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Multiple Bilateral Apocrine Cystadenomas of the Lower Eyelids
Multiple Bilateral Apocrine Cystadenomas of the Lower Eyelids Light and Electron Microscopic Studies EVAN SACKS, MD,* FREDERICK A. JAKOBIEC, MD'*t REAGAN McMILLAN, MD,* FREDERICK FRAUNFELDER, MD,* TAKEO IWAMOTO, MD§
Abstract: An 88-year-old man presented with 13 apocrine cystadenomas of both lower eyelids of at least 10 years' duration. The cysts were remarkable for possessing a superior dome of either creamy or yellowish material (probably reflecting the lipid-rich decapitation secretion), surmounting a clearer fluid inferiorly, as well as for being restricted to the eyelid margins where the glands of Moll are located. Light microscopy disclosed a double-layered cuboidal cellular lining, which focally became more plump or hobnailed, exhibited apical decapitation secretion, and was occasionally thrown into papillary folds. Electron microscopy demonstrated cellular debris and segments of interrupted plasmalemmas within the cystic cavity, intercellular widenings constituting canaliculi, cytoplasmic election-dense secretory granules, flocculent mucous vacuoles, and swirls of smooth-surfaced endoplasmic reticulum. Basal cells were focally interspersed between the secretory cells and the basement membrane, and occasionally manifested spotty myofilamentary differentiation. These findings are supportive of an origin of the lesions from the secretory rather than the ductal portion of the glands of Moll. They corroborate conclusions drawn from dermatologic investigations that the cysts are an essentially proliferative process as opposed to the result of passive ductal dilatation. [Key words: adnexal cyst, apocrine cyst, cystadenoma, eccrine hidrocystoma, electron microscopy, eyelids, hidrocystoma.] Ophthalmology 94:65-71,1987
A wide variety of benign and malignant cutaneous appendage tumors occur on the eyelids. l -6 Apocrine cysts are common benign tumors7- 1O that are usually asympFrom the Departments of Ophthalmology and Pathology, the Manhattan Eye, Ear & Throat Hospital: the Edward S. Harkness Eye Institute of the Columbia-Presbyterian Medical Center,t the Department of Ophthalmology, New York Hospital-Comell Medical Center, New York,§ and the Department of Ophthalmology, the Oregon University Health Sciences Center, Portland.:j: Supported in part by a grant form the Zelda Radow Weintraub Foundation, Inc., New York. Reprint requests to Frederick A. Jakobiec, MD, Manhattan Eye, Ear & Throat Hospital, 210 East 64th Street, New York, NY 10021.
tomatic and typically solitaryy,12 Apocrine cysts occur for the most part on the face, but lesions of the ears, chest, shoulders, and orbit have been reported. II ,I3-IS Although their size varies from 3 to 5 mm, II a case of a giant apocrine cyst (70 X 50 X 50 mm) has been reported. 14 The skin overlying the cysts is smooth and shiny, especially at the apex of the dome-shaped structure. Although translucent, the walls are thick and hardly ever spontaneously rupture. 7 These cysts move readily in relation to the overlying epidermis and to the deeper subcutaneous tissues. Rupture of the cystic structure, intentionally or during surgical removal, results in the collapse of the wall with loss of a thin, clear, brownish, or black fluid from black cysts, and colorless fluid from the others. 65
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The classification of cutaneous adnexal cysts hinges on their segregation into eccrine or apocrine, and furthermore, whether they are derived from the ductal or secretory portions of the glands. 7,16-19 The historic confusion in the classification of sweat gland lesions and cysts is exemplified by the entities referred to as "hidrocystomas." \0 A variety of terms has been used to describe this otherwise benign set of conditions, including apocrine hidrocystoma,17,20,21 apocrine cystadenoma,2,12,22,23 black hidrocystoma,24,25 apocrine retention cyst,26 sudoriferous cyst, and Moll's cyst. 27 Although electron microscopy and histochemistry have partially clarified this area, 12, 17,20,28,29 contemporary nomenclature of the apocrine and eccrine cysts remains confusing. We report the following unusual case of multiple apocrine cysts of the eyelids because of its distinctive clinical, pathologic, and ultrastructural findings. Remarkably, this entity has received almost no critical attention in the recent ophthalmic literature. 1-4,8,21,27,30 We believe that the term apocrine cystadenoma is preferable to alternative ones for this entity because of experimental evidence that the condition is fundamentally proliferative rather than a retention cyst secondary to ductal dilatation-the usual circumstance with eccrine cysts, Our electron microscopic findings showed that the lining cells in our patient's multiple cysts exhibited the features of the secretory portion of the glands of Moll and that the basal cells evinced focal myofilamentary differentiation, further confirming the essentially proliferative nature of the lesions.
