Conjunctival Amyloidosis: Report of Six Cases and Review of the Literature

SURVEY OF OPHTHALMOLOGY

VOLUME 51  NUMBER 4  JULY–AUGUST 2006

CLINICAL PATHOLOGIC REVIEWS STEFAN SEREGARD AND MILTON BONIUK, EDITORS

Conjunctival Amyloidosis: Report of Six Cases and Review of the Literature Hakan Demirci, MD,1 Carol L. Shields, MD,1 Ralph C. Eagle, Jr, MD,2 and Jerry A. Shields, MD1 1

Oncology Service, and 2Pathology Department, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Abstract. Conjunctival amyloidosis is an uncommon condition that occasionally is associated with systemic involvement. The clinical presentations of conjunctival amyloidosis are diverse. We present six patients with conjunctival amyloidosis who were referred to us with the suspicion of another conjunctival lesion. The conjunctival lesion was circumscribed in two patients and diffuse in four patients. The lesion color was yellow in one patient and yellow-pink in five patients. The associated features were intrinsic vascularization (six patients), recurrent subconjunctival hemorrhage (four patients) and blepharoptosis that involved the palpebral conjunctiva (two patients). Systemic evaluation revealed primary systemic amyloidosis in one patient and no related systemic abnormalities in five patients. Management consisted of complete excisional biopsy for the two circumscribed lesions and incisional biopsy for the four diffuse lesions. Two patients with diffuse involvement showed progressive involvement of the conjunctiva over 3 years following incisional biopsy and the other four patients remained stable. Additionally, there was no systemic involvement in five patients. In conclusion, conjunctival amyloidosis generally manifests as a yellowish-pink, hemorrhagic mass deep to the epithelium. Most patients show no evidence of systemic amyloidosis. (Surv Ophthalmol 51:419-433, 2006. Ó 2006 Elsevier Inc. All rights reserved.) Key words. adnexa  amyloid  amyloidosis subconjunctival hemorrhage  tumor



conjunctiva



eye



lymphoma



physiologic damage.7 Likewise, with regard to the eye, amyloidosis can occur as a localized mass or as a part of a systemic disorder.24 Eyelid involvement with amyloidosis has been found associated with both immunologic (primary) and reactive (secondary) systemic amyloidoses. However, conjunctival amyloidosis generally is thought to be the manifestation of a local immunologic disorder and affected patients rarely have systemic amyloidosis.18,39,46

Introduction Amyloidosis is a spectrum of disorders characterized by the deposition of amyloid, an extracellular protein in an abnormal fibrillar form, with highly characteristic histopathologic staining properties.37 The clinical presentation can vary from a focal, localized lesion where amyloidosis has minor clinical consequences, to extensive systemic disease that can involve almost any organ system of the body, leading to severe patho419 Ó 2006 by Elsevier Inc. All rights reserved.

0039-6257/06/$--see front matter doi:10.1016/j.survophthal.2006.04.007

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Surv Ophthalmol 51 (4) July--August 2006

Conjunctival amyloidosis is an uncommon condition. In a review of 2,455 conjunctival lesions submitted to a pathology laboratory, only five patients (0.002%) were found to have conjunctival amyloidosis.14 Because of its rarity, the clinical diagnosis is often overlooked and systemic evaluation might be neglected. Failure to recognize conjunctival amyloidosis might lead to extensive surgical procedures often complicated by hemorrhage. We report six patients with conjunctival amyloidosis, all of whom were referred to us with the suspicion of another conjunctival lesion. PATIENTS AND METHODS

We reviewed the computerized files of the Ocular Oncology Service at Wills Eye Hospital between January 1974 to November 2002. We identified and reviewed six patients with the diagnosis of conjunctival amyloidosis. We compared our findings with those reported in the literature. RESULTS

The patient findings are summarized in Table 1.

Illustrative Patient Reports PATIENT 1

A 45-year-old white man noted 10 years of intermittent conjunctival hyperemia and a growth on conjunctiva of his right eye. He had been treated with topical antihistamines and corticosteroids for allergic conjunctivitis. Persistence of symptoms prompted referral to us. The visual acuity was 20/20 in each eye. The left eye was normal. Anterior segment examination of the right eye showed a waxy-yellow caruncular mass measuring 9 3 5 3 4 mm, with intrinsic vessels (Fig. 1). The clinical suspicion was papilloma or pyogenic granuloma and excisional biopsy and cryotherapy were performed. Histopathologically, the mass was composed of acellular amorphous eosinophilic material that stained intensely with Congo-red stain and showed apple-green birefringence and dichroism with polarization microscopy. Immunohistochemistry staining showed monocloclonal lambda chains and B cell lymphoma immunoglobulin light chain amyloid. Evaluation for systemic amyloidosis and lymphoma was negative. After 51 months follow-up, there was no evidence of systemic involvement or recurrent conjunctival mass.

