British Journal of Ophthalmology 1996;80:1083-1086

Primary localised amyloidosis of the orbit

I E Murdoch, T J Sullivan, I Moseley, P N Hawkins, M B Pepys, S Y Tan, A Garner,J E Wright

AbstractAimslbackground-Primary localisedamyloidosis is rarely encountered in theorbit. The typical clinical and radiologicalappearances have not been clearly estab-lished, in particular the single site deposi-tion of amyloid has never been proved.Methods-Six cases were reviewed indetail and their clinical and radiologicalcharacteristics are described here. Fourpatients had scintigraphy with 123I serumamyloid P component and one patient hadtyping ofthe amyloid fibrils.Results-All the patients had a firm massin the upper orbit with a predilection forthe region of the lacrimal gland. Com-puted tomography showed a homogene-ous mass with thickening and irregularityof the adjacent bone and/or calcificationwithin the mass. None was associated withsystemic disease. Scintigraphy with 123Iserum amyloid P component demon-strated that the amyloid was confined tothe orbit. In one patient the amyloid fibrilswere derived from an IgG4 heavy chainconstant domain. The lesions were par-tially excised with subsequent clinical sta-bility over 6 months to 18 years in all butone patient who had continued enlarge-ment ofthe lesion.Conclusion-There is a characteristicclinical and radiological pattern for pri-mary localised amyloidosis of the orbit.The disease process is truly local and notpart of a systemic process. A majorityrespond to simple debulking with subse-quent observation.(BrJ7 Ophthalmol 1996;80: 1083-1086)

Amyloidosis is a disorder of protein metabo-lism characterised by the extracellular deposi-tion of abnormal protein fibrils." It may belocalised or distributed throughout the body,causing organ damage and serious morbidity.Major visceral involvement, especially of thekidneys and heart, is usually fatal. The fibrilswhich form the bulk of amyloid deposits arederived from a variety of precursor proteins indifferent forms of the disease but are alwaysintimately associated with sulphated gly-cosaminoglycans. In addition, the normalcirculating glycoprotein, serum amyloid Pcomponent (SAP), specifically binds to thefibrils and is a universal constituent of amyloiddeposits.Amyloid in the orbit is rare; there are only 27

previously reported cases. It usually occurs inisolation, not as part of a systemic disease. Pre-vious reports have usually been limited tosingle case histories and the overall clinical

pattern of presentation and radiology has notbeen well documented. Localisation of amyloidjust to the orbit has usually not been estab-lished and apart from one of the cases in thepresent study' the fibril protein has been iden-tified only once before.

MethodsSix cases ofprimary localised amyloidosis werereviewed in detail.

CASE 1A 60-year-old man noticed a slowly progressivedrooping ofthe right upper lid for 12 years anddouble vision when looking down for 4months. He was fit and healthy with noprevious illness. There was a right ptosis of 2mm. The right eye was proptosed 4 mm anddisplaced downwards 10 mm. There was noother significant ocular abnormality.

Plain films of the orbits were normal. Com-puted tomography (CT) revealed a 2 x 2 cmsoft tissue mass, slightly denser than the brain,in the upper portion of the right orbit. Thelesion was rounded, but more irregular superi-orly, moulded to the globe, which it displacedanteroinferiorly, and extended forwards intothe upper lid. There was questionable irregu-larity of the adjacent bone of the roof of theorbit, with possibly a small spicule of calcificdensity related to it. The paranasal sinusesshowed evidence of widespread inflammatorydisease.The lesion was approached trans-septally

and the major portion of the mass excised.Histology showed a hypocellular mass offibrous tissue and amyloid. The amyloid had apredominantly perivascular location. A smallnumber of lymphoid cells were also present.Scintigraphy with '23I SAP was performed.There has been no recurrence during a followup of 6 years.

CASE 2An 87-year-old man with mild bronchitis andan 8 year history of non-insulin dependentdiabetes mellitus noticed a painless progressiveswelling of his left upper lid for 6 months. Theleft eye was displaced medially 3 mm by a firmsubcutaneous mass in the upper lid whichextended subconjunctivally over the lateralpart of the globe. The palpebral aperture wasnarrowed by 6 mm and there was restriction ofvertical and horizontal movement of the globe.Ocular examination was otherwise normal.CT showed a 2 x 1 cm homogeneous soft

tissue mass in the region of the left lacrimalgland, whose density was slightly higher thanthat of the brain. The mass appeared to involvethe anterior end of the lateral rectus muscle.There was generalised sinusitis.

