LOCALIZED CONJUNCTIVAL AMYLOIDOSIS F R E D E R I C K C. B L O D I , M.D.,
AND D A V I D J. A P P L E ,
M.D.
Iowa City, Iowa
Amyloidosis connotes a group of dis eases of varying etiology and pathogenesis, which have in common certain unique histopathologic features. A hy aline proteinaceous material, the exact nature of which remains obscure, is depos ited in various tissues and can be specif ically recognized by the use of appropriate histopathologic techniques. Amyloid tumors localized to the con junctiva and eyelids are relatively rare and are usually not considered to be im portant in the differential diagnosis of isolated eyelid-conjunctival tumors. Most such lesions are located in the palpebralconjunctival or fornix-conjunctival re gions; the bulbar conjunctiva, including the limbal area, is much less frequently involved. We describe herein the clinicopathologic features of an unusual form of conjunctival amyloid, confined to the bulbar conjunctiva, that simulated a neo plasm. CASE REPORT A 66-year-old white man came here in June 1978. He had a growth on the right eye, which he had noticed for about six months (Figure, top left). It was gradually increasing in size. There was associated itching and tearing in the region of the mass. The tumor consisted of a soft, yellow, sharply circum scribed nodular mass on the inferotemporal bulbar conjunctiva, which measured approximately 8 x 13 X 5 mm. The eye showed no other significant abnormalities and there was no history of anteced ent inflammatory or degenerative disease of the conjunctiva in the region of the tumor. As the result of congenital esotropia and amblyopia, the visual acuity in the right eye was 6/60 (20/200). The visual acuity in the uninvolved left eye was 6/7.5 (20/25),
From the Department of Ophthalmology, Univer sity of Iowa Hospitals and Clinics, Iowa City, Iowa. This study was supported in part by a grant from the National Cancer Institute (1-325-CA18017-04). Reprint requests to F. C. Blodi, M.D., Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, la 52242. 346
and ocular examination revealed no noteworthy changes. Since about 1961, the patient had suffered from severe rheumatoid arthritis, which manifested as a recurrent polyarthralgia with periodic swelling, red ness, stiffening, and pain in the shoulders, ankles, knees, feet, and hands. Treatment included tablets containing sodium salicylate, sodium amino benzoate, and aspirin. There was no clinical evidence of primary or secondary systemic amyloidosis. There was no history and no clinical or laboratory evi dence of hepatic, splenic, renal, or cardiac disease. Apart from marked debility caused by the rheuma toid arthritis, the patient was in good general health. The epibulbar mass was removed, with the patient under local anesthesia, one week after the first clinic visit. The lesion appeared to invade the superficial scleral layers, but it could easily be peeled away and was completely excised. The specimen was submit ted in toto for pathologic examination. RESULTS
The specimen consisted of a yellow, oval mass measuring 8 x 13 x 5 mm. The specimen was soft to palpation, and the cut surface was smooth, shiny, and waxy. Microscopically, the mass was com posed primarily of an amorphous, palely eosinophilic hyaline substance, which was deposited within a scanty connective tissue framework (Figure, top right). De posits were also present within walls of blood vessels. Chronic inflammatory cell infiltrates were seen in scattered areas between the amyloid deposits. These cells consisted primarily of lymphocytes and occasional foreign body giant cells. The deposits showed the following staining characteristics: metachromasia with cresyl violet, birefringence and dichroism with Congo red (Figure, bottom left), and a brilliant yellow-green fluores cence with thioflavin-T (Figure, bottom right). DISCUSSION
Amyloid was so designated because of its affinity to iodine dyes, giving a starch like reaction. It is now known to be com-
AMERICAN JOURNAL O F OPHTHALMOLOGY 88:346-350, 1979
VOL. 88, NO. 3, PART I
LOCALIZED CONJUNCTIVAL AMYLOIDOSIS
347
Figure (Blodi and Apple). Top left, Clinical photograph of epibulbar mass showing rich vascularity and confinement to bulbar conjunctiva. Top right, Characteristic amyloid deposits within stroma of loose conjunctival connective tissues (hematoxylin and eosin, x 150). Bottom left, Birefrigence of scattered deposits as seen through polarizing lenses (Congo red stain, x 80). Bottom right, Brilliant fluorescence of amyloid deposits (light areas) in sections stained with thioflavin-T (x 250).
