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ORIGINAL ARTICLE
Year : 2002  |  Volume : 50  |  Issue : 3  |  Page : 183-188

Intraocular osseous metaplasia. A clinico-pathological study


Ophthalmic Pathology Division, L.V. Prasad Eye Institute, L V Prasad Marg, Banjara Hills, Hyderabad-500 034, India

Correspondence Address:
Geeta K Vemuganti
Ophthalmic Pathology Division, L.V. Prasad Eye Institute, L V Prasad Marg, Banjara Hills, Hyderabad-500 034
India
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Source of Support: None, Conflict of Interest: None


PMID: 12355691

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  Abstract 

Purpose: To evaluate the clinico-pathologic features of intraocular osseous metaplasia.
Methods: Pathology specimens of enucleated eyes submitted to the ophthalmic pathology service at a tertiary eye-care referral center between January 1995 and June 1999 were studied for intraocular osseous metaplasia. Specific histopathologic features noted in specimens with osseous metaplasia were the presence of retinal detachment, gliosis, retinal pigment epithelial hyperplasia, drusen, epiretinal membrane, fibrovascular proliferation and inflammation. Immunohistochemistry using monoclonal antibody against glial fibrillary acidic protein was performed to assess the glial component within the membranes and the proliferative vitreoretinal mass. Clinical records were reviewed and correlated with histopathologic findings.
Results: Osseous metaplasiaS was noted in 8 of 151 (5.2%) eyes examined. Clinical diagnosis in these was phthisis bulbi, staphyloma, absolute glaucoma and microphthalmos. Enucleation was performed for relief of symptoms (in painful blind eyes) or for cosmesis, and in an eye inciting sympathetic ophthalmia. Retinal detachment, gliosis and retinal pigment epithelial hyperplasia were noted in all the cases. Drusen with calcification or ossification (5 of 8), fibrovascular proliferation in the vitreous (5 of 8) and active inflammation (4 of 8) were the other associated histologic features. Location of ossification was subretinal in 3 cases, preretinal (ora serrata) in 1 case and in both locations in 4 cases. The eyes with subretinal osseous metaplasia had associated calcified drusen, while preretinal ossification was seen within the fibrovascular membranes.
Conclusion: Chronic retinal detachment, hyperplasia and transdifferentiation of retinal pigment epithelium appear to be a few of the prerequisites for intraocular osseous metaplasia. Ossification can occur at isolated subretinal and preretinal locations or can involve both. Though a larger study is required to postulate the chronology of events, in this small series, isolated subretinal ossification appears to be initiated by calcification and ossification of drusen, while in the pre-retinal region it is associated with vitreoretinal proliferation.

Keywords: Osseous metaplasia, enucleated eyes, histopathology, staphyloma


How to cite this article:
Vemuganti GK, Honavar SG, Jalali S. Intraocular osseous metaplasia. A clinico-pathological study. Indian J Ophthalmol 2002;50:183-8

How to cite this URL:
Vemuganti GK, Honavar SG, Jalali S. Intraocular osseous metaplasia. A clinico-pathological study. Indian J Ophthalmol [serial online] 2002 [cited 2019 Nov 18];50:183-8. Available from: http://www.ijo.in/text.asp?2002/50/3/183/14789

RD=RETINAL DETACHMENT, RPEH=RETINAL PIGMENT EPITHELIAL HYPERPLASIA, ERM=EPIRETINAL MEMBRANE, F=FEMALE, M=MALE, +=PRESENT, -=ABSENT

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RD=RETINAL DETACHMENT, RPEH=RETINAL PIGMENT EPITHELIAL HYPERPLASIA, ERM=EPIRETINAL MEMBRANE, F=FEMALE, M=MALE, +=PRESENT, -=ABSENT

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Intraocular osseous metaplasia is known to occur in association with phthisis bulbi, longstanding retinal detachment, chronic inflammation, age-related macular degeneration, microphthalmos, buphthalmos, and trauma.[1][2][3][4][5][6][7] It is also seen with intraocular tumours such as choroidal haemangioma, choroidal osteoma, choroidal melanoma, and teratoma.[8-9] In most of these situations the bone is found in the subretinal location.[1][2][3][4][5][6][7] Suggested pathogenic mechanisms involved in intraocular osseous metaplasia are vascular delivery of osteoblasts to tissues with inherent high vascularity, such as choroid, or the transdifferentiation of the retinal pigment epithelial cells into fibroblastic or osteoblastic phenotype.[1] Recent studies have reported osseous metaplasia in preretinal membranes removed from eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy.[10],[11] Preretinal osseous metaplasia could result from metaplasia of retinal pigment epithelial cells that migrate along the back surface of the detached retina, through retinal breaks, and then along the anterior retinal or the posterior hyaloid plane.[10],[11] We reviewed 8 cases of intraocular osseous metaplasia in 8 enucleated eyes to analyse the associated clinical and histological features with pre and subretinal location of ossification.


