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Primary localized orbital amyloid: case report and literature review; 2004-2015

      Amyloid fibril protein is a protein that is deposited as insoluble fibrils, mainly in extracellular spaces of organs and tissues as a resrult of a sequence of changes in protein folding.
      • Sipe J.D.
      • Benson M.D.
      • Buxbaum J.N.
      Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.
      By definition, amyloid must exhibit both affinity for Congo red and green birefringence when samples that are stained with Congo red are viewed under polarized light.
      • Sipe J.D.
      • Benson M.D.
      • Buxbaum J.N.
      Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.
      It can accumulate in all body tissues, including the brain, skin, respiratory tract, genitourinary tract, gastrointestinal tract, heart, spleen, soft tissues, and ocular and orbital tissues.
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      Amyloidosis results when amyloid proteins accumulate in any location in sufficient quantities to be clinically significant.
      Only 4% of head and neck amyloidosis involves the orbit.
      • Gean-Marton A.D.
      • Kirsch C.F.E.
      • Vezina L.G.
      • et al.
      Focal amyloidosis of the head and neck: evaluation with CT and MR imaging.
      Depositions most commonly occur in the tarsal conjunctiva, eyelids, and lacrimal gland. The lack of lymphatic drainage in other orbital structures, and the involvement of clonal B-lymphocytes in the pathophysiology of this disease have been quoted as putative explanations for this observation.
      • Murdoch I.E.
      • Sullivan T.J.
      • Moseley I.
      • et al.
      Primary localized amyloidosis of the orbit.
      • Lucas D.R.
      • Knox F.
      • Davies S.
      Apparent monoclonal origin of lymphocytes and plasma cells infiltrating ocular adnexal amyloid deposits: report of 2 cases.
      • Taban M.
      • Piva A.
      • See R.F.
      • et al.
      Review: orbital amyloidosis.

      Methods

      In addition to describing in detail the presentation and management of a case of primary localized eyelid and orbital amyloidosis, an English-language search was conducted using PubMed and OvidSP MEDLINE with the terms “orbital amyloidosis,” “conjunctival amyloidosis,” “eyelid amyloidosis,” and “ocular adnexal amyloidosis.” The reference sections of all resulting articles were screened for further articles. Only cases in which the amyloidosis was confined to the orbital and ocular adnexa were included in this review. Because Taban et al. covered this topic (excluding conjunctival amyloidosis) until early 2004, this review includes reports published since then.
      • Taban M.
      • Piva A.
      • See R.F.
      • et al.
      Review: orbital amyloidosis.

      Results

      Case Report

      A 38-year-old male presented to the emergency eye clinic with 4 weeks of gradual-onset, painless left upper eyelid ptosis. Medical history was non-contributory, and ophthalmic history was unremarkable. In particular, there was no history of trachoma, surgery, or trauma to the eyelid. On examination, left upper eyelid swelling and left globe ptosis were noted in addition to blepharoptosis (Fig. 1A). Vision was 20/20 OU. Pupils, intraocular pressure, extraocular motility, and alignment were within normal limits. Marginal reflex distance 1 (MRD1) was 5 mm OD and 2 mm OS. Pupillary fissures were 10 mm OD and 7 mm OS. Levator function was normal and symmetrical bilaterally. There was no proptosis. Eversion of the left upper eyelid showed a thickened reddish-brown plaque overlying the tarsal plate (Fig. 1B). Eversion of the other 3 eyelids, as well as anterior and posterior segment examination, revealed no abnormalities.
      Fig. 1
      Fig. 1A, Patient at presentation, showing lid thickening, ptosis, and slight globe ptosis. B, Patient at presentation, showing mass on palpebral surface of left upper lid.
      Pathological examination of a 2.5-mm punch biopsy of the lesion suggested amyloid light chain amyloid deposits within the conjunctival substantia propria. There was extensive eosinophilic amorphous material occupying the substantia propria associated with focal chronic inflammation in the form of lymphocytes and plasma cells scattered throughout the lesion as well as occasional multinucleated giant cells. The overlying epithelium was absent. Congo red staining showed apple green dichroism and birefringence. Immunohistochemistry for the amyloid precursor protein was negative, but kappa and lambda light chains were strongly positive. Transthyretin and fibrin stains were negative (Fig. 2).
      Fig. 2
      Fig. 2A, High-power photomicrograph of conjunctival excision showing amorphous eosinophilic material in the substantia propria with associated chronic inflammatory infiltrate. B, Material shows birefringence and dichroism with Congo red staining characteristic of amyloid.
      Computed tomography of the head and orbits showed no intracranial masses, but there was subtle thickening of the superolateral preseptal soft tissues of the left orbit with probable extension into thickened pre- and postseptal components of the left lacrimal gland (Fig. 3).
      Fig. 3
      Fig. 3Coronal section of noncontrast computed tomography scan of orbits showing subtle thickening of the superolateral preseptal soft tissues of the left orbit with probable extension into thickened pre- and postseptal components of the left lacrimal gland.
      Systemic evaluation revealed no evidence of amyloidosis elsewhere. The eyelid lesion was resected surgically by approaching it from the side of the tarsal conjunctiva. Over the course of the next 10 months, the ptosis and lid swelling resolved. A small amount of globe ptosis remains (Fig. 4).
      Fig. 4
      Fig. 4Ten months after surgical excision of palpebral amyloid deposits, upper eyelid ptosis and lid thickening have resolved, but slight globe ptosis remains.