CLINICAL HISTORY In March 1984, an 88-year-old white man was referred for additional consultation because of multiple cystic lesions on his lower eyelids. He had no previous history of eye disease and no medical problems except for Alzheimer's disease. He used no systemic or ocular medications on any regular basis. Although the patient's dementia precluded obtaining direct details on the rate of progression or any changes in the lesions before examination, his 77-year-old brother noticed that the lesions had been present for approximately 10 years, and further enlarged over the course of the previous 12 months. No other family member was affected by a condition like this or any other ocular disorder. Occupational exposures included a 2-year period of service as a first sergeant in a European field hospital during World War I and 40 years as a salesman for a railroad company, which included the various exposures found in railroad yards. During examination, the patient was nonverbal but appeared entirely asymptomatic. Upon inspection, he was noted to have five cystic lesions on his right lower lid and eight on his left lower lid (Fig 1). Several lesions on each lid had confluent margins with the neighboring cyst. The cysts' superior margins were noted at the lash line and continued inferiorly on the skin side ofthe lower lids (Fig 2); the conjunctiva was uninvolved. The inferior twothirds of the cysts contained slightly turbid fluid, which 66
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had the consistency of water on palpation. The superior one-third of each lesion contained a more firm, yellowishwhite lipoidal substance and resembled the clinical appearance ofxanthelasma. The overlying skin was taut but seemed otherwise normal. The remainder of the objective ophthalmic examination was within normal limits. An excisional biopsy was performed in May 1984 and fresh tissue was submitted for light and electron microscopic study.
PATHOLOGIC FINDINGS Light microscopy was performed on several of the excised cysts. The lesions were composed of a dominant cavity containing a pink, amorphous, secretory material (Fig 3). The cyst lining was gnerally constituted by a double layer of low cuboidal cells (Figs 4,5). Occasionally, the cells had a swollen apical or hobnailed appearance, and separation of apical portions of the cytoplasm into the secretion could also be observed (apical snouts or decapitation secretion) (Fig 6). The lining of the cyst was occasionally thrown into papillary projections (Fig 7). Vacuoles were present in the cytoplasms of many of the lining cells, but neither the alcian blue nor mucicarmine stains gave positive results in the cytoplasm nor in the cyst contents. The iron stain also failed to reveal cytoplasmic staining. Adjacent to the cysts were dilated ducts of pre-existent apocrine glands (Fig 4). There was no inflammatory infiltrate in the dermis surrounding the cysts. A portion of one of the cyst walls was submitted fresh for study by electron microscopy. The wall consisted of an inner secretory layer and an outer basal cell layer (Figs 8,9). The secretory cells frequently bowed forward into the lumen of the cyst and possessed many projecting microvilli. The inner cells were related to adjacent ones by intercellular junctions. Apical junctional complexes consisted of a desmosome and a tight junction sealing the intercellular space from the lumen. Focally, the intercellular space was widened into intercellular canaliculi, which also possessed projecting villi. The cytoplasm of the inner secretory cells was generously endowed with profiles of rough-surfaced endoplasmic reticulum and whorls of smooth-surfaced endoplasmic reticulum. Secretory granules demonstrated either an intense electron density or strands of more amorphous fibrillar mucoid content. Basal cells were occasionally present beneath the secretory cells, and displayed focal myofilamentary differentiation in the cytoplasm (Fig 9, top). They were connected to each other and to the inner secretory cells by desmosomes. A continuous basement membrane ensheathed the outer aspects of each cyst's wall, which also exhibited a thick collagenous adventitial envelope with blood vessels.