  Material and Methods Top


Between January 1995 and June 1999, the ophthalmic pathology service at a tertiary-care referral center received 151 enucleated eyes, the slides of which were reviewed by an ophthalmic pathologist (GKV) for the presence of intraocular osseous metaplasia. Eight consecutive cases with intraocular osseous metaplasia in enucleated eyes were included for further study. Clinical records of these patients were reviewed for clinical data, details of the inciting event, duration of the disease, ophthalmic findings at the time of surgery, and indication for enucleation.

Routine formalin-fixed, paraffin-processed tissues from the specimens with osseous metaplasia were stained with haematoxylin-eosin and periodic acid Schiff stain. They were reviewed specifically for location and degree of bone formation, the presence of retinal detachment, gliosis, retinal pigment epithelial hyperplasia, drusen, epiretinal membrane, fibrovascular proliferation and inflammation. Immunohistochemsitry using polyclonal antibody against glial fibrillary acidic protein (GFAP) was performed to assess the glial component in the surrounding fibrovascular proliferations and the membranes.

The location of the intraocular bone was designated as preretinal, subretinal or both. The location, extent and severity of osseous metaplasia and associated histological changes were noted in each case. We classified the ossification as mild (ossification confined to 1 to 2 anatomical layers), moderate (ossification involving >2 anatomical layers) and severe (ossification involving >2 anatomical layers and associated with bone marrow formation). The anatomical level of bone formation was correlated with clinical features as well as with histopathologic characteristics.


  Results Top


Intraocular osseous metaplasia was observed in 5.3% (8 of 151) enucleated eyes received over a period of 3.5 years. Age of the patients undergoing enucleation ranged from 8 to 66 years (mean 22 11.3 years; median, 17.5 years), with equal gender distribution. Duration between the onset of the inciting disease and enucleation ranged from 6 months to 22 years (mean 9.6 5.8 years; median, 10.5 years).

The clinical presentation and indications for enucleation in eight cases are shown in [Table - 1]. Indication for enucleation was a painful blind eye in 4 patients, for cosmesis in 3 patients, and sympathetic ophthalmia (an inciting phthisical eye) in 1 patient. The primary event was intraocular inflammation in 4 patients, trauma in 3 patients, and congenital microphthalmos in 1 patient. The histopathologic features are summarized in [Table - 1]. Of the 8 enucleated eyes, the location of bone was purely preretinal in 1 eye, solely subretinal in 3 eyes, and involved both locations in 4 eyes. The severity of osseous metaplasia was graded as mild in 4 eyes and severe in 4 eyes.

The preretinal location of the metaplastic bone was noted within the fibrovascular membrane at the base of the vitreous, ora serrata and retrolental area (case 8, [Figure - 1]a and [Figure - 1]b. The other associated histological features were drusen formation over the retinal pigment epithelium with evidence of calcification, exudative retinal detachment, calcific band keratopathy and vitreoretinopathy.

Isolated subretinal (sub RPE) bone formation was seen within the choroid in 3 eyes (case 2, 4, 7, [Figure - 2], two of which were staphylomatous. All the three eyes were associated with mild degree of osseous metaplasia and formation of drusen. Drusen showed variable degree of fusion [Figure - 3], calcification, and ossification. In one case these calcified drusen were incorporated into the overlying retina [Figure - 4]. Two of these cases (cases 2,7) had associated retrolental membrane and pre-retinal membrane formation. Inflammation was noted in two cases (cases 2 and 7)

In 4 cases (cases 1, 3, 5, 6; [Figure - 5]), the osseous metaplasia was noted in both pre-retinal and sub-retinal locations. Three of these eyes were phthisical with disorganisation of all layers; one was microophthalmic and one was a case of extensive proliferative vitreoretinopathy. The ossification was noted in choroid, retina, vitreous and in the fibrovascular vitreoretinal mass. It was of moderate to severe grade with evidence of fibrofatty marrow in all the cases. One case of post-traumatic phthisical eye (case 5), in addition, showed features of granulomatous inflammation [Figure - 6], consistent with sympathetic ophthalmia. Associated inflammation was noted in two cases (cases 1,3).

Retinal detachment, gliosis and retinal pigment epithelial hyperplasia were noted on histopathology in all the enucleated eyes. Retinal detachment, however, could be artifactual in some specimens. Epiretinal membranes and proliferative vitreoretinal mass were found in 7 eyes, five of which showed evidence of osseous metaplasia. The glial component was confirmed in all these 7 cases by immunohistochemical localization, using polyclonal antibody against glial fibrillary acidic protein [Figure - 7].


