Choroidal neovascular membrane in a treated choroidal hemangioma.

Association of choroidal neovascular (CNV) membrane with circumscribed choroidal hemangioma is rare, and the CNV development after photodynamic therapy (PDT) is also rare. Etiopathogenesis of these associations is poorly understood. We noted the development of CNV over choroidal hemangioma after PDT therapy in a young female patient in our hospital. Temporal association of CNV development after PDT treatment points toward the possible side effects of PDT. Repeat injections of antivascular endothelial growth factor (ranibizumab) regressed the CNV resulting in a favorable visual outcome.

Choroidal neovascularization (CNV) rarely occurs in association with circumscribed choroidal hemangioma (CCH) or after its treatment. Shields et al.[1] in their series of 200 patients of CCH observed that three CCH patients had concomitant CNV. Photodynamic therapy (PDT) is considered the standard and the safest modality to treat choroidal hemangioma at the cost of insignificant side effects, among which the development or progression of CNV post-PDT has been rarely reported.[2] The pathogenesis of such rare associations is poorly understood. Relationship of CNV with either choroidal hemangioma or post-PDT therapy effect focuses our attention to possible triggering factors and also strategies for the successful management of these unusual presentations. We observed CNV in a young patient with CCH, who underwent treatment with PDT which was later managed with antivascular endothelial growth factor (VEGF) therapy to regain the lost vision.

Case Report

A 12-year-old female presented with the complaints of decreased vision in the right eye of recent onset. Clinical examination showed classical CHH superotemporal to fovea with subfoveal fluid which was the cause for drop in vision to 20/80. The lesion was confirmed by fundus fluorescein angiography (FFA), ultrasound, and optical coherence tomography (OCT). OCT showed subretinal fluid (SRF) under fovea [composite Fig. 1]. Because of proximity to macula and symptomatic presentation, PDT was done using a 6 mg/m2 dose of verteporfin and a 689 nm laser (Visulas 690S, Carl Zeiss Meditec, Inc. Germany) with 25 J/cm2 of laser light (half-fluence) delivered over a duration of 83 s on γ-linolenic acid of 2.5 mm as determined by FFA.

Figure 1

Composite photographs showing (a) circumscribed choroidal hemangioma with overlying subretinal fluid; (b) fundus fluorescein angiography showing patchy staining of superotemporal region corresponding to circumscribed choroidal hemangioma; (c) spectral domain-optical coherence tomography image scan passing through macula showing elevated retinal pigment epithelium with subretinal fluid

Three months post-PDT, vision improved to 6/5 with a complete resolution of SRF and regressed CCH. OCT showed normal foveal dip with increased surface reflectivity of choriocapillary layer superotemporal to foveal center [composite Fig. 1]. Eight months later, the patient presented with recurrence of SRF; OCT confirmed the same with grossly normal-looking underlying retinal pigment epithelium (RPE) and choriocapillary layers. The patient underwent the 2nd PDT with similar parameters (half-fluence), almost on the same area of the previous target.

Two months follow-up showed improvement in vision to 6/5. After 1 month follow-up, the patient presented with drop in vision and was noted to have active choroidal neovascular membrane (CNVM), which was confirmed on FFA and OCT [Fig. 2]. The patient was treated with two intravitreal ranibizumab injections over 2 months. The CNV regressed completely with the resolution of intraretinal and SRF, which was later confirmed on OCT. The patient was under follow-up for 18 months and has had no reactivation of either CNV or CCH till the time of this write-up.

Figure 2

Composite fundus picture showing the course of circumscribed choroidal hemangioma and choroidal neovascular membrane. (a) Linear ridge over circumscribed choroidal hemangioma after the 1st photodynamic therapy and (d) corresponding optical coherence tomography image; (b) progression of choroidal neovascularization and (c) corresponding active leakage site on fundus fluorescein angiography (e) optical coherence tomography showing subretinal pigment epithelium location of choroidal neovascular membrane; (f and g) fundus picture of resolved choroidal neovascular membrane with corresponding optical coherence tomography image

Discussion

Retinal and disc neovascularization has been described in the eyes with retinal or choroidal tumors without obvious triggering factors such as retinal artery or vein occlusion,[3] capillary dropout, or inflammation. Tumor-related CNV is rarely reported, especially with CCH. Among 200 cases of CCH studied by Shields et al.,[1] three cases had associated CNV and only one needed active intervention.