DISCUSSION Cystic lesions of the eyelids are very common, and are typically epidermal inclusion cysts or pilar canal ectasias,
Fig 1. Top left, multiple bilateral lower eyelid cysts, Fig 2. Top right, the cysts have a vascularized wall, and their upper poles contain a yellowishwhite content. Fig 3. Second row left, excised specimen of one of the cysts displays homogeneous eosinophilic material within the lumen (hematoxylineosin; original magnification, X20). Fig 4. Second row right, most of the cyst wall is lined by a double layer of cuboidal epithelium. The upper portion of the lining toward the right displays plumper cells with apical expansions, so-called snouts of decapitation secretion. Toward the bottom in the stroma are multiple profiles of a contiguous apocrine gland (hematoxylin-eosin; original magnification, X200). Fig 5. Third row left, a double layer of llattened epithelial cells lines the cyst wall below. The eosinophilic material of the cyst displays clefting artifacts and vacuoles (hematoxylin-eosin; original magnification, X200). Fig 6. Third row right, a portion of the cyst lining contains cells with cytoplasmic vacuoles; strands of cytoplasm at the apex break off into the lumen (hematoxylin-eosin; original magnification, X200). Fig 7. Bottom, a region of the cyst lining demonstrating papillary projections (hematoxylin-eosin; original magnification, X200).
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Fig 8. Transmission electron micrograph of a portion of the cyst wall. Top. the lumen (L) is present toward the left, and multiple surface microvilli (mv and arrows) project into this central cavity. In this segment of the wall, the lining cells, which are secretory in character, rest directly on the basement membrane (BM and arrowheads) without an intervening myoepithelial layer. The cytoplasm contains numerous large secretory granules (sg) that are typical of apocrine type cells. A blood vessel (BY), shown in longitudinal section in the connective tissue portion of the wall of the cyst, possesses distorted erythrocytes (original magnification, XII ,5(0). Bottom. a higher power electron micrograph of the same cells displays to better advantage the cytoplasmic organelles and intercellular relationships. In addition to the dominant secretory granules (sg), also present are many mitochondria (M) and lamellae of the Golgi apparatus (G). The intercellular zone manifests intercellular canaliculi (ICC), into which villi (v) foca11y project. The apical regions of adjacent cells are sealed by tight junctions (tj and arrow) and intercellular desmosomes (parentheses) (original magnification,
X23,OOO).
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Fig 9. Top, the cells from another portion of the epithelial lining contain numerous mitochondria (M), profiles of the Golgi apparatus (G), short profiles of rough-surfaced endoplasmic reticulum (rER), and a swirl of smoothsurfaced endoplasmic reticulum (sER). Desmosomes (parentheses) are present around a dilated portion of the intercellular zone and intercellular canaliculus (ICC). A basal cell (BC) exhibits focal myofilamentary differentiation (mf and small arrows). Basement membranes (BM) and arrowheads (original magnification, X27,OOO). Bottom, an inner secretory cell possesses apical villi. The cyst cavity contains decapitated cytoplasmic debris (CD) and associated surviving remnants of a cell membrane (large arrow). The intercellular regions of the inner secretory cells manifest tight junctions (tj and small arrow) as well as subadjacent desmosomes (parentheses). Typical secretory granules (sg), many mitochondria (M), a phagolysosome (PL), and mucous granules (mg) with a floccular content are also identified. The basal cells (BC) in this region are connected to each other by desmosomes (parentheses), but do not show myofilamentary differentiation. BM and arrowheads-basement membrane (original magnification, X23,OOO).