posed of a variety of immunoglobulins, and histopathologic diagnosis is made on the empirical staining reactions of the deposits found in tissue sections. The major forms of amyloidosis and their systemic and ocular manifestations are summarized in the Table. Although the type of amyloidosis most frequently encountered in general medicine is the secondary systemic form, which is associ ated with a number of underlying diseas es, ophthalmologic lesions attributable to amyloid infiltration are rare in any type of systemic amyloidosis. 1 - 3 The most common form of amyloidosis affecting the eye and adnexa is probably the secondary localized type, in which the deposits evolve secondary to local ante cedent ocular disease. 1 A The diagnosis of
localized amyloidosis depends on the demonstration of amyloid material in tis sues in the absence of clinical evidence of systemic amyloid disease. Conjunctival amyloidosis is often asymptomatic, often occurring as a pain less enlargement or swelling of the eyelid or conjunctiva. 5 - 8 The upper eyelids are more frequently affected by a typically yellow, subconjunctival mass. The forma tion of a localized isolated tumor on the bulbar-limbal conjunctiva, as in the pres ent case, is unusual. 9 Most cases primari ly involve palpebral and fornix conjunc tiva. This was true in most patients described in two series of localized amy loidosis of the eyelid or conjunctiva, or both, by Richlin and Kuwabara 7 (three cases), and Smith and Zimmerman 8
Co
00
Usually associated with underlying effusive pyogenic or granulomatous inflam matory disease: tuber culosis, rheumatoid arthritis, leprosy, osteomyelitis, syphi lis, collagen disease associa ted with malignancies 10% of patients with myeloma develop amyloid deposits
Amyloid deposits same as in primary systemic amy loidosis
Plasma cell myelomat
Usually no underlying dis ease
A S S O C I A T E D OR P R E D I S P O S I N G SYSTEMIC DISEASE
Primarily affects kidneys, spleen, liver, adrenal gland
Primarily affects muscles (especially heart, tongue, and gastrointestinal tract), skin, nerves (chronic sensorimotor polyneuropathy), and blood vessels
(Organs Involved)
SYSTEMIC FINDINGS
Secondary systemic (Most common form)
Primary systemic Nonfamilial Familial
TYPE
TABLE CLASSIFICATION O F AMYLOIDOSIS*
Amyloid deposits in eye in multiple myeloma
Eye involvement rare
Eye involvement rare Vitreal-retinal deposits, plaque-like infiltrates in retinal and uveal vessels secondary glaucoma Extraocular muscle and or bital infiltrates, external ophthalmoplegia Trigeminal nerve involve ment, neuroparalytic keratitis Eyelid nodules, blepharoptosis, purpura, and ecchymoses of eyelid skin and conjunctive Pupillary abnormalities secondary to neuropathy
OCULAR FINDINGS
w ■t-
Localized form of hereditary amyloidosis; characteristic lattice lines in corneal stroma, recurrent erosions None
None
Most common form with eye in volvement. Associated with pre vious localized eyelid and conjunctival disease: basal cell carcinoma and other tumors, previous infections, trachoma, blepharitis, degenerative dis eases, trauma, formation in a corneal scar
None
None
Eye involvement unusual; localized nodular deposits in cornea, eyelid, conjunctiva, and orbit; sometimes produces blepharoptosis, exophthalmos, decreased tearing, trigeminal nerve involvement
None
Predilection for localized deposits in certain sites: skin, larynx, tracheobronchial tree, heart, ureters, urinary bladder, urethra, eye, and adnexa; not lifethreatening
*Based on and modified and expanded from Brownstein, Elliott, and Helwig. 1 tAlthough strictly speaking this is a form of "secondary" amyloidosis, it is classified separately because the distribution of the amyloid deposits more closely resembles that of primary amyloidosis.