DEMIRCI ET AL

her left eye. A conjunctival mass was noted, prompting referral to us. Four years previously, she has had an attack of arteritic ischemic optic neuropathy in her left eye. The visual acuity was 20/20 in her right eye and 20/200 in her left eye. The right eye was normal. Anterior segment examination of the left eye showed a diffuse, yellow-pink mass on the superior bulbar conjunctiva that overhung the superior limbus and had intrinsic blood vessels and subconjunctival hemorrhage. The clinical differential diagnosis included lymphoma, metastasis, or amyloidosis; and incisional biopsy was performed. Histopathological examination revealed acellular amorphous eosinophilic material that was congophilic and showed apple-green birefringence and dichroism with polarization microscopy. Systemic evaluation for amyloidosis was negative. Three years later, residual amyloidosis on the superior bulbar conjunctiva enlarged involving the entire bulbar conjunctiva (Fig. 2). There was no systemic involvement after 3 years follow-up. PATIENT 3

An 86-year-old white woman noted a palpable mass on her right upper eyelid. With the diagnosis of lacrimal gland tumor, excisional biopsy was performed elsewhere and the histopathological examination showed nonspecific inflammation. Eight months later, ptosis of the right upper eyelid and a mass on the right lower palpebral conjunctiva developed. The ptosis was repaired and incisional biopsy of conjunctival mass was performed. Histopathologic examination showed conjunctival amyloidosis. Fourteen months later, recurrence of the ptosis and the development of a more extensive conjunctival mass prompted to referral to us. The visual acuity was 20/50 in the right eye and 20/30 in the left eye. The left eye was normal. There was 4 mm ptosis of the right upper eyelid, and a yellow-pink, diffuse mass was present on the inferior and nasal bulbar conjunctiva. The mass overhung the superonasal limbus and had prominent intrinsic blood vessels and subconjunctival hemorrhage (Fig. 3). Evaluation for systemic amyloidosis was negative. Four years later, the area of amyloidosis had enlarged, involving the entire bulbar conjunctiva. The patient was followed with conservative management. There was no systemic involvement. PATIENT 4

PATIENT 2

A 65-year-old African-American woman presented with a 4-week history of conjunctival hyperemia of

A 69-year-old white woman presented with a 7-month history of a growth on conjunctiva of her right eye. The visual acuity was 20/25 in each

CONJUNCTIVAL AMYLOIDOSIS

TABLE 1

Overview of 6 Patients with Conjunctival Amyloidosis Age /Race/ Patients Sex

Systemic Disease

Systemic Work-up CXR, CBC, El, SPEP

Initial Diagnosis Elsewhere

Eye Symptoms

1

45 W M None

Allergic OD conjunctivitis

2

65 B F

OS

3

86

OD

4

69

5

42

6

56

Temporal CXR, CBC, Lymphoma arteritis El, SPEP W F None SPEP, MRI Lacrimal gland of abd and chest tumor W F None CBC, CT of lymphoma abd and chest B F None Echo, CBC, Subconj hem SPEP, UPEP, Abd bx, UA W M Primary CBC, UA, Subconj Systemic UPEP, hem Amyloidosis SPEP

OU

Clinical Features

Redness, Conj mass Conj mass Redness Conj mass, subconj hem Ptosis, Ptosis, Conj Conj mass, mass subconj hem Conj Conj mass mass

Color of Conjunctival Mass

Subconjunctival Hemorrhage

Conjunctival Site

Conjunctival Quadrant

Other Ocular Sites

Therapy

Histopathologic Examination Outcome

Waxy-yellow

None

Caruncle

Nasal

None

Exc bx, Amyloid cryo

Stable

Yellow-pink

Yes

Bulbar

Superior

None

Inc bx

Amyloid

Progression

Yellow-pink

Yes

Bulbar and palpebral

Diffuse

Progression

Yellow -pink

None

Fornix

Inferior

Anterior Inc bx Amyloid orbit and eyelid None Exc bx, Amyloid cryo Amyloid

Stable

Exc bx, Amyloid cryo

Stable

OS

Subconj Ptosis, conj Yellow-pink hem mass, subconj hem

Yes

Bulbar and palpebral

Diffuse

Anterior Inc bx orbit and eyelid

OS

Subconj Conj mass, Yellow -pink hem subconj hem

Yes

Semilunar fold

Nasal

None

Stable

W 5 White; B 5 African-American; M 5 Male; F 5 Female; CXR 5 Chest X-Ray; CBC 5 Complete blood count; El 5 Serum electrolyte levels; SPEP 5 Serum protein electrophoresis; MRI 5 Magnetic resonance imaging; abd 5 abdominal; CT 5 Computed tomography; Echo 5 Echocardiography; UPEP 5 Urine protein electrophoresis; Exc bx 5 Excisional biopsy; UA 5 Urine analysis; OD 5 Right eye; OS 5 Left eye; Subconj 5 Subconjunctival hem 5 Hemorrhage; conj 5 Conjunctival; cryo 5 Cryotherapy.