the latter associated with the eyelid cilia or vellous hairs elsewhere on the eyelid. Next most common are the sweat gland cysts, which include both apocrine and eccrine origins. Eccrine cysts are also called sudoriferous cysts and arise from the sweat-producing eccrine glands scattered
throughout the eyelid; when multiple, small, and translucent, they are termed milia. Less common, but also encountered in clinical practice, are apocrine cysts, which arise only from the glands of Moll at the eyelid margin. The glands of Moll are associated with the cilia and empty
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their secretions into the pilar canals of these structures. 21 Finally, rare solid adenomas and carcinomas may arise from the glands of Moll.5,6 We report this case because we believe that it offers diagnostic clinical findings, including restriction of the cysts to the eyelid margin. The presence of yellowish material in the apical regions of the cyst contents probably represents cellular debris attendant upon the decapitation secretion, which is lipid-rich and rises to the top of the cyst, much in the manner that fat rose to the top of a milk bottle before the era of homogenization. The electron microscopic findings in this case are the first reported of apocrine cysts of the glands of Moll, and will be compared with the ultrastructure of normal apocrine glands31 and that of apocrine cystadenomas appearing elsewhere throughout the integument. 22,28 Reports of multiple apocrine cysts have been uncommon; our patient had a total of 13 cysts on both lower eyelids. Smith and Chernoskyll reported a dermatologic series of 42 patients with apocrine cysts: one patient had four lesions, one had three lesions, and three had two lesions. Grinspan et al 32 described one patient with six lesions, and Hassan et al28 reported over 40 lesions on the face and ears of one patient. In their review, it was calculated that 93% of apocrine cysts are solitary, 89% occur on the head and face and approximately 50% are pigmented in appearance. The lesions are asymptomatic, and there is no seasonal variation in their size. 7,1O,1I,17,27 Eccrine cysts, on the other hand, enlarge during hot seasons when sweating is increased. Apocrine cysts are most common during the later years oflife, although they are occasionally encountered in young persons. 7,11 The origin of the bluish color seen in about 50% of lesions, but not observed in our case, remains unclear. Some authors I 1,28 explain it as a Tyndall effect, the color being caused by light scattering in a colloidal system with the resultant reflection of blue light created by the presence of particles less than one-twentieth the wavelength of light. 33 The darker blue and black colors are probably due to the same pigments that cause apocrine chromhidrosis. 28 Carotenoids, melanin, hemoglobin, and porphyrins are not implicated in the chromhidrosis of apocrine cystS. 26,34 Prominent lipofuscins have been found in apocrine secretions. These latter heterogenous pigments are derived from lipoproteins and lipids, the various colors of which are dependent on the degree of exudation, which could explain the various hues of apocrine cysts. 12 Our light microscopic findings are consistent with previous descriptions of apocrine cystadenomas from cutaneous regions other than the eyelids. The lesions are located in the dermis and harbor several cystic spaces into which may extend papillary projections. The inner surface of the cyst wall and the papillary projections are lined by a double row of cuboidal to high columnar secretory epithelial cells, which have round nuclei at their bases, and which display the "decapitation" secretion characteristic of apocrine cells. The apocrine nature of the secretion of the luminal cells is confirmed not only by the presence of numerous large periodic acid-Schiff (PAS)-positive,