Lattice corneal
Secondary localized
Primary localized (So-called "tumorforming" amyloidosis)
350
AMERICAN JOURNAL OF OPHTHALMOLOGY
(17 cases). When the eyelid is involved, the infiltrates are found primarily in the subconjunctival tissues rather than in the skin surface itself. Because of the history and physical findings of rheumatoid arthritis in this patient, the lesion may possibly represent an unusual instance of an early manifes tation of the secondary systemic form. However, it cannot be classified as such because to date there is no proved clini cal, biochemical, or histopathologic evi dence of systemic amyloidosis in this patient. The diagnosis in this case must therefore be that of a primary localized amyloidosis. In some cases, small, apparently local ized amyloid tumors involving the eye lid-conjunctiva may actually be an early localized manifestation of a general ized amyloidosis. Some of the supposed ly localized cases may represent formes frustes of generalized amyloidosis. For this reason, the mere recognition of amy loid in an ocular structure can no longer be considered a complete diagnosis. The possibility of amyloidosis in extraocular sites associated with underlying diseases or other immunoglobulin abnormalities must be considered, particularly in a pa tient such as ours, in whom an underlying disease known to cause secondary sys temic amyloid is present. Such patients should be followed u p to rule out the possibility of future generalized lifethreatening disease. SUMMARY
We treated a patient with localized amyloidosis of the bulbar conjunctiva,
SEPTEMBER, 1979
which strongly resembled a neoplastic growth. Although the patient suffered from a long-standing, debilitating rheu matoid arthritis, suggesting the possibili ty of a secondary systemic amyloidosis caused by the chronic effusive process, no specific clinical evidence of systemic amyloidosis was noted. The ocular lesion was, therefore, classified as a primary localized amyloidosis. However, the sim ple recognition of amyloid in the ocular adnexa should not be considered a com plete diagnosis. For such cases in which a prominent underlying systemic disease is present, a thorough medical evaluation and future follow-up should be ensured to rule out the possibility that this repre sents the initial manifestation of a poten tially life-threatening secondary systemic amyloidosis caused by rheumatoid arthri tis. REFERENCES 1. Brownstein, M. H., Elliott, R., and Helwig, E. B.: Ophthalmologic aspects of amyloidosis. Am. J. Ophthalmol. 69:423, 1970. 2. Dhermy, P.: Oeil et amylose. Arch. Ophtalmol. 33:39, 1973. 3. Stansbury, J. R.: Conjunctival amyloidosis in association with systemic amyloid disease. Am. J. Ophthalmol. 59:24, 1965. 4. Behal, M. L.: Secondary amyloid infiltration around the limbus. Br. J. Ophthalmol. 48:622, 1964. 5. Elles, N. B.: Amyloid disease of the conjunc tiva. Am. J. Ophthalmol. 28:486, 1945. 6. Mathur, S. P., and Mathur, B. P.: Conjunctival amyloidosis. Br. J. Ophthalmol. 43:765, 1959. 7. Richlin, J. J., and Kuwabara, T.: Amyloid dis ease of the eyelid and conjunctiva. Arch. Ophthalmol. 67:138, 1962. 8. Smith M. E., and Zimmerman, L. E.: Amyloi dosis of the eyelid and conjunctiva. Arch. Ophthalmol. 75:42, 1966. 9. Bisaria, K. K., Garg, K. C , and Sud, S. D.: Paralimbal amyloid tumor. Br. J. Ophthalmol. 5 1 : 136, 1967.
AND D A V I D J. A P P L E ,
M.D.
Iowa City, Iowa
Amyloidosis connotes a group of dis eases of varying etiology and pathogenesis, which have in common certain unique histopathologic features. A hy aline proteinaceous material, the exact nature of which remains obscure, is depos ited in various tissues and can be specif ically recognized by the use of appropriate histopathologic techniques. Amyloid tumors localized to the con junctiva and eyelids are relatively rare and are usually not considered to be im portant in the differential diagnosis of isolated eyelid-conjunctival tumors. Most such lesions are located in the palpebralconjunctival or fornix-conjunctival re gions; the bulbar conjunctiva, including the limbal area, is much less frequently involved. We describe herein the clinicopathologic features of an unusual form of conjunctival amyloid, confined to the bulbar conjunctiva, that simulated a neo plasm. CASE REPORT A 66-year-old white man came here in June 1978. He had a growth on the right eye, which he had noticed for about six months (Figure, top left). It was gradually increasing in size. There was associated itching and tearing in the region of the mass. The tumor consisted of a soft, yellow, sharply circum scribed nodular mass on the inferotemporal bulbar conjunctiva, which measured approximately 8 x 13 X 5 mm. The eye showed no other significant abnormalities and there was no history of anteced ent inflammatory or degenerative disease of the conjunctiva in the region of the tumor. As the result of congenital esotropia and amblyopia, the visual acuity in the right eye was 6/60 (20/200). The visual acuity in the uninvolved left eye was 6/7.5 (20/25),
From the Department of Ophthalmology, Univer sity of Iowa Hospitals and Clinics, Iowa City, Iowa. This study was supported in part by a grant from the National Cancer Institute (1-325-CA18017-04). Reprint requests to F. C. Blodi, M.D., Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, la 52242. 346
and ocular examination revealed no noteworthy changes. Since about 1961, the patient had suffered from severe rheumatoid arthritis, which manifested as a recurrent polyarthralgia with periodic swelling, red ness, stiffening, and pain in the shoulders, ankles, knees, feet, and hands. Treatment included tablets containing sodium salicylate, sodium amino benzoate, and aspirin. There was no clinical evidence of primary or secondary systemic amyloidosis. There was no history and no clinical or laboratory evi dence of hepatic, splenic, renal, or cardiac disease. Apart from marked debility caused by the rheuma toid arthritis, the patient was in good general health. The epibulbar mass was removed, with the patient under local anesthesia, one week after the first clinic visit. The lesion appeared to invade the superficial scleral layers, but it could easily be peeled away and was completely excised. The specimen was submit ted in toto for pathologic examination. RESULTS