421

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Surv Ophthalmol 51 (4) July--August 2006

Fig. 1. A 45-year-old white man presented with waxyyellow caruncular mass measuring 9 3 5 3 4 mm, with intrinsic vessels.

eye. Anterior segment examination of the right eye showed a yellow-pink, diffuse conjunctival mass in the inferior fornix with prominent intrinsic blood vessels. (Fig. 4, top left) A similar, subtle conjunctival mass was found at the inferior fornix of her left eye. The differential diagnosis included conjunctival lymphoma, leukemia, or amyloidosis. Histopathologic examination of incisional biopsy disclosed acellular amorphous eosinophilic material consistent with amyloid (Fig. 4, top right and bottom). Flow cytometric analysis of conjunctiva revealed light chain shift with lambda kappa ratio of 10.5 to 3.2. Systemic evaluation for amyloidosis and lymphoma was negative. After 8 months of follow-up, there was no systemic involvement or recurrent conjunctival mass.

DEMIRCI ET AL

Fig. 3. A 86-year-old white woman presented with a yellow-pink, diffuse conjunctival mass on the inferior and nasal bulbar conjunctiva and overhanging the superonasal limbus, with prominent intrinsic vessels and subconjunctival hemorrhage. PATIENT 5

A 42-year-old African-American woman had a 4year history of recurrent subconjunctival hemorrhage in her left eye. The hemorrhage lasted for 1 week and recurred two to three times yearly. She developed ptosis of the left upper eyelid and a yellow-pink, diffuse mass on the superior bulbar conjunctiva of her left eye. Incisional biopsy of the lesion revealed amyloid in the conjunctival stroma. The patient was referred to the oncology service. The visual acuity was 20/20 at each eye. The right eye was normal. Anterior segment examination of the left eye disclosed a diffuse, yellow-pink mass involving the bulbar and palpebral conjunctiva with prominent intrinsic blood vessels and subconjunctival hemorrhage. Systemic evaluation for amyloidosis and lymphoma was negative. After 44 months of follow-up and conservative management, her conjunctiva remained stable and there was no evidence of systemic involvement. PATIENT 6

Fig. 2. A 65-year-old African-American woman presented with unilateral diffuse, yellow-pink conjunctival mass involving the entire bulbar surface.

A 56-year-old white man presented with a 2-month history of subconjunctival hemorrhage in his left eye. After the hemorrhage partly resolved, residual thickening prompted referral to us. The visual acuity was 20/20 at each eye. The right eye was normal. Anterior segment examination of the left eye showed a yellow-pink conjunctival mass with subconjunctival hemorhage, measuring 8x4x4 mm located in the stroma of the semilunar fold. (Fig. 5, top left) The differential diagnosis included lymphoma, leukemia, or amyloidosis. The patient had excisional biopsy of the lesion followed by cyotherapy to the surrounding conjunctiva.

423

CONJUNCTIVAL AMYLOIDOSIS

Fig. 4. Top left: A 69-year-old white woman presenting with a yellow-pink, diffuse conjunctival mass in the inferior fornix on the right eye. Top right: Histopathological examination showing acellular amorphous eosinophilic material consistent with amyloid filling conjunctival stroma (Hemotoxyline-eosin 350). Bottom: Polarization microscopy displaying applegreen birefringence and dichroism.

Histopathologically, the lesion was composed of acellular, amorphous, eosinophilic material that was congophilic and displayed apple-green birefringence and dichroism with polarization microscopy (Fig. 5, top right and bottom) Serum protein electrophoresis disclosed an IgA kappa monoclonal protein in the serum, and bone marrow aspiration revealed 26% plasmacytosis. The diagnosis of primary systemic amyloidosis was made. Two years later, primary systemic amyloidosis involved kidney

and liver, and the patient had systemic chemotherapy and stem cell transplantation. After 4 years follow-up, the patient was asymptomatic without ocular recurrence and had no evidence of further systemic organ involvement.

Summary In summary, regarding the six patients, the lesion was circumscribed in two patients (33%) and diffuse

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Surv Ophthalmol 51 (4) July--August 2006

DEMIRCI ET AL

Fig. 5. Top left: A 56-year-old white man presented with a yellow-pink conjunctival mass with subconjunctival hemorrhage, measuring 8 3 4 3 4 mm located in the stroma of the semilunar fold. Top right: Histopatogic examination showing amorphous, acellular, eosinophilic material consietent with amyloid (Hemoxyline-eosin 350). Bottom: Polarization microscopy revealing apple-green birefringence and dichroism.

in four patients (67%). The color of the lesion was described as yellow in one patient (17%) and yellowpink in five patients (83%). Associated intrinsic vascularization was present in all patients (100%), recurrent subconjunctival hemorrhage in four patients (67%) and blepharoptosis in two patients (33%) with involvement of superior palpebral conjunctiva. Systemic evaluation revealed primary

systemic amyloidosis in one patient (17%) and no related systemic abnormalities in five patients (83%). Management consisted of complete excisional biopsy in the two circumscribed lesions and incisional biopsy in the four diffuse lesions. At a mean follow-up of 35 months, two patients with diffuse involvement showed progressive involvement of the conjunctiva following incisional biopsy and

425

CONJUNCTIVAL AMYLOIDOSIS

Fig. 5.

the other four patients remained stable. Additionally, no systemic involvement was found in the five patients. The patient with systemic amyloidosis developed bone marrow, kidney, and liver involvement after 2 years follow-up and treated with systemic chemotherapy and stem cell transplantation. After 4 years follow-up, the patient was asymptomatic without ocular recurrence and had no evidence of further systemic organ involvement.