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diastase-resistant granules in the secretory cells, 11,22 but also by the electron microscopic findings. 28,35 An electron microscopic study31 of the normal apocrine glands of the eyelids (glands of Moll) has shown a layer of inner secretory cells with apical villi projecting into the lumens, which contain cytoplasmic debris. An outer layer of myoepithelial cells, possessing filaments and fusiform densities, is separated from the interstitial connective tissue by a thick basement membrane; myoepithelial cells are present only in the secretory region and not among the ductal cells. 31 Two ultrastructural studies of apocrine cysts28 ,35 demonstrated abundant, moderately dense secretory granules contained within the inner secretory cells, particularly of their luminal portions. Normal apocrine decapitation secretion,28 with numerous secretory granules in the detaching apical cap, has been demonstrated in apocrine cysts36 ; abnormal mitochondria with increased matrical density have also been noted. 28,35 Hassan et al28 observed fewer myofilaments in cystadenomas than in normal apocrine gland secretory cells; among the basal cells in our case, we discovered focal cytoplasmic evidence of myofilamentary differentiation that was not pronounced. Our study did not reveal the annulate lamellae observed by Gross,35 but not confirmed by Hassan et al. 28 In the classic paper by Robinson,37 the tenet was established that hidrocystomas are retention cysts, often multiple, seasonal in their occurrence, and commonly found on the faces of women who become exposed to moist heat and who are inclined to hyperhidrosis. His observations, however, were made on cysts of eccrine origin which are retention cysts; in contrast apocrine cysts are from their inception a proliferative disorder. In an effort to underscore the truly proliferative nature of apocrine cystic lesions, Mehregan22 redesignated the apocrine hidrocystoma a cystadenoma, based on the findings of papillary projections into the lumens of the cystic spaces. Although the term hidrocystoma is still preferable for eccrine cysts, it remains in use in most standard texts for lesions of apocrine origin. 7,17,21 Considerable additional data indicate that apocrine cysts are not merely retention cysts. 12,17,22 Application of nitric acid to axillary apocrine gland orifices produces cystic dilatation of the duct without affecting the deeper secretory coil region. 34 In addition to the secretory lining of high columnar cells with areas of papillomatous hyperplasia extending centrally, apocrine cystadenomas have a surrounding well-organized adventitial fibrous stroma, characteristic of adnexal tumors but not of retention cystS. IO- 12,22 For the foregoing reasons, we recommend the adoption within ophthalmic pathology of the term apocrine cystadenoma for the lesions we have described in this report. The current case of multiple bilateral inferior lid apocrine cystadenomas must be distinguished from the recently reported syndrome of bilateral apocrine cysts of all four eyelids associated with hypodontia, palmar-plantar hyperkeratosis, and onychodystrophy (i.e., an ectodermal dysplasia syndrome).38 None of these additional features was present in our patient, nor were all four eyelids involved as in this syndrome.
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REFERENCES 19. 1. Jakobiec FA. Tumors of the lids. In: Symposium on Diseases and Surgery of the Lids, Lacrimal Apparatus, and Orbit: Transactions of the New Orleans Academy of Ophthalmology. St. Louis: CV Mosby, 1982; 264-307. 2. Ni C, Dryja TP, Albert DM. Sweat gland tumors in the eyelids: a clinicopathological analysis of 55 cases. Int Ophthalmol Clin 1982; 22(1): 1-22. 3. Zimmerman LE, Sobin L. Histological typing of tumors of the eye and its adnexa. In: Zimmerman LE, Sobin L (eds). International Histological Classification of Tumors. No. 24, Geneva, World Health Organization, 1980. 4. Aurora AL, Blodi FC. Lesions of the eyelids: a clinicopathological study. Surv Ophthalmol1970; 15:94-104. 5. Jakobiec FA, Austin P, Iwamoto T, Trokel SL, Marquardt MD, Harrison W. Primary infiltrating signet ring carcinoma of the eyelids. Ophthalmology 1983; 90:291-9. 6. Jakobiec FA, Streeten BW, Iwamoto T, Harrison W, Smith B. Syringocystadenoma papilliferum of the eyelid. Ophthalmology 1981; 88: 1175-81. 7. Luckasen JR, Goltz RW. Clinical Dermatology. Vol. 4, Unit 22-1. Hagerstown, Maryland: Harper & Row, 1979. 8. Reese AB. Discussion of "common tumors of the eyelids." JAMA 1936; 107:937-8. 9. O'Brien CS, Braley AE. Common tumors of the eyelids. JAMA 1936; 107:933-7. 10. Srnith JD, Chernosky ME. Hidrocystomas. Arch Dermatol1973; 108: 676-9.