  Discussion Top


Intraocular osseous metaplasia is a well-recognized entity and frequently occurs in end stage eye disease, congenital conditions, or tumours.[1-9] Bone formation in general requires a precursor cell, which could be either a determined osteogenic precursor cell present only in the marrow stroma or an inducible osteogenic cell present in many tissues and circulating blood.[12] The inducible osteogenic cell forms bone only in the presence of an inducing agent which could be cells of living epithelium or a protein-like bone morphogenic protein. [12,13] In the eye, the inducible cell for osteogenesis appears to be the pleuripotential retinal pigment epithelial cell,[1],[14],[15] while the inducing agents though not specifically identified, could possibly be mediated by trauma, inflammation, or anoxia subsequent to chronic retinal detachment.[1],[14][15][16][17][18] Though the location of osseous metaplasia has been reported predominantly in the subretinal location (sub RPE or in choroid), recent reports suggest a preretinal location within the membrane and enucleated eye.[10],[11] In this study, we attempted a clinical and histological evaluation to identify the inducing factors for osseous metaplasia in the enucleated eyes. A brief discussion on incidence, clinical and predisposing factors, location of osseous metaplasia, and the role of drusen in the pathogenic mechanisms in osseous metaplasia is presented along with a review of literature.


  Incidence of osseous metaplasia Top


In large series of enucleated eyes, the reported incidence of osseous metaplasia varies from 5% to 18%.[1],[3] In our series, the incidence of osseous metaplasia was 5.3%. Intraocular osseous metaplasia is usually reported in the older age group (>50 years). The mean age of the patients in our series was 22 18.5 years (range 8-66 years) and 87.5% (7 of 8) of our patients were below 25 years of age. This could be related to the difference in indications for enucleation in different clinical settings. It is agreed that at least 10 years must usually lapse between an initiating insult and the occurrence of osseous metaplasia, though in exceptional cases it can occur early.[1],[3] In our series, the duration of the inciting disease before enucleation varied from 6 months to 22 years (mean 9.6 5.8 years; median, 10.5 years). Early onset of osseous metaplasia was found in an inflamed post-traumatic phthisical eye that incited sympathetic ophthalmia and was enucleated 6 months after the initial injury.


  Predisposing factors Top


Like any heterotopic tissue, intraocular osseous metaplasia may be considered broadly as derived from embryological, metaplastic and organizational sources, displayed respectively in microphthalmos, choroidal haemangioma, and disorganised ocular contents following injury.[4] It is reported to occur mostly in the subretinal location in phthisical eyes resulting from trauma or inflammation and associated retinal detachment.[1-5] It can occasionally occur in association with buphthalmos, persistent hyperplastic primary vitreous, teratoma, choroidal melanomas, adenoma of the retinal pigment epithelium, and age-related macular degeneration.[1][2][3][4][5]

Trauma remains the most common likely stimulus for tissue disorganisation leading to ossification.[1],[3] Monsalie and associates[3] found an interesting correlation between age and aetiological factors. In the 10-50 age group trauma was the leading aetiological factor while in the 51-90 age group inflammation was the leading cause. They also found the presence of retinal detachment more important than inflammation in the causation of osseous metaplasia. Four patients (50%) in our series had inflammation as the inciting event while 3 had trauma and 1 patient had congenital microphthalmos. The nature of inflammation in these 4 cases was infectious keratitis following attack of polio (case 3), infectious keratitis (case 4), suspected toxoplasmosis (case 6) and endophthalmitis (case 7).

Intraocular osseous metaplasia does not occur only in phthisical eyes; 40% of patients with osseous metaplasia did not have phthisis bulbi as reported by Monsalie et al.[3] Only 4 of 8 (50%) eyes in our series were phthisical, while two eyes with osseous metaplasia in our series were staphylomatous. Only one case of intraocular ossification in a staphylomatous eye (which also harboured an adenoma of the retinal pigment epithelium) has been reported.[19] Another rare presentation in our series was sympathetic ophthalmia elicited by a phthisical eye with osseous metaplasia, enucleated 6 months following trauma. Interesting features in this case were the relatively short interval of developing osseous metaplasia and the association with sympathetic ophthalmia. The disorganisation of the layers following trauma, and the associated inflammation could have accelerated osseous metaplasia in this case. One patient in our series had congenital microphthalmos.

Presence of fibrofatty bone marrow was noted in 4 of 8 enucleated specimens. All these eyes had severe ossification involving both the pre- and the subretinal locations, but none of them revealed haematopoietic cells. The haematopoietic elements in the fatty marrow may be present (5-70%) [1,3] or may be totally absent, despite the close association of osteogenesis and hematopoiesis.[1] It could possibly be related to blood supply to the area of ossification,[3] or to its severity. The degree of ossification had no bearing on the duration of symptoms.