      Literature Review

      Our extensive review of the literature for all cases of primary localized orbital and ocular adnexal amyloidosis since 2004 yielded 71 cases (Table 1): 64% were female, sex was unspecified in 2 cases, and 22% showed bilateral disease. The age range was 15 to 86 years, with most cases clustered in the fifth to seventh decade of life. See Table 2 for location of involvement and Table 3 for presenting symptoms and signs.
      Table 1Review of all cases of primary localized orbital and ocular adnexal amyloidosis reported in the literature since 2004
      AuthorNo.Age, SexSymptomsLocation of Amyloid DepositionAmyloid TypeRTreatment
      Dithmar et al.
      • Dithmar S.
      • Linke R.P.
      • Kolling G.
      • et al.
      Ptosis from localized A-lambda-amyloid deposits in the levator palpebrae muscle.
      136, FRight ptosisLevator palpebrae muscle infiltration, years later inferior fornixALYLevator resection—twice
      Kaplan et al.
      • Kaplan B.
      • Martin B.M.
      • Cohen H.I.
      • et al.
      Primary localized orbital amyloidosis biochemical identification of immuno globulin light chain K subtype tissue sample.
      144, sex unavailableLeft-sided slight visual disturbance and orbital swellingLeft orbitAL kV-IIINSurgical excision
      Dinkaran et al.
      • Dinkaran S.
      • Singh A.D.
      • Rennie I.G.
      Orbital amyloidosis presenting as ptosis.
      260, FPtosis, recurrent conjunctival hemorrhage, orbital massSuperior orbital mass prolapsing through fornixN/AN/ASurgical debulking
      61, FLeft ptosis and eyelid massLacrimal gland massN/AN/ABiopsy only
      Biewend et al.
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      165, sex unavailableLeft conjunctival massBulbar conjunctival mass, perilimbal almost 360 degALYConservative
      Tyradellis et al.
      • Tyradellis C.
      • Peponis V.
      • Kulwin D.R.
      Surgical management of recurrent localized eyelid amyloidosis.
      167, FEctropion, eyelid thickeningLeft medial lower lidALYSurgical resection
      DiBari et al.
      • DiBari R.
      • Guerriero S.
      • Giancipoli G.
      • et al.
      Primary localized orbital amyloidosis: a case report.
      164, FLeft-sided orbital mass, mild exophthalmos with downward ocular displacement, ptosis, visual acuity loss, ocular hypertension, ischemic optic neuropathyExtraconal mass, following the course of the superior rectus muscleN/AN/ASurgical debulking
      Demirci et al.
      • Demirci H.
      • Shields C.L.
      • Eagle R.C.
      • Shields J.A.
      Conjunctival amyloidosis: report of six cases and review of the literature.
      62, M; 4, F; age range 42–86 yrPtosis (2), conjunctival mass (6), subconjunctival hemorrhage (4)All: conjunctiva (2): anterior orbit and eyelid, 1 bilateralAvailable for 2: predominantly kappa; IgA Kappa2 of 62: excisional biopsy of focal lesions
      4: incisional biopsy of diffuse lesions
      Leibovitch et al.
      • Leibovitch I.
      • Selva D.
      • Goldberg R.A.
      • et al.
      Periocular and orbital amyloidosis: clinical characteristics, management, and outcome.
      2415, F; 9, M; mean age 57 ± 17 yrVisible mass (23), ptosis (13), discomfort (25), proptosis or globe displacement (5), ocular motility disturbance (4), recurrent periocular subcutaneous hemorrhage (3), diplopia (2)Orbit (7), periocular (17), unilateral (19), bilateral (5)AL (7), unclear (4), unavailable (13)5 of 248 observed, 10 surgical excision/debulking, 2 radiotherapy
      1 systemic amyloidosis: not included in analysis
      Lezrek et al.
      • Lezrek M.
      • Dahreddine M.
      • Bencherif Z.
      • et al.
      Bilateral primary pseudotumoral palpebral amyloidosis. A case report.
      157, FBilateral upper eyelid swelling and ptosisBilateral upper eyelidsN/ANSurgical resection
      Hill et al.
      • Hill V.E.
      • Brownstein S.
      • Jordan D.R.
      Ptosis secondary to amyloidosis of the tarsal conjunctiva and tarsus.
      163, FLeft ptosisTarsus and tarsal conjunctivaN/ANSurgical resection, levator advancement
      Khaira et al.
      • Khaira M.
      • Mutamba A.
      • Meligonis G.
      • et al.
      The use of radiotherapy for the treatment of localized orbital amyloidosis.
      159, FDiplopia, lateral left upper eyelid swelling, 2 mm proptosisLateral and inferior rectus muscles—encased by amyloidALNPartial surgical resection, radiotherapy (30 Gy in 15 fractions, 6 MV photons)
      Spitellie et al.
      • Spitellie P.H.
      • Jordan D.R.
      • Gooi P.
      • et al.
      Primary localized conjunctival amyloidosis simulating a lymphoproliferative disorder.