20. 21. 22.
23. 24. 25. 26. 27. 28. 29. 30. 31.
32. 33.
11. Smith JD, Chernosky ME. Apocrine hidrocystoma (cystadenoma). Arch Dermatol1974; 109:700-2. 12. Kruse TV, Khan MA, Hassan MO. Multiple apocrine cystadenomas. Br J Dermatol1979; 100:675-81. 13. Benisch B, Peison B. Apocrine hidrocystoma of the shoulder. Arch DermatoI1977; 113:71-2. 14. Holder WR, Smith JD, Mocega EE. Giant apocrine hidrocystoma. Arch Dermatol 1971; 104:522-3. 15. Saunders JF. Congenital sudoriferous cyst of the orbit. Arch Ophthalmol 1973; 89:205-6. 16. Hashimoto K, Lever WF. Histogenesis of skin appendage tumors. Arch Dermatol1969; 100:356-69. 17. Lever WF, Schaumberg-Lever G. Histopathology of the Skin. 6th ed. Philadelphia: JP Lippincott, 1982: 522-89. 18. Lever WF. Pathogenesis of benign tumors of cutaneous appendages
34.
35. 36.
37. 38.
and of basal cell epithelioma. Arch Dermatol Syphilol1948; 57:67985. Pinkus H, Mehregan AH. A Guide to Dermatohistopathology. New York: Appleton-Century-Crofts, 1969: 430. Fitzpatrick TB. Dermatology in General Medicine. New York: McGrawHill Book Company, Inc., 1971: 451-2. Yanoff M, Fine BS. Ocular Pathology: A Text and Atlas. 2nd ed. Philadelphia: Harper & Row, 1982: 237-63. Mehregan AH. Apocrine cystadenoma: A clinicopathologic study with special reference to the pigmented variety. Arch Dermatol 1964; 90:274-9. Montgomery H. Dermatopathology. New York: Harper & Row, 1967: 901. Monfort J. Les hidrocystomes noirs. Sem Hop Paris 1962; 8:328-31. Cramer HJ. Das schwarze hidrozystom (Monfort). Dermatol Monatsschr 1980; 166:114-8. Shelly WB, Levy EJ, Weidman FD. Apocrine sweat retention in man. III. Apocrine retention cysts. Arch Dermatol1955; 72:171-2. Duke-Elder S, MacFaul P. System of Ophthalmology. Vol. XIII. The Ocular Adnexa, Part 1. St Louis: CV Mosby 1974: 391-8. Hassan MO, Khan MA, Kruse TV. Apocrine cystadenoma. Arch Dermato11979; 115:194-200. Hassan MO, Khan MA. Ultrastructure of eccrine cystadenoma. Arch Dermatol1979; 115:1217-21. Hogan MJ, Zimmerman LE. Ophthalmic Pathology: An Atlas and Textbook. 2nd ed. Philadelphia: WB Saunders Co., 1962: 194-5. Jakobiec FA, Iwamoto T. Ocular adnexa: introduction to lids, conjunctiva and orbit. In: Jakobiec FA, ed. Ocular Anatomy, Embryology and Teratology. Philadelphia: Harper & Row, 1982: 677-731. Grinspan D, Abulafia J, Jaimovich L, Chouela A. Hidrocistoma. Dermatologia Ibero Latino Americana 1968; 10:397-408. Van Winkle Q. Tyndall effect. In: McGraw-Hili Encyclopedia of Science and Technology. 4th ed. New York: McGraw Hill Book Co., 1977: 185. Hurley HJ Jr, Shelly WB. Apocrine sweat retention in man. I. Experimental production of asymptomatic form. J Invest Dermatol1954; 22: 397-404. Gross BG. The fine structure of apocrine hidrocystoma. Arch Dermatol 1965; 92:706-12. SChaumberg-Lever G, Lever WF. Secretion from human apocrine glands: an electron microscopic study. J Invest Dermatol 1975; 64: 38-41. Robinson AR. Hidrocystoma. J Cutan Genitourin Dis 1893; 11 :293303. Font RL, Stone MS, Schanzer MC, et al. Apocrine hidrocystomas of the lids, hypodontia, palmar-plantar hyperkeratosis, and onychodystrophy. Arch Ophthalmol1986; 104:1811-3.
