortunately , we could not retrieve blood from the patient before removal of the ccrcc to evaluate the plasma levels of vegf . in conclusion , our report shows that increased circulatory levels of vegf , due to an angiogenic - factor secreting tumour , may inhibit the therapeutic effect of intravitreal anti - vegf in wet amd patients . removal of the vegf - secreting ccrcc led to a fading of angiogenic activity at the choroidal level and withheld the need for re - treatment . importantly , it represents a novel mechanism in a patient with wet amd never addressed before . in cases of wet amd that maintain neovascular activity despite aggressive intravitreal anti - vegf therapy , poor response to treatment may be due to increased levels of circulating vegf caused by proangiogenic neoplasias elsewhere . therefore , we postulate that a systemic evaluation , including plasma levels of vegf and/or systemic screening for tumours , should be considered in wet amd whenever resistance to anti - vegf therapy remains to be clarified .
purposewet age - related macular degeneration ( amd ) is an ocular disorder that can be successfully treated with intravitreal antivascular endothelial growth factor ( vegf ) therapy . 
 we report a case of incomplete response to intravitreal therapy associated with a clear cell renal cell carcinoma ( ccrcc).methodsa 72-year - old male with wet amd responded poorly to intravitreal bevacizumab and ranibizumab injections . 
 the removal of a ccrcc led to the spontaneous stabilization of the choroidal neovascular lesion . 
 the renal carcinoma was examined for von hippel - lindau ( vhl ) gene alterations . 
 immunohistochemical profiling of the hypoxia - inducible factor ( hif ) pathway addressing the marker hif-1 and its downstream targets vegf , glucose transporter 1 and carbonic anhydrase ix was performed.resultsgenotyping of the ccrcc revealed the presence of a truncating vhl mutation ( p.e134fs*25 ) . 
 immunohistochemistry displayed hif pathway target activation and vegf expression in the ccrcc tumour cells . 
 following tumour removal , the neovascular lesion remained stable for 6 months without any further anti - vegf therapy.conclusionthe somatic vhl mutation correlates with persistent high levels of hif-1 pathway targets and vegf expression in the ccrcc . 
 we postulate that this increased vegf in the tumour and subsequently in the plasma levels could have caused the incomplete response to intravitreal anti - vegf therapy . 
 stabilization of the wet amd following tumour removal indicates that the angiogenic secreting tumour ( ccrcc ) abrogates the response to vegf inhibitor therapy . 
 thus , in cases of poor response to intravitreal anti - vegf therapy , systemic evaluation including plasma levels of vegf and/or systemic screening for vegf - producing tumours should be considered .