Discussion The current nomenclature and classification of amyloidosis is based on the varieties of proteins that comprise the amyloid deposits.10 The three major types of amyloidosis include primary, secondary, and heredofamilial.7 Primary amyloidosis (AL) is typified by deposits composed of the variable portion of monoclonal immunoglobulin light chains. Primary amyloidosis is usually caused by a proliferation of monoclonal plasma cells in the bone marrow that produce monotypic immunoglobulins that are amyloidogenic.13 The age-adjusted incidence of primary amyloidosis is estimated to be 5.1 to 12.8 per million persons, which corresponds to 1,275 to 3,200 new patients annually in the USA.23 Secondary

(Cont.).

(AA) amyloidosis is typified by deposits of amyloid A formed from serum protein A, an acute phase reactant produced in response to inflammation. It occurs in patients with rheumatoid arthritis, inflammatory bowel disease, and untreated familial Mediterranean fever.10 The amyloid deposits in the heredofamilial amyloidosis are composed of mutant forms of the transport protein transthyretin.43 A larger number of mutations in the transthyretin gene have been reported. Most patients of vitreous amyloidosis occur in patients with heredofamilial amyloidosis.43 Conjunctival amyloidosis usually is a localized process that rarely is associated with systemic involvement. Of 50 well-documented patients of conjunctival amyloidosis reported in the literature, 44 (88%) were reported to be localized non-systemic conjunctival amyloidosis, three (6%) were secondary conjunctival amyloidosis, and three (6%) were associated with systemic amyloidosis (Table 2).1--6, 8,9,12,15--19,21,25--31,33--36,38--43,46,48,49 Conjunctival amyloidosis usually is seen in middle-aged adults. It can present as confluent fusiform lesions or polypoidal papules that have a waxy or yellow color.47 Most patients of conjunctival amyloidosis have involved the palpebral conjunctiva; however, the deposit can

426

TABLE 2

Clinical Findings in 43 Well-documented Patients with Conjunctival Amyloidosis

Elles9 (1945) Mathur28

38 WF (1959) 50 M

Systemic Disease None Amebiasis

45 F

None

Guerry5 (1960)

62 WF

None

Pico38 (1960)

38 H F

Hypothyroidism

36 HF

Hypo-t hyroidis m

Madangopal26 25T (1962) M Richlin40 (1962) 30 F

Trachoma

Gingival bx CBC, UA, El, Bm Asp, ECG, stool exam CBC, El, UA, Bm Asp, stool exam NA

Eye

Symptoms

Clinical Features

Color of Conjunctival Mass

OD, 1,5 yrs later OS OU

Hyperemia, discomfort Conj mass

Conj mass

Yellow

Conj mass

Yellow

OD

Ptosis

Ptosis, conj mass

OS, 8 mos later OD

Ptosis, hyperemia

OU

Conjunctival Site

Conjunctival Quadrant

Therapy

Histopathologic Examination Outcome

Palpebral and fornix Bulbar and palpebral

Inferior

Inc bx

Amyloid

Stable

Diffuse

Exc bx, mucous Amyloid memb graft

Stable

Yellow

Palpebral

Superior

Exc bx

Amyloid

NA

Ptosis, conj mass

Grayishwhite

Palpebral and fornix

Exc bx

Amyloid

NA

Conj mass

Conj mass

Pink

Semilunar fold

Superior and inferior Nasal

Inc bx, thyroid Amyloid replacement

NA

CBC, UA, El SPEP, I 131uptake UA, CBC, El, Stool exam, SPEP, I131 uptake NA

OU

Ptosis, hyperemia, edema

Ptosis, conj mass

Pink

Bulbar and palpebral

Diffuse

Exc bx, thyroid Amyloid replacement

NA

OS

Ptosis

Superior

Exc bx

Amyloid

NA

OS

Conj mass

Grayishpink Yellow

Palpebral

NA

Ptosis, conj mass Conj mass

Nasal

Exc bx

Amyloid

NA

Superior Superior

Amyloid Amyloid

NA NA

Amyloid

Stable

Syphilis None

CBC, El, UA CXR, SPEP, UPEP

OD OS

Hyperemia Ptosis

Conj mass Ptosis, conj injection

Yellow NA

Norn33 (1964)

30 F

NA

Palpebral

Inferior

Conj mass

NA

NA

Amyloid

NA

NA

OS

NA

NA

NA

OD

Discomfort

NA

Superior NA and inferior Inferior NA

Amyloid

None

Ptosis, conj mass Conj mass

Bulbar and Palpebra! Palpebral and fornix Fornix

Diffuse

None

Lid swelling Thickening of eyelids Ptosis

Lid swelling

49 WF 47 W M 24 W F 64 W M 26 P M 60 I F

ESR, RF, Ig levels, SPEP, NA

OS

Smith48 (1966)

Hyperglobulinaemia None

Inc bx Exc bx and eyelid repair Inc bx

Amyloid

NA

None

NA

NA

NA

Conj mass

NA

Palpebral

NA

Amyloid

NA

Trachoma

NA

OU

Conj mass

Conj mass

NA

Palbebral

Amyloid

NA

CBC, ESR, CXR, X-Ray of long bones

OS

Conj mass

Conj and corneal mass

Pink

Bulbar

Superior NA and inferior Diffuse Exc bx

Amyloid

Stable

Bisaria (1967)