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Abstract: An 88-year-old man presented with 13 apocrine cystadenomas of both lower eyelids of at least 10 years' duration. The cysts were remarkable for possessing a superior dome of either creamy or yellowish material (probably reflecting the lipid-rich decapitation secretion), surmounting a clearer fluid inferiorly, as well as for being restricted to the eyelid margins where the glands of Moll are located. Light microscopy disclosed a double-layered cuboidal cellular lining, which focally became more plump or hobnailed, exhibited apical decapitation secretion, and was occasionally thrown into papillary folds. Electron microscopy demonstrated cellular debris and segments of interrupted plasmalemmas within the cystic cavity, intercellular widenings constituting canaliculi, cytoplasmic election-dense secretory granules, flocculent mucous vacuoles, and swirls of smooth-surfaced endoplasmic reticulum. Basal cells were focally interspersed between the secretory cells and the basement membrane, and occasionally manifested spotty myofilamentary differentiation. These findings are supportive of an origin of the lesions from the secretory rather than the ductal portion of the glands of Moll. They corroborate conclusions drawn from dermatologic investigations that the cysts are an essentially proliferative process as opposed to the result of passive ductal dilatation. [Key words: adnexal cyst, apocrine cyst, cystadenoma, eccrine hidrocystoma, electron microscopy, eyelids, hidrocystoma.] Ophthalmology 94:65-71,1987
A wide variety of benign and malignant cutaneous appendage tumors occur on the eyelids. l -6 Apocrine cysts are common benign tumors7- 1O that are usually asympFrom the Departments of Ophthalmology and Pathology, the Manhattan Eye, Ear & Throat Hospital: the Edward S. Harkness Eye Institute of the Columbia-Presbyterian Medical Center,t the Department of Ophthalmology, New York Hospital-Comell Medical Center, New York,§ and the Department of Ophthalmology, the Oregon University Health Sciences Center, Portland.:j: Supported in part by a grant form the Zelda Radow Weintraub Foundation, Inc., New York. Reprint requests to Frederick A. Jakobiec, MD, Manhattan Eye, Ear & Throat Hospital, 210 East 64th Street, New York, NY 10021.
tomatic and typically solitaryy,12 Apocrine cysts occur for the most part on the face, but lesions of the ears, chest, shoulders, and orbit have been reported. II ,I3-IS Although their size varies from 3 to 5 mm, II a case of a giant apocrine cyst (70 X 50 X 50 mm) has been reported. 14 The skin overlying the cysts is smooth and shiny, especially at the apex of the dome-shaped structure. Although translucent, the walls are thick and hardly ever spontaneously rupture. 7 These cysts move readily in relation to the overlying epidermis and to the deeper subcutaneous tissues. Rupture of the cystic structure, intentionally or during surgical removal, results in the collapse of the wall with loss of a thin, clear, brownish, or black fluid from black cysts, and colorless fluid from the others. 65
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The classification of cutaneous adnexal cysts hinges on their segregation into eccrine or apocrine, and furthermore, whether they are derived from the ductal or secretory portions of the glands. 7,16-19 The historic confusion in the classification of sweat gland lesions and cysts is exemplified by the entities referred to as "hidrocystomas." \0 A variety of terms has been used to describe this otherwise benign set of conditions, including apocrine hidrocystoma,17,20,21 apocrine cystadenoma,2,12,22,23 black hidrocystoma,24,25 apocrine retention cyst,26 sudoriferous cyst, and Moll's cyst. 27 Although electron microscopy and histochemistry have partially clarified this area, 12, 17,20,28,29 contemporary nomenclature of the apocrine and eccrine cysts remains confusing. We report the following unusual case of multiple apocrine cysts of the eyelids because of its distinctive clinical, pathologic, and ultrastructural findings. Remarkably, this entity has received almost no critical attention in the recent ophthalmic literature. 1-4,8,21,27,30 We believe that the term apocrine cystadenoma is preferable to alternative ones for this entity because of experimental evidence that the condition is fundamentally proliferative rather than a retention cyst secondary to ductal dilatation-the usual circumstance with eccrine cysts, Our electron microscopic findings showed that the lining cells in our patient's multiple cysts exhibited the features of the secretory portion of the glands of Moll and that the basal cells evinced focal myofilamentary differentiation, further confirming the essentially proliferative nature of the lesions.