Orbital Clinic,Moorfields EyeHospital, LondonI E MurdochT J SullivanI MoseleyJ E Wright

ImmunologicalMedicine Unit,HammersmithHospital, LondonP N HawkinsM B PepysS Y Tan

Institute ofOphthalmology,LondonA Garner

Correspondence to:I Murdoch, MoorfieldsEye Hospital, LondonEC1V 2PD.

Accepted for publication16 September 1996

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Murdoch, Sullivan, Moseley, Hawkins, Pepys, Tan, Garner, Wright

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Figure 1 Primary localised amyloidosis of the orbit, case 3, showing mass in right uppereyelid.

Figure 2 Primary localised amyloidosis of the orbit, CT scan of case 3 showing oculardisplacement by mass, calcification within mass, and thickening of the lateral wall of theorbit.

Figure 3 Primary localised amyloidosis of the orbit, showing the extensive amorphousmaterial typical of amyloid in case 3.

Biopsy of the mass revealed dense interstitialand vascular wall amyloid, with small chronicinflammatory cell aggregates. Follow up is lim-ited to the immediate postoperative period.

CASE 3

A 29-year-old woman with no history of previ-ous illness had a 4 year history of recurrentperiorbital bruising and a lump in the lateralpart of her right upper eyelid (Fig 1). She

experienced periocular discomfort once ortwice a week, aggravated by vomiting or strain-ing. There was a firm fixed mass of 2 cm by 1cm attached to bone at the right lateral canthuswith a palpable irregularity of the adjacentbone. The right eye was proptosed 1 mm anddisplaced 4 mm medially. There was no otherocular abnormality.CT showed a mass in the right lacrimal

fossa, 1 cm in transverse and 2 cm inanteroposterior diameter. The lower part of thelesion was of soft tissue density, slightly denserthan the brain, but its upper part was denselycalcified, resembling a lobulated nodule ofbone (Fig 2), with a less dense centre. Theanterior portion of the lateral rectus musclemay have been involved by the mass, which wasmoulded to the globe, displacing it downwardsand forwards. An apparent plane of cleavagewas visible between the calcified or ossifiedcomponent and the lateral wall of the orbit, butthe latter was thickened and there was also asmall fleck of calcification near its outersurface, in the temporal fossa. CT 15 monthslater showed some progression of the mass,particularly the calcified or ossified portion.Two orbital biopsies were taken 12 months

apart. The amyloid tissue was exposed and fur-ther dissection showed that the superotempo-ral orbital wall was soft and red. Biopsies takenfrom this area and from the amorphous mate-rial in the lacrimal fossa contained abundantamyloid (Fig 3). The bone around the amyloidwas decalcified and showed formation ofwoven bone and remodelling of lamellar bonewith osteoclastic activity. There was variablerecalcification. Scintigraphy with 123I SAP wasperformed. The lesion has remained static overa further 4 years of follow up.

CASE 4A 42-year-old woman had noticed a swelling inthe inner aspect of her left upper lid for 18months. There were no past illnesses. The lefteye was displaced 4 mm laterally and 2 mminferiorly by a firm mass deep to the medialupper lid, measuring 4 x 1 cm. This mass couldbe seen in the upper fornix as an area of greytissue beneath the conjunctiva. There was noother ocular or orbital abnormality.CT demonstrated a somewhat inhomogene-

ous soft tissue mass, slightly denser than thebrain, in the superior temporal quadrant of theright orbit. It measured 2.5 cm in anteroposte-rior diameter, 2 cm across, and was 1 cm thick.The mass was rounded, moulded to the globe(Fig 4), and appeared to involve the superiorrectus muscle. The overlying bone was thick-ened with a focal zone of irregular calcificationor ossification posteriorly either on the under-surface of the bone or separate from it. Therewas generalised sinusitis.The lesion was biopsied and showed exten-

sive amorphous material staining positively foramyloid with occasional blood vessels andsome mild chronic inflammatory cell infiltra-tion. Scintigraphy with "23I SAP was per-formed. Over 3 years of follow up the mass hasslowly enlarged. As vision is not threatened ithas been decided that the risks of surgical

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Primary localised amyloidosis of the orbit

Figure 4 Primary localised amyloidosis of the orbit, non-homogeneous orbital tissue masslateral to and above right eye, case 4.

intervention outweigh the benefits, so a con-servative approach has been adopted.