      139, FPtosis, inferior globe displacementLeft superomedial conjunctiva, anterior orbit, left upper eyelidKappa light chains and transthyretinNObservation
      Mesa-Gutierrez et al.
      • Mesa-Gutiérrez J.C.
      • Huguet T.M.
      • Garcia N.B.
      • Ginebreda J.A.
      Primary localized conjunctival amyloidosis: a case report with a ten-year follow-up period.
      157, FVisible conjunctival massNear left semilunar foldAAN/ASurgical excision
      Fraunfelder
      • Fraunfelder F.W.
      Liquid nitrogen therapy for conjunctival amyloidosis.
      42, M; 2, F; age range 50–70 yrPtosis, epiphora, all unilateralConjunctivaN/A2 of 4Surgical biopsy and liquid nitrogen cryotherapy (3), liquid nitrogen cryotherapy alone (1)
      Cagiattii et al.
      • Cagiattii A.
      • Campanella A.
      • Tenna S.
      • et al.
      Primary amyloidosis of the eyelid: a case report.
      130, MBilateral, assymetrical upper lid ptosis, lower lid edemaSubcutaneous lid, palpebral and bulbar conjunctivaN/ANElectrocauterization, CO2 laser vaporization of conjunctival lesions, surgical resection of eyelid lesion
      Naxer et al.
      • Naxer S.
      • Behnes C.L.
      • Schittkowski M.P.
      Amyloidosis—a rare differential diagnosis of an orbital tumour.
      250, FLeft ptosis, proptosis, motility deficit, globe ptosisLeft orbitN/AN/ASurgical debulking
      68, MRight ptosisRight pretarsal conjunctivaN/AN/ASurgical excision
      Al-Nuaimi et al.
      • Al-Nuaimi D.
      • Bhatt P.R.
      • Steeples L.
      • et al.
      Amyloidosis of the orbit and adnexae.
      104, F; 6, M; age range 38–86 yrPtosis (5), visible conjunctival mass (7), proptosis (2)Palpebral conjunctiva (8), bulbar conjunctiva (2), orbit (2), lacrimal gland (1) bilateral (4)N/A3 of 106: surgery
      4: conservative
      Al Hussain
      • Al-Hussain H.
      • Edward D.
      Anterior orbit and adnexal amyloidosis.
      62, M; 4,F; age range 25–75 yr; mean 46.3 yrPtosis (5), lacrimal gland mass (2), lid mass (5)Lacrimal gland, anterior orbit, conjunctiva (3)2 available: polyclonal IgG-associated amyloid deposition in 1 patient and AL kappa amyloid2 of 6Surgical resection for all, ptosis repair for 3
      eyelid only (3)
      Aryasit et al.
      • Aryasit O.
      • Preechawai P.
      • Kayasut K.
      Clinical presentation, treatment, and prognosis of periocular and orbital amyloidosisin a university-based referral center.
      65, F; 1, M; mean 39.7 yr; range 15–79 yrMass lesion (83.3%), irritation (66.7%), bloody tears (16.7%), epiphora (16.7%), eye pain (16.7%), ptosis (16.7%)Eyelid (4), lacrimal gland (1), conjunctiva (2), punctum (1)N/A2 of 65: surgical excision or debulking
      1: canaliculotomy
      bilateral (4)1: levator resection
      Murchison et al.
      • Murchison A.P.
      • Bilyk J.R.
      • Savino P.J.
      Orbital amyloidosis masquerading as metastatic breast carcinoma.
      182, FRight progressive binocular diplopia, enophthalmosRight inferolateral intraconal fat and possible lacrimal gland enlargementALNRadiotherapy
      M, male; F, female; #, number of patients in report; R, recurrence; Y, yes; N, no; N/A, not available; AL, amyloid light chain; AA, protein A amyloid.
      Table 2Location of amyloid deposition among 72 cases of primary localized orbital and ocular adnexal amyloidosis reported since 2004
      Location of Amyloid DepositionPercent of Cases
      Eyelid54
      Orbit28
      Conjunctiva26
      Lacrimal gland10
      Extraocular muscle1.3
      Punctum1.3
      Levator palpebrae muscle1.3
      Table 3Presenting signs and symptoms among 72 cases of primary localized orbital and ocular adnexal amyloidosis reported since 2004
      Sign or SymptomPercent of Cases
      Visible mass (usually conjunctiva or eyelid)72
      Ptosis62
      Discomfort42
      Proptosis14
      Subconjunctival or subcutaneous hemorrhage11
      Extraocular motility deficits7.0
      Diplopia5.5
      Eyelid thickening or edema5.5
      Globe ptosis4.2
      Epiphora2.8
      Visual disturbance or decline2.8
      Bloody tears1.4
      Enophthalmos1.4
      Ocular hypertension1.4
      At least 6 out of 71 cases (8.5%) had amyloid deposits in the orbit with extension to either the lids or the conjunctiva. While the vast majority of cases were treated surgically with either excision or at least debulking, 5.5% were treated with external beam radiation, 4% of cases were observed, another 4% received levator resection, 2.6% received liquid nitrogen, 1.3% needed canaliculotomy, and 1.3% received electrocauterization and CO2 laser vaporization of conjunctival vegetations. Recurrence was reported in 19.4%, but many of these cases had not received complete excision at initial presentation, and some studies reported excising the same lesion more than once.