None

NA

NA

DEMIRCI ET AL

73 F 61 F

Bulbar and semilunar fold Bulbar Palpebral

1

None

Systemic Work-up

Surv Ophthalmol 51 (4) July--August 2006

Author(Year)

Age/ Race /Sex

59 BF 51 W F

Knowles21 (1975) 41 H M 40 W M

Rodrigues41 (1976)

13 WM

Blodi2 (1979)

66 W M 32 F

Meisler30 (1981)

None None

None Addison

History of strabismus surgery RA ChurgStrauss synd

CBC, UA, ESR, CXR CBC, UA, CXR, El, SPEP El, CXR, UA NA

OD

Conj mass

Conj mass

Yellow

Bulbar

Diffuse

Exc bx

Amyloid

OD

Conj mass

Conj mass

Flesh

Palpebral

Inferior

Inc bx

OS

Lid swelling Lid swelling

Conj mass

Yellow

Palpebral

Inferior

Exc bx

Pseudomembrane NA formation

Palpebral

Superior

Plasmocytoma Stable (1958), later Amyloid (1968) Stable Amyloid Amyloid Rec

OU

NA

OU

Conj mass

Conj mass

Yellow

Bulbar

Temporal

Exc bx, mucous memb graft Exc bx

NA

OD

Conj mass

Conj mass

Yellow

Bulbar

Temporal

Exc bx

CBC, ESR, Ig levels, CXR

OU

Lid swelling, bloody discharge Irritation, ptosis Subconj hem

Conj mass

Yellow

Palpebral and fornix

Ptosis, conj mass Conj mass, subconj hem Subconj hem

Pink

Palpebral

Yellow

Bulbar

Superior Inc bx, and inferior high dose of CS Superior Inc bx, EBRT, Exc bx Temporal Exc bx

Yellow

Bulbar

Diffuse

Pecora 36 (1982) Jensen19 (1983)

80 WF 37 WF

None

ESR

OS

None

OD

Purcell39 (1983)

41 W M

PSA

CBC, ESR, lg levels, ANA Bm Asp, kidney and rectal bx

OU

Subjconj hem

Inc bx

Stable

Amyloid

NA

Amyloid

NA

Amyloid

Stable

Amyloid

Stable

Amyloid

Rec

NA Amyloid, 1, IgG, IgM, IgA, k, and l, light chain Amyloid NA 1,IgD l, light chain Stable Amyloid, 1, IgG, IgA, k, and l, light chain

Schaldenbrand29 21 M (1983)

None

NA

OS

Ptosis, conj mass

Ptosis, conj mass

Gray

Palpebral

Superior Exc bx and inferior

Borodic3 (1984)

30 WF

None

OD

Ptosis

Thickened upper eyelid, conj mass

Fleshy

Palpebral

Superior

Exc bx

Rosenblatt42 (1986)

27 M

None

CXR, CBC, UA, ESR, Ig levels, SIE, UIE, El, RF, ANA, cryo, LFT, Fat Bx NA

OS

Conj mass

Conj mass

Yellow

Bulbar

Nasal

Exc bx

Amyloid

NA

26 M 62 WM

None Lymphoma

NA CBC, El, CXR, SPEP, Bm Asp, SIE, liver-spleen scan

OD OD

Hyperemia Conj mass

Conj mass Conj mass

Yellow Pink

Bulbar Palpebral

Inferior Inferior

Exc bx Exc bx

Amyloid Amyloid, 1,Ig G l, light chain, Ig, A, IgM, k, light chains

NA Rec

Marsh27 (1987)

CONJUNCTIVAL AMYLOIDOSIS

Herndon16 (1968) Glass12 (1971)

427

(continued)

Systemic Disease

Systemic Work-up

Eye

Symptoms

None

SPEP, SIE, rectal bx

OU

Irritation, lid swelling, rec subconj hem

51 F

None

NA

OD

Ptosis

Iijima18 (1992)

52 AF

PSA

O’Donnell34 (1995)

43 F

None

OS, 3 yrs later Lid CBC, SPEP, OD swelling, Ig levels, conj mass Coagulation studies, UPEP, ECG, CT of orbit, Bm Asp, Rectal bx NA OU Hyperemia

19F

None

NA

OU

Ptosis, subconj hem

52 F

None

NA

OD, 18 years later OS

Irritation, lid swelling

36 F

None

NA

OS

63 WF 55 M

None

NA

None

79 F

72 M

Hill17 (1997) Moorman31 (1997)

Color of Conjunctival Mass

Conjunctival Site

Conjunctival Quadrant

Therapy

Histopathologic Examination Outcome

Yellowpink

Palpebral

Superior and inferior

Exc bx

Amyloid

Rec

NA

Bulbar and palpebral

Superior

Exc bx

Amyloid

Rec

Yellow

Bulbar and palpebral

Diffuse

Exc bx

Amyloid, Anti-amyloid P Ab, k, and l, light chain

Rec

Yellow

Bulbar and palpebral

Diffuse

Amyloid AL type

Stable

Red

Palpebral

Superior and inferior

Inc bx, cryotherapy, ptosis repair, mucous memb graft Inc bx, ptosis repair

Amyloid AA type

NA

NA

Palpebral

Amyloid AA type

NA

Ptosis, conj massPtosis, conj mass

Red

Palpebral

Amyloid

NA

OS

Ptosis

Yellow

Palpebral

Superior Inc bx, and inferior mucous memb graft Superior and Inc bx, inferior ptosis repair Superior Inc bx