CASE 5

A 67-year-old man noticed drooping andswelling of his left upper lid for 7 months.There was a firm subcutaneous, mobile masssuperotemporally in his left orbit with no prop-tosis or displacement of the globe. His leftpalpebral aperture was narrowed by 2 mm. Noother ocular or orbital abnormality was found.CT showed generalised but predominantly

anterior, smooth expansion of the left lacrimalgland, which was of slightly higher density thanthe brain. The gland was moulded to the globe,which was-displaced downwards and forwards.The adjacent bone appeared normal.The lesion was biopsied and found to be

within the lacrimal gland. Histology showedamyloid interspersed with blood vessels andmild chronic inflammatory cell infiltration.Over the subsequent 6 months there has beenno progression of the lesion.

CASE 6

A 75-year-old woman, blind in her left eyefrom childhood trauma, noticed drooping ofher right upper eyelid for approximately 1 year.She had no history of any systemic illness. Heracuity was 6/9 and colour vision was normal.There was right periorbital oedema with 6 mmproptosis, 6 mm medial and 3 mm inferiordeviation of the globe. The right eye could notabduct and all other movements were severelyrestricted.CT showed a mass, generally smooth and

lobulated, in the superior temporal quadrant ofthe right orbit. It was 3 cm in anteroposteriordiameter, 2.5 cm across, and 2 cm vertically.The mass could not be separated radiologicallyfrom the lateral rectus muscle, and the superiorrectus was also swollen. It was moulded to theglobe, which it displaced downwards andforwards. The overlying bone was thinned. Asmall focus of calcification, resembling a phle-bolith, was seen within the lateral part of themass, adjacent to but separate from the bone ofthe lateral wall of the orbit.

Biopsy showed amyloid within the lacrimalgland, particularly around vessels, and achronic inflammatory cell infiltrate. Wholebody scintigraphy with 123I SAP was per-formed. Amyloid fibrils were isolated fromresected tissue and the subunit protein wascharacterised by amino acid sequencing. Therehas been no progression of the lesion over 2years of subsequent review.

ResultsThe most common presenting symptoms ofprimary localised orbital amyloid are ptosis,proptosis, and global displacement with novisual impairment. The lesion is typically afirm, non-tender, easily palpable mass in thesuperotemporal aspect of the orbit. In fivecases the lacrimal gland was intimately in-volved with the amyloid mass.CT scanning is the most helpful method of

imaging. It typically shows a soft tissue mass inthe superotemporal quadrant ofthe orbit, oftencentimetres in diameter and extending for-wards to involve the upper lid. It is usuallyrather homogeneous, slightly denser thanbrain, and may show homogeneous contrastenhancement. Associated thickening and ir-regularity of adjacent bone and/or calcificationwithin the soft tissue mass are changes sugges-tive of the diagnosis.

In no case was the biopsy proved orbitalamyloid found to be part of a systemic disease.Scintography in cases 1, 3, 4, and 6 proved thelesion to be unique to the orbit. Amino acidsequencing of the protein chain in the amyloidfibrils of case 6 showed it to be a constantdomain of the heavy chain of IgG4.'

DiscussionAmyloid P component (AP) is a universal con-stituent of amyloid deposits and is derivedfrom the normal circulating plasma protein,serum amyloid P component. Isolated purehuman SAP radiolabelled with 123I has beendeveloped as a highly specific, sensitive, quan-titative diagnostic tracer for all types ofamyloidosis.45 It was used in four of ourpatients to demonstrate that the amyloid wasconfined to the orbit. Although SAP scintigra-phy cannot exclude microscopic amyloid de-posits elsewhere the negative results were inaccord with the absence of any demonstrablevisceral or other organ dysfunction.Conlon et al in 1991 reported that the amy-

loid deposits in a 72-year-old woman who pre-sented with bilateral lacrimal gland swellingshowed immunohistochemical and immuno-electron microscopic staining for immuno-globulin X light chains.6 Case 6 in this series isthe first case of localised orbital amyloidosis inwhich amyloid fibrils have been extracted,allowing direct chemical identification of thefibril protein in this individual as the third con-stant domain of y heavy chains of IgG4subclass.' While amyloid derived from Ig heavychains is extremely rare, this being only thethird reported example, monoclonal Ig lightchains are very commonly the cause of bothsystemic and localised forms of amyloidosis. Inall such cases there is an underlying clonal