Hua et al.[2] had reported a case of a rare association of CCH with CNV in a HIV patient. The author postulated multiple causes for pathogenic association including possible complication of potent antiretroviral therapy associated with immune recovery uveitis or active role of exogenous HIV-1 transactivator protein that could alter the tight junction integrity and function of RPE.

Many reasons have been attributed to the development of CNV in CCH. Vascular leakage of CCH facilitates angiogenesis because of the leakage of plasma proteins and fibrins creating gel-like environment which is conductive to endothelial cell growth and infiltration.[4] CCH stimulates release of angiogenic factors due to subtle inflammation and chronic ischemia.[5]

Querques et al.[5] noted an active CNV with an underlying inactive CCH in a 66 yr old female with no features of age-related macular degeneration. The author successfully treated the CNVM with nine consecutive ranibizumab injections rather than PDT. He believed that chronic inflammation and ischemia secondary to CCH resulted in CNV. The present case had no CNV before the initiation of PDT, became active after the 2nd PDT session, speculating the possible role of PDT in triggering the development and progression of CNV rather than de novo development of CNV over CCH.

PDT is considered the most effective treatment modality for CH over macular area. Subtle complications including RPE alterations and loss of photoreceptors have been described after PDT therapy. Anecdotal evidences documented the development of retinal neovascularization,[3] RPE hyperplasia,[6] and polypoidal choroidal vasculopathy[7] after PDT. Many have theorized that multiple sessions of PDT may cause laser-induced necrosis of the tumor and release of VEGF.

PDT is known to increase growth factors by the destruction of RPE. RPE releases VEGF under hypoxic condition, and on the other hand, RPE may be responsible for preventing CNV induction by secreting inhibitory factors such as transforming growth factor-B and promoting maturation of neovascularization. Okay et al. in their histopathological analysis of 42 surgically excised CNV specimens with or without presurgery PDT made some relevant observations. The author analyzed changes in intricate balance between VEGF and PDGF and noted that a significant increase in RPE produced VEGF, but there was a decrease in pigment epithelial-derived growth factor (PEDF) (antiangiogenic factor) from RPE, endothelial cells, and stromal cells. The author concluded that PDT causes a trauma followed by enhanced VEGF and decreased PEDF expression leading to angiogenesis.[8]

Clinically, the role of PDT in CNV pathogenesis, however, is poorly supported. Barbazetto et al.[6] during their preliminary studies on the efficacy of PDT in choroidal hemangioma (CH) applied a radiant exposure of 100 J/cm2 for 168 s at a dose of 60 mg/m2 and at more frequent multiple sessions. He observed choroidal nonperfusion with secondary RPE atrophy, but no neovascular growth was noted. Even full-fluence PDT for CNV lesions in paediatric and young adult patients had only RPE alterations, which had neither effect on vision nor secondary sight-threatening complications.[9]

Several clinical series of patients with CCH treated by PDT with different protocols (using 50–100 J/cm2) have been described, with authors reporting an overall favorable outcome, and also previous authors have noted nonsignificant RPE changes with a radiant exposure dose of 50 J/cm2.[10] In view of young age and location of hemangioma adjacent to macular area, it was decided to have half-fluence therapy to prevent RPE atrophy, but retaining its efficacy.

Optimal management of tumor-related CNV is at present unknown. On the basis of extensive evidences of the efficacy of anti-VEGF in varied pathogenic CNV, especially in pediatric population,[2511] our patient was successfully treated with intravitreal ranibizumab but with just two injections compared to nine injections in a previous report.[5] The recurrence rate after anti-VEGF in these situations is unknown, but fortunately in the present case, the lesion became quiescent after two injections with no recurrence during 18-month of follow-up.

Conclusion

We report a case of CCH that developed CNV after the 2nd PDT. Possible pathology triggering the CNV formation needs better understanding. Anti-VEGF therapy completely regressed the lesion, regaining the lost vision.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.