Amyloid

Stable

NA

OD

Irritation

Yellow

Inferior

Exc bx

Amyloid

Stable

None

SPEP, RF

OU

Hyperemia

Bulbar and fornix Bulbar and fornix

Inferior

Inc bx

Stable

None

CBC, ESR, LFT, SPEP, UPEP, CXR

OD 9 years later OS

Conj mass

Palpebral and fornix

Diffuse

Exc bx

Amyloid Amyloid-P prt Amyloid Amyloid-P ptr

Ptosis, thickened eyelids, conj mass, subconj hem Conj mass, thickened upper eyelid, ptosis Lid swelling, conj mass, purpura, subconj hem

Thickened eyelid, ptosis, conj mass, subconj hem Ptosis, thickened conj, subconj hem Thickened conj

Ptosis, conj mass Conj mass Papillary hypertrophy, subconj hem Conj mass

Yellow

Yellow

Stable

DEMIRCI ET AL

Patrinely35 (1992) 51 F

Clinical Features

Surv Ophthalmol 51 (4) July--August 2006

Author(Year)

Age/ Race /Sex

428

Table 2 Continued

38 F

Shields46 (2000) 56 WM

None

PSA

Chaturvedi5 (2001)

43 M

None

Cheong-Leen6 (2001)

84 M

None

Van Cleynenbre ugel49 (2002)

67 M

None

Brozou4 (2003)

59 M

None

Dithmar8 (2004) 32 F

None

NA

OU

Subconj hem

Conj mass, subconj hem

Yellow

Bulbar and palpebral

Diffuse

CBC, UA, UPEP, SPEP, Bm Asp CBC, El, USG, SPEP, UPEP, CT CBC, SPEP, Bm Asp, Rec Bx CBC, ESR, LFT, SPEP, UPEP, CXR, Rec Bx CBC, TFT, LFT SPEP, UPEP

OS

Subconj hem

Conj mass, subconj hem

Yellowpink

Semilunar fold

Nasal

OS

Swelling

Conj mass

NA

Palpebral

OS

Subconj hem

Conj mass, subconj hem

NA

OU

Discomfort

Conj mass, subconj hem, hematoma

OD

Subconj hem

OD

Ptosis

Conj mass, subconj hem Conj mass

Inc bx, artificial tears Exc bx 1,cryotherapy

Amyloid

Stable

Amyloid

Stable

Superior Obs and inferior

Amyloid

Stable

Bulbar

Temporal

Exc bx

Amyloid

NA

Yellow

Palpebral

Superior and inferior

Exc bx 1, cryotherapy

Amyloid

Stable

Yellow

Bulbar

Temporal

Exc bx

NA

NA

Palpebral and fornix

Inferior

Inc bx

Amyloid AA type Amyloid

CONJUNCTIVAL AMYLOIDOSIS

Lee25 (2000)

Stable

All cited articles are published in English literature and well-documented patients. F 5, Female, M 5, Male; W 5 White; B 5 African-American; A 5 Asian; I 5 Indian; P 5 Pakistani; H 5 Hispanic; CXR 5 Chest X-Ray; CBC 5 Complete blood count; UA 5 Urine analysis; ESR 5 Erythrocyte sedimentation rate; Ig levels 5 Serum immunoglobulin levels; SIE 5 Serum immunoelectrophoresis; UIE 5 Urine immunoelectrophoresis; El 5 Serum electrolytes; RF 5 Rheumatoid factor; ANA 5 Antinuclear antibody; LFT 5 Liver function tests; cryo 5 serum cryoglobulin leves; Fat Bx 5 Pericutaneous abdominal fat pad biopsy; subconj 5 subconjunctival; OD 5 right; OS 5 left; IgG 5 Immunoglobulin G; IgA 5 Immunoglobulin A; PSA 5 Primary systemic amyloidosis; Bm Asp 5 Bone marrow aspiration biopsy; Exc bx 5 Exciosional biopsy; Inc bx 5 Incisional biopsy; NA 5 Non-available; synd 5 syndrome; Rec 5 Recurrence; EBRT 5 External beam radiotherapy; RA 5 Rheumatoid arthritis; prt 5 protein; mucous memb graft 5 mucous membrane grafting; conj 5 conjunvtival; ECG 5 Electrocardiogram; exam 5 examination; B 5 Both upper and lower eyelid; U 5 Upper eyelid; L 5 Lower eyelid; mos 5 months; SPEP 5 Serum protein electrophoresis; Inf 5 Inferior; Sup 5 Superior; RA 5 Rheumatoid arthritis; UPEP 5 Urine protein electrophoresis; Rec Bx 5 Rectal biopsy; USG 5 Ultrasonography; CT Computered tomography.