  Location of intraocular osseous metaplasia Top


Earlier studies reporting intraocular osseous metaplasia mostly included enucleated eyes and the site of ossification was solely external to the neurosensory retina.[1-7] Because of improved vitreoretinal surgical techniques, epiretinal membranes are now available for histopathologic studies. [10,11] There are two recent reports of osseous metaplasia in epiretinal membranes obtained at vitreoretinal surgery.[10],[11] We have recently reported a case of ossification within a epiretinal membrane obtained at vitreoretinal surgery from a diagnosed case of Eales' disease.[20] This patient had traction retinal detachment for 7 years and a recent history of rhegmatogenous retinal detachment.

In our series, ossification in the subretinal (sub RPE) location was noted in 3 cases, pre-retinal location in 1 case and in both locations in 4 cases. In 3 eyes with osseous metaplasia purely in the subretinal location, ossification was seen within the choroid, with associated drusen which showed varying degrees of fusion, calcification and ossification. Though there could be intraretinal calcification in certain conditions, the presence of calcification and bony spicules mainly along the Bruch's membrane, and corresponding to the drusen site prompts us to speculate that the drusen may form the nidus for subsequent ossification.

Ossification limited to the preretinal location (retrolental region extending to vitreous base and ora serrata) was seen in an enucleated eye which also showed fibrovascular epiretinal membrane; calcified drusen in the subretinal location.


  Pathogenic mechanisms Top


It was earlier believed that predisposition of choroid to ossification was due to its inherent high vascularity resulting in vascular delivery of osteoblasts.[1-3] However, it is now suggested that osseous metaplasia results from osteoblastic transformation of the retinal pigment epithelium.[14-18] Retinal pigment epithelium is now known to be a multipotential cell with the capacity to differentiate into a mesenchymal phenotype, including fibroblast and bone.[14] Based on our observations and the review of literature,[14-18] in eyes with chronic retinal detachment, retinal pigment epithelial hyperplasia, and drusen formation appear to be important for intraocular ossification.

Drusen, a nodular excrescence over the Bruch's membrane secreted by the retinal pigment epithelial cells is suggested to be an important step in the transdifferentiation of retinal pigment epithelium following retinal detachment,[16],[17] Drusen formation is also implied in the pathogenesis of age-related macular degeneration and has varying morphological presentations.[21] It is possible that some of the components within the drusen could act as a nidus or an inducing agent in the initial stages of osteogenesis within the eye. This could explain the calcification and ossification of drusen in the subretinal location in 3 cases as observed in our series. Ratnakar et al[22] also reported a close association of drusen with osteogenic areas in intraocular ossification. In advanced cases, however, the ossification could be extensive and involve more than one layer of the eyeball, wherein the exact chronology of events cannot be assessed. This stage of ossification is invariably associated with disorganization of all layers, fibrous proliferation incorporating the RPE, vitreous and retina, as evidenced by the GFAP positivity in our series.

The suggested mechanism in preretinal ossification is migration of retinal pigment epithelium from the sub-retinal space to the retinal surface, along the back surface of the detached retina (through retinal breaks).[10],[11] The principal source of fibrous and osseous metaplasia appears to be retinal pigment epithelium. Since the ossification in preretinal location is invariably seen within the fibrous membranes or the proliferating vitreoretinal mass, it could be speculated that there is a multi-directional metaplasia of the retinal pigment epithelial cells. The GFAP positivity of the epiretinal membranes and associated pigment hyperplasia could be either due to the transdifferentiation in the RPE or the intricate involvement of both retinal pigment epithelium and the neurosensory retina.[23] However, more than one mechanism may be involved in the advanced stage of ossification. It appears that though the retinal pigment epithelial cells are essential for intraocular ossification, the pathogenic mechanisms involved in the initial stages at pre and subretinal location are possibly different.

To summarise, in eyes with chronic retinal detachment and ossification, hyperplasia and transdifferentiation of retinal pigment epithelium appear to be among the prerequisites. While ossification is common in the subretinal location, preretinal osseous metaplasia is being increasingly identified. Drusen could possibly act as a nidus for subretinal ossification in the early stages. Preretinal osseous metaplasia is associated with retinal pigment epithelial metaplasia and proliferative vitreoretinopathy. The rare association of ossification in staphylomatous eye, and its early onset in a phthisical eye that incited sympathetic ophthalmia is a distinct possibility.

 
  References Top

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Casaroli-Marano RP, Pagan R, Vilaro S. Epithelial-mesenchymal transition in proliferative vitreo-retinopathy:intermediate filament protein expression in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 1999;40:2062-72.  Back to cited text no. 23
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    Figures

  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7]
 
 
    Tables

  [Table - 1]


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