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Murdoch, Suglivan, Moseley, Hawkins, Pepys, Tan, Garner, Wright

disorder of cells of B lymphocyte lineage, lead-ing to monoclonal gammopathy that may beovert, as in multiple myeloma or so calledbenign monoclonal gammopathy, or occult,presenting only with amyloid. All forms ofextracerebral solitary amyloid mass lesions thathave been biochemically characterised havebeen of this Ig light chain, so called AL type.

IW. five of our cases the lacrimal gland wasintimately involved with the amyloid mass.There are no lymphatic vessels within the orbitwith the exception of the lacrimal gland.' Thepredilection for the lacrimal gland in themajority of patients with orbital amyloid maybe due to the presence of these lymphatics andis compatible with a clonal B lymphocyte basisfor this condition. All of our cases remainedunilateral in contrast with systemic amyloidosisin which the lacrimal gland is frequentlyinvolved bilaterally.Twenty seven cases of orbital amyloid have

been reported previously. Three of these werepossibly secondary to infection8 or systemicdisease.910 The remaining 24 cases6 11-32 show avery similar patern of presentation to ourpresent series. The reported cases also find thethree most common presenting symptoms tobe ptosis, proptosis, and global displacement,with visual impairment due to the lesion beingrecorded only three times.....3 The amyloiddeposit is characteristically unilateral (19reported cases) and confined to the upper partof the orbit (18 reported cases). Most (15)were described as hard or firm, fairly easily pal-pable and not tender. In one of our cases and infive other cases891 1617 the mass was noted to befixed to bone. Two further reports record afixed mass.'4 15

Comprehensive radiological reports of pri-mary amyloid masses in the orbits are rare.Moseley and Sanders reported a patient with alarge mass in the upper part of the right orbitwhich was radiologically inseparable from thelateral and superior rectus muscles. There wasno other abnormality on the films and the massincreased in size over an 8 month period ofradiological observation.2' In four of our casesthere was some involvement of the rectus mus-cles, an observation made three times be-fore.232526 These radiological findings are non-specific but in four of our cases and a furtherfour reported cases" 2224 associated thickeningand irregularity of the adjacent bone and/orzones of calcification or ossification within thesoft tissue mass were apparent. These changesare much more suggestive of the diagnosis.Only one case report exists of magnetic reso-

nance imaging in this condition.2" A protondensity axial section showed a lesion ofnon-specific soft tissue intensity in an unusualposition, below and abutting the optic nerve,which the authors mistook for a meningioma.Since calcification is helpful in differentiatingamyloid from other lesions MRI is less suitedthan CT for imaging orbital amyloid.The management of orbital amyloidosis is

difficult. Most lesions slowly enlarge and causeproblems by displacing the globe. Total exci-sion is usually impossible and surgery shouldbe directed to the excision of the major portion

of the mass with the preservation of the palpe-bral lobe of the lacrimal gland, the lebator pal-pabrae superioris, and the rectus muscles.

We thank the many other ophthalmologists involved in themanagement of these patients for their help. Characterisation ofthe amyloid fibril protein and studies ofwith 123I SAP were sup-ported by MRC Programme Grant G7900510 to MBP. Mr GRose, consultant ophthalmologist, kindly donated the photo-graph used for Figure 1.

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4 Hawkins PN, Lavender JP, Pepys MB. Evaluation ofsystemic amyloidosis by scintigraphy with 123I-labeledserum amyloid P component. NEnglJMed 1990;323:508-13.

5 Hawkins PN. Studies with radiolabelled serum amyloid Pcomponent provide evidence for turnover and regression ofamyloid deposits in vivo. Clin Sci 1994;87:289-95.

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