429

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occur anywhere in the conjunctiva.42,47 Patients may present with ocular symptoms that simulate conjunctival malignancies or inflammation. Furthermore, conjunctival malignancies can lead to amyloid deposition. In one patient, conjunctival plasmacytosis led to localized conjunctival amyloidosis over 9 years.12 Secondary conjunctival amyloidosis is the deposition of amyloid as a result of an antecedent local conjunctival disorder.26,41,48 It is more common in the regions where trachoma is endemic. Only three well-documented patients of secondary conjunctival amyloidosis have been published.26,41,48 Two patients had prior history of trachoma, one had prior strabismus surgery.26,41,48 Additionally, there are reported patients that show the association of conjunctival amyloidosis with lymphoma, rheumatoid arthritis, Churg-Strauss syndrome, syphilis, hyperglobulinemia, hypothyroidism and Addison disease.2,21,27,30,33,38,40 However, there was no evidence of systemic secondary amyloidosis in these patients. In our series, the patients had no systemic conditions believed to be precursors to amyloid deposition. Perhaps localized conjunctival amyloidosis could be an early localized manifestation of systemic amyloidosis. Affected patients should be evaluated for systemic amyloidosis, a life-threatening disease, as well as other diseases as listed above. Conjunctival amyloidosis can rarely be associated with primary systemic amyloidosis. Of 50 patients previously published in the literature, three patients (6%) were reported to have primary systemic amyloidosis1--6,8,9,12,15--19,21,25--31,33--36,38--43,46,48,49 (Table 2). Purcell and co-workers reported conjunctival involvement in a 41-year-old man with known primary systemic amyloidosis and kidney, heart, gastrointestinal system, and bone marrow involvement, who presented with recurrent subconjunctival hemorrhages.39 Iijima reported a 5-year-old history of recurrent bilateral upper eyelid swelling and diffuse translucent bulbar conjunctival mass. Systemic evaluation revealed primary systemic amyloidosis with heart, liver, spleen and bone marrow involvement.18 Shields and associates reported a 56-year-old man who presented with a fleshy, hemorrhagic lesion of the semilunar fold of the left conjunctiva. Subsequent systemic evaluation disclosed primary systemic amyloidosis with involvement in bone marrow, liver, and kidney46 (Patient 6, Table 1). Marsh and coworkers reported a 62-yearold man who presented with an asymptomatic amyloid lesion of the conjunctiva. One year later, the patient developed extranodal lymphoma with amyloid in the scapula. Immunostaining showed the amyloid of both conjunctival and scapular tumor to be of polyclonal immunoglobulin type (AL) type,

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most prominently Ig G and lambda chains, with lesser staining for Ig A and kappa chains.27 It is suggested that patients with localized conjunctival amyloidosis should have a systemic evaluation for primary systemic amyloidosis or lymphoma. The suggested systemic work-up for the patients with conjunctival amyloidosis is summarized in Table 3. The demographics of primary conjunctival amyloidosis may differ from primary systemic amyloidosis. A review of 229 patients found that primary systemic amyloidosis had a male preponderance (65%) and occurred at a mean age of 65 years with only 1% of patients younger than 40 years.22 In contrast, the mean patient age of the published 44 patients of localized non-systemic conjunctival amyloidosis in the literature was 48 years (median 44 years, range 13--81 years) and 41% were under age of 40 years. Additionally, 37% were male and 63% were female1--6,8,9,12,15--19,21,25--31,33,34--36,38--43,46,48,49 (Table 2). In our study, the mean age of our 6 patients was 61 years (median 61 years, range 42 to 86 years) and 33% were male / 67% were female. The clinical diagnosis of conjunctival amyloidosis is often overlooked because of the diverse clinical

TABLE 3

Diagnostic Pathway for Primary Systemic Amyloidosis in the Patients with Conjunctival Amyloidosis Consider primary systemic amyloidosis when a patient presents with Nephrotic-range proteinuria (nondiabetic) Cardiomyopathy (no ischemic history) Hepatomegaly (no filling defect by imaging) Peripheral neuropathy (nondiabetic) Heighten suspicion If monoclonal protein is detected in immunoelectrophoresis and immunofixation of the serum and the urine Confirm diagnosis Subcutaneous fat aspirate, bone marrow biopsy, and rectal biopsy stain with Congo red (90% sensitive) Baseline investigations at the time of diagnosis of conjunctival amyloidosis Complete blood count Urine analysis and serum electrolytes including Ca 12 levels Liver function tests b2-microglobulin Prothrombin time and activated partial prothrombin time Ig levels 24 hr urinary protien Bence Jones protein Electrocardiography Skeletal survey if myeloma suspected Assess prognosis Two-dimensional Doppler echocardiography Based on data in Gertz et al.