      Discussion

      In a review of the literature, Taban et al. uncovered 31 cases of primary localized orbital amyloidosis reported until 2004.
      • Taban M.
      • Piva A.
      • See R.F.
      • et al.
      Review: orbital amyloidosis.
      The most predominant symptoms were ptosis, proptosis, and globe displacement, and 81% of cases were unilateral and most were also in the upper part of the orbit. Visual impairment was only recorded in 5 patients.
      Our patient exhibits some typical features such as ptosis, globe displacement, extension into upper orbit, and unilaterality. As with most other cases in the literature, he did not require levator resection and was treated with surgical excision of the palpebral portion of the amyloid. However, his sex and younger age make him somewhat atypical. Nonetheless, given the high recurrence rate of amyloidosis especially in patients with orbital extension,
      • Taban M.
      • Piva A.
      • See R.F.
      • et al.
      Review: orbital amyloidosis.
      he will require regular follow-up well into the foreseeable future.
      Most studies defined ptosis based on a reduction in the distance from the upper eyelid margin to the corneal light reflex (MRD1). While ptosis was present in 62.5% of cases, only 1.3% of cases showed levator muscle infiltration by amyloid, and only 4% required levator resection. This illustrates the multifactorial nature of the ptosis caused by orbital and ocular adnexal amyloidosis. The downward mechanical effect of the amyloid deposits on the eyelid was implicated in many cases, including ours, and eyelid edema–caused amyloid deposits were the cause of ptosis in a few others.
      Orbital and ocular adnexal amyloidosis has been reported in association with multiple myeloma,
      • Knowles D.M.
      • Jakobiec F.A.
      • Rosen M.
      • Howard G.
      Amyloidosis of the orbit and adnexa.
      monoclonal gammopathy of unknown significance,
      • Oishi A.
      • Miyamoto K.
      • Yoshimura N.
      Orbital amyloidosis-induced compressive optic neuropathy accompanied by characteristic eyelid pigmentation.
      cardiomyopathy,
      • Oishi A.
      • Miyamoto K.
      • Yoshimura N.
      Orbital amyloidosis-induced compressive optic neuropathy accompanied by characteristic eyelid pigmentation.
      extranodal marginal zone lymphoma,
      • Khaira M.
      • Mutamba A.
      • Meligonis G.
      • et al.
      The use of radiotherapy for the treatment of localized orbital amyloidosis.
      and plasma cell myeloma.
      • Chee E.
      • Kim Y.D.
      • Lee J.H.
      • Woo K.I.
      Chronic eyelid swelling as an initial manifestation of myeloma-associated amyloidosis.
      Moreover, amyloidosis, with and without orbital and ocular adnexal involvement, has been found in the gastrointestinal tract,
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      • Stack R.R.
      • Vote B.J.
      • Evans J.L.
      • Elder M.J.
      Bilateral ptosis caused by localized superficial eyelid amyloidosis.
      • Bernardini F.P.
      • Schneider S.
      • Conciliis C.
      • Devoto M.H.
      Advanced periocular, facial, and oral amyloidosis.
      respiratory tract,
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      • Wu A.Y.
      • Chapman W.B.
      • Witterick I.J.
      • DeAngelis D.D.
      Bifocal orbital and nasopharyngeal amyloidomas presenting as Graves disease.
      genitourinary tract,