The specimen consisted of a yellow, oval mass measuring 8 x 13 x 5 mm. The specimen was soft to palpation, and the cut surface was smooth, shiny, and waxy. Microscopically, the mass was com posed primarily of an amorphous, palely eosinophilic hyaline substance, which was deposited within a scanty connective tissue framework (Figure, top right). De posits were also present within walls of blood vessels. Chronic inflammatory cell infiltrates were seen in scattered areas between the amyloid deposits. These cells consisted primarily of lymphocytes and occasional foreign body giant cells. The deposits showed the following staining characteristics: metachromasia with cresyl violet, birefringence and dichroism with Congo red (Figure, bottom left), and a brilliant yellow-green fluores cence with thioflavin-T (Figure, bottom right). DISCUSSION
Amyloid was so designated because of its affinity to iodine dyes, giving a starch like reaction. It is now known to be com-
AMERICAN JOURNAL O F OPHTHALMOLOGY 88:346-350, 1979
VOL. 88, NO. 3, PART I
LOCALIZED CONJUNCTIVAL AMYLOIDOSIS
347
Figure (Blodi and Apple). Top left, Clinical photograph of epibulbar mass showing rich vascularity and confinement to bulbar conjunctiva. Top right, Characteristic amyloid deposits within stroma of loose conjunctival connective tissues (hematoxylin and eosin, x 150). Bottom left, Birefrigence of scattered deposits as seen through polarizing lenses (Congo red stain, x 80). Bottom right, Brilliant fluorescence of amyloid deposits (light areas) in sections stained with thioflavin-T (x 250).
posed of a variety of immunoglobulins, and histopathologic diagnosis is made on the empirical staining reactions of the deposits found in tissue sections. The major forms of amyloidosis and their systemic and ocular manifestations are summarized in the Table. Although the type of amyloidosis most frequently encountered in general medicine is the secondary systemic form, which is associ ated with a number of underlying diseas es, ophthalmologic lesions attributable to amyloid infiltration are rare in any type of systemic amyloidosis. 1 - 3 The most common form of amyloidosis affecting the eye and adnexa is probably the secondary localized type, in which the deposits evolve secondary to local ante cedent ocular disease. 1 A The diagnosis of
localized amyloidosis depends on the demonstration of amyloid material in tis sues in the absence of clinical evidence of systemic amyloid disease. Conjunctival amyloidosis is often asymptomatic, often occurring as a pain less enlargement or swelling of the eyelid or conjunctiva. 5 - 8 The upper eyelids are more frequently affected by a typically yellow, subconjunctival mass. The forma tion of a localized isolated tumor on the bulbar-limbal conjunctiva, as in the pres ent case, is unusual. 9 Most cases primari ly involve palpebral and fornix conjunc tiva. This was true in most patients described in two series of localized amy loidosis of the eyelid or conjunctiva, or both, by Richlin and Kuwabara 7 (three cases), and Smith and Zimmerman 8
Co
00
Usually associated with underlying effusive pyogenic or granulomatous inflam matory disease: tuber culosis, rheumatoid arthritis, leprosy, osteomyelitis, syphi lis, collagen disease associa ted with malignancies 10% of patients with myeloma develop amyloid deposits
Amyloid deposits same as in primary systemic amy loidosis
Plasma cell myelomat
Usually no underlying dis ease
A S S O C I A T E D OR P R E D I S P O S I N G SYSTEMIC DISEASE
Primarily affects kidneys, spleen, liver, adrenal gland
Primarily affects muscles (especially heart, tongue, and gastrointestinal tract), skin, nerves (chronic sensorimotor polyneuropathy), and blood vessels
(Organs Involved)
SYSTEMIC FINDINGS
Secondary systemic (Most common form)
Primary systemic Nonfamilial Familial
TYPE
TABLE CLASSIFICATION O F AMYLOIDOSIS*
Amyloid deposits in eye in multiple myeloma
Eye involvement rare
Eye involvement rare Vitreal-retinal deposits, plaque-like infiltrates in retinal and uveal vessels secondary glaucoma Extraocular muscle and or bital infiltrates, external ophthalmoplegia Trigeminal nerve involve ment, neuroparalytic keratitis Eyelid nodules, blepharoptosis, purpura, and ecchymoses of eyelid skin and conjunctive Pupillary abnormalities secondary to neuropathy
OCULAR FINDINGS
w ■t-
Localized form of hereditary amyloidosis; characteristic lattice lines in corneal stroma, recurrent erosions None
None
Most common form with eye in volvement. Associated with pre vious localized eyelid and conjunctival disease: basal cell carcinoma and other tumors, previous infections, trachoma, blepharitis, degenerative dis eases, trauma, formation in a corneal scar
None
None
Eye involvement unusual; localized nodular deposits in cornea, eyelid, conjunctiva, and orbit; sometimes produces blepharoptosis, exophthalmos, decreased tearing, trigeminal nerve involvement
None
Predilection for localized deposits in certain sites: skin, larynx, tracheobronchial tree, heart, ureters, urinary bladder, urethra, eye, and adnexa; not lifethreatening
*Based on and modified and expanded from Brownstein, Elliott, and Helwig. 1 tAlthough strictly speaking this is a form of "secondary" amyloidosis, it is classified separately because the distribution of the amyloid deposits more closely resembles that of primary amyloidosis.