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presentations. Of the 50 well-documented patients in the literature, the most common presenting manifestations included conjunctival mass in 42 patients (84%), subconjunctival hemorrhage in 16 (33%), blepharoptosis in 15 (30%), and thickened palpebral conjunctiva in 7 (14%). The mass involved the palpebral conjunctiva in 26 patients (52%), bulbar conjunctiva in 17 (34%) and both palpebral and bulbar conjunctiva in seven (14%). Localized conjunctival involvement was observed in 18 patients (36%) and diffuse conjunctival involvement in 32 (64%). Nineteen patients (38%) showed bilateral involvement and 31 (62%) had unilateral involvement (Table 2).1--6,8,9,12,15--19,21,25--31,33,34--36,38-43,46,48,49 In our series, the most common presenting manifestations included conjunctival mass in six patients (100%), subconjunctival hemorrhage in four patients (67%), and blepharoptosis in two patients (33%). The mass involved bulbar conjunctiva in four patients (67%) and both bulbar and palpebral conjunctiva in two (33%). The conjunctival lesion was circumscribed in two patients (33%) and diffuse in four (67%). All six patients (100%) were unilateral involvement. The diagnosis of conjunctival amyloidosis usually is confirmed histopathologically. On hematoxylineosin staining, amyloid has a homogeneous eosinophilia with a granular and filamentous texture. The most characteristic staining pattern is seen with Congo red stain. With Congo red, amyloid shows two phenomena; the first is green-apple birefringence, which indicates the ability of the material to rotate a plane of polarized light exactly 90  . The second is dichroism, which if green light is planepolarized parallel to the long axis of the amyloid protein, it gives the deposit a bright green color. When the green light is plane-polarized perpendicular to the long axis of the amyloid protein, it gives the deposit a dull red color.24 Immunohistochemistry staining in three patients of localized conjunctival amyloidosis showed monoclonal light chains of IgD lambda, IgA lambda, or IgG kappa.3,27,29,46 Thus, the amyloid deposits in localized conjunctival amyloidosis maybe of AL type associated with local monoclonal B cell or plasma cell proliferation.34,43 It is postulated that amyloid protein can accumulate in the conjunctiva as a localized immunological reaction to a foreign antigenic material.34 Additionally, amyloid fibrillary protein was found to infiltrate and deposit in vessel walls.44 These deposits increase the rigidity and disrupt the integrity of conjunctival vessels, predisposing to tears in vessel wall and spontaneous subconjunctival hemorrhage. The clinical differential diagnosis of conjunctival amyloidosis includes lymphoma, leukemia, metastatic carcinoma, sarcoidosis and other granulomas,

papilloma, pyogenic granuloma, nevus, melanoma and sebaceous carcinoma.47 The smooth pink appearance of amyloidosis is similar to lymphoma or leukemia. However, palpebral conjunctival involvement and hemorrhages are rare with conjunctival lymphoma and occasionally seen with leukemia.32,45 Metastatic conjunctival tumors are much more vascular and usually occur in patients with known primary cancers.20 The management of conjunctival amyloidosis depends on the extent of local involvement and the systemic status of the patient. Conservative management with ocular lubricants is useful.34 Excision of solitary lesions or debulking of diffuse lesions can relieve symptoms caused by the mass effect of the amyloid deposits.35 Of the 45 published patients with available management data, 29 (64%) had excisional biopsy and 15 (33%) had incisional biopsy of the lesion. One patient (2%) preferred observation. Additionally, four patients (9%) required mucous membrane grafting and four (9%) underwent eyelid reconstruction or ptosis repair surgery (Table 2).1--6,8,9,12,15--19,21,22,25--31,33--43,46,48,49 Of the 26 published patients in which treatment results have been discussed, 20 (77%) were stable, without recurrence, and six (23%) showed local recurrence (Table 2).1--6,8,9,12,15--19,21,22,25--31,33-43,46,48,49 In our series, two patients had excisional biopsy because of the solitary, localized conjunctival involvement and remained asymptomatic after a mean follow-up of 35 months. The other four patients were observed following incisional biopsy of the conjunctiva because of the diffuse conjunctival involvement. At a mean follow-up of 35 months, two patients remained stable, and 2 patients developed progressive conjunctival involvement.

Conclusion In summary, conjunctival amyloidosis is a rare clinical entity, found in the middle-aged to older patients. It can have a variety of clinical presentations, ranging from a localized, pink, vascular conjunctival mass to diffuse, yellow tumor. Localized, circumscribed conjunctival lesions can be managed with excisional biopsy, and extensive diffuse lesions can be observed conservatively following biopsy confirmation and managed with ocular lubricants. Systemic evaluation for primary systemic amyloidosis and lymphoma is warranted.

Method of Literature Search Articles in all languages were searched in MEDLINE with the combination of key words amyloidosis and conjunctiva between 1970 and 2005. Well-documented

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individual patient reports and patient series of conjuntival amyloidosis in English literature were reviewed. In addition, references cited in the articles obtained by MEDLINE were sought for this review.

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CONJUNCTIVAL AMYLOIDOSIS primary (localized non-familial) conjunctival amyloidosis: a case report. Bull Soc Belge Ophthalmol 285:45--50, 2002 The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Support was provided by the Paul Kayser International Award of

433 Merit in Retina Research, Houston, TX (J. Shields), Macula Foundation, New York, NY (C. Shields), the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital (R. Eagle, Jr.) and the Eye Tumor Research Foundation, Philadelphia, PA (C. Shields). Reprint address: Carol L. Shields, M.D., Oncology Service, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA 19107.