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      liver,
      • Demirci H.
      • Shields C.L.
      • Eagle R.C.
      • Shields J.A.
      Conjunctival amyloidosis: report of six cases and review of the literature.
      pancreas,
      • Onur M.R.
      • Yalnız M.
      • Poyraz A.K.
      • et al.
      Pancreatic islet cell amyloidosis manifesting as a large pancreas.
      • Tomita T.
      Amyloidosis of pancreatic islets in primary amyloidosis (AL type).
      salivary glands,
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      central nervous system,
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      skin,
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      and soft tissue.
      • Sipe J.D.
      • Benson M.D.
      • Buxbaum J.N.
      Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.
      • Biewend M.L.
      • Menke D.M.
      • Calamia K.T.
      The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature.
      Therefore, patients presenting with amyloid accumulations in 1 organ system should be worked up for systemic involvement. The following tests are commonly used: physical examination, complete blood count, serum electrolytes, urine analysis, serum/urine protein electrophoresis and immunofixation, liver function tests, prothrombin time, activated partial prothrombin time, 24-hour urine protein, Bence Jones protein, electrocardiogram, abdominal ultrasound, and bone scan.
      • Taban M.
      • Piva A.
      • See R.F.
      • et al.
      Review: orbital amyloidosis.
      • Spitellie P.H.
      • Jordan D.R.
      • Gooi P.
      • et al.
      Primary localized conjunctival amyloidosis simulating a lymphoproliferative disorder.
      • Leibovitch I.
      • Selva D.
      • Goldberg R.A.
      • et al.
      Periocular and orbital amyloidosis: clinical characteristics, management, and outcome.
      Furthermore, compressive optic neuropathy,
      • Oishi A.
      • Miyamoto K.
      • Yoshimura N.
      Orbital amyloidosis-induced compressive optic neuropathy accompanied by characteristic eyelid pigmentation.
      vision loss, and ocular hypertension have all been reported with orbital amyloid.
      • DiBari R.
      • Guerriero S.
      • Giancipoli G.
      • et al.
      Primary localized orbital amyloidosis: a case report.

      Conclusions

      This case and the subsequent review of the literature serve to reinforce several important points. First, amyloidosis of the orbit or ocular adnexa can have varying presentations, the most common of which is ptosis and visible mass. Second, since conjunctival or palpebral amyloidosis can coexist with orbital amyloidosis in at least 8.5% of cases, orbital imaging is warranted in all cases of ocular adnexal amyloidosis. Third, although surgical excision or debulking is the most common treatment option, observation and other modalities have been reported. Fourth, although most cases of orbital and ocular adnexal amyloid are localized, systemic associations with many organ systems have been reported and can be ruled out through extensive blood work and selected imaging modalities. Lastly, because of a substantial rate of recurrences, patients require long-term follow-up.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

      Acknowledgements

      This material has not been presented elsewhere, and we received no funding from any source to complete this work.

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