Lattice corneal
Secondary localized
Primary localized (So-called "tumorforming" amyloidosis)
350
AMERICAN JOURNAL OF OPHTHALMOLOGY
(17 cases). When the eyelid is involved, the infiltrates are found primarily in the subconjunctival tissues rather than in the skin surface itself. Because of the history and physical findings of rheumatoid arthritis in this patient, the lesion may possibly represent an unusual instance of an early manifes tation of the secondary systemic form. However, it cannot be classified as such because to date there is no proved clini cal, biochemical, or histopathologic evi dence of systemic amyloidosis in this patient. The diagnosis in this case must therefore be that of a primary localized amyloidosis. In some cases, small, apparently local ized amyloid tumors involving the eye lid-conjunctiva may actually be an early localized manifestation of a general ized amyloidosis. Some of the supposed ly localized cases may represent formes frustes of generalized amyloidosis. For this reason, the mere recognition of amy loid in an ocular structure can no longer be considered a complete diagnosis. The possibility of amyloidosis in extraocular sites associated with underlying diseases or other immunoglobulin abnormalities must be considered, particularly in a pa tient such as ours, in whom an underlying disease known to cause secondary sys temic amyloid is present. Such patients should be followed u p to rule out the possibility of future generalized lifethreatening disease. SUMMARY
We treated a patient with localized amyloidosis of the bulbar conjunctiva,
SEPTEMBER, 1979
which strongly resembled a neoplastic growth. Although the patient suffered from a long-standing, debilitating rheu matoid arthritis, suggesting the possibili ty of a secondary systemic amyloidosis caused by the chronic effusive process, no specific clinical evidence of systemic amyloidosis was noted. The ocular lesion was, therefore, classified as a primary localized amyloidosis. However, the sim ple recognition of amyloid in the ocular adnexa should not be considered a com plete diagnosis. For such cases in which a prominent underlying systemic disease is present, a thorough medical evaluation and future follow-up should be ensured to rule out the possibility that this repre sents the initial manifestation of a poten tially life-threatening secondary systemic amyloidosis caused by rheumatoid arthri tis. REFERENCES 1. Brownstein, M. H., Elliott, R., and Helwig, E. B.: Ophthalmologic aspects of amyloidosis. Am. J. Ophthalmol. 69:423, 1970. 2. Dhermy, P.: Oeil et amylose. Arch. Ophtalmol. 33:39, 1973. 3. Stansbury, J. R.: Conjunctival amyloidosis in association with systemic amyloid disease. Am. J. Ophthalmol. 59:24, 1965. 4. Behal, M. L.: Secondary amyloid infiltration around the limbus. Br. J. Ophthalmol. 48:622, 1964. 5. Elles, N. B.: Amyloid disease of the conjunc tiva. Am. J. Ophthalmol. 28:486, 1945. 6. Mathur, S. P., and Mathur, B. P.: Conjunctival amyloidosis. Br. J. Ophthalmol. 43:765, 1959. 7. Richlin, J. J., and Kuwabara, T.: Amyloid dis ease of the eyelid and conjunctiva. Arch. Ophthalmol. 67:138, 1962. 8. Smith M. E., and Zimmerman, L. E.: Amyloi dosis of the eyelid and conjunctiva. Arch. Ophthalmol. 75:42, 1966. 9. Bisaria, K. K., Garg, K. C , and Sud, S. D.: Paralimbal amyloid tumor. Br. J. Ophthalmol. 5 1 : 136, 1967.
![[Conjunctival amyloidosis].](/assets/img/hold.png)