CLINICAL HISTORY In March 1984, an 88-year-old white man was referred for additional consultation because of multiple cystic lesions on his lower eyelids. He had no previous history of eye disease and no medical problems except for Alzheimer's disease. He used no systemic or ocular medications on any regular basis. Although the patient's dementia precluded obtaining direct details on the rate of progression or any changes in the lesions before examination, his 77-year-old brother noticed that the lesions had been present for approximately 10 years, and further enlarged over the course of the previous 12 months. No other family member was affected by a condition like this or any other ocular disorder. Occupational exposures included a 2-year period of service as a first sergeant in a European field hospital during World War I and 40 years as a salesman for a railroad company, which included the various exposures found in railroad yards. During examination, the patient was nonverbal but appeared entirely asymptomatic. Upon inspection, he was noted to have five cystic lesions on his right lower lid and eight on his left lower lid (Fig 1). Several lesions on each lid had confluent margins with the neighboring cyst. The cysts' superior margins were noted at the lash line and continued inferiorly on the skin side ofthe lower lids (Fig 2); the conjunctiva was uninvolved. The inferior twothirds of the cysts contained slightly turbid fluid, which 66
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had the consistency of water on palpation. The superior one-third of each lesion contained a more firm, yellowishwhite lipoidal substance and resembled the clinical appearance ofxanthelasma. The overlying skin was taut but seemed otherwise normal. The remainder of the objective ophthalmic examination was within normal limits. An excisional biopsy was performed in May 1984 and fresh tissue was submitted for light and electron microscopic study.
PATHOLOGIC FINDINGS Light microscopy was performed on several of the excised cysts. The lesions were composed of a dominant cavity containing a pink, amorphous, secretory material (Fig 3). The cyst lining was gnerally constituted by a double layer of low cuboidal cells (Figs 4,5). Occasionally, the cells had a swollen apical or hobnailed appearance, and separation of apical portions of the cytoplasm into the secretion could also be observed (apical snouts or decapitation secretion) (Fig 6). The lining of the cyst was occasionally thrown into papillary projections (Fig 7). Vacuoles were present in the cytoplasms of many of the lining cells, but neither the alcian blue nor mucicarmine stains gave positive results in the cytoplasm nor in the cyst contents. The iron stain also failed to reveal cytoplasmic staining. Adjacent to the cysts were dilated ducts of pre-existent apocrine glands (Fig 4). There was no inflammatory infiltrate in the dermis surrounding the cysts. A portion of one of the cyst walls was submitted fresh for study by electron microscopy. The wall consisted of an inner secretory layer and an outer basal cell layer (Figs 8,9). The secretory cells frequently bowed forward into the lumen of the cyst and possessed many projecting microvilli. The inner cells were related to adjacent ones by intercellular junctions. Apical junctional complexes consisted of a desmosome and a tight junction sealing the intercellular space from the lumen. Focally, the intercellular space was widened into intercellular canaliculi, which also possessed projecting villi. The cytoplasm of the inner secretory cells was generously endowed with profiles of rough-surfaced endoplasmic reticulum and whorls of smooth-surfaced endoplasmic reticulum. Secretory granules demonstrated either an intense electron density or strands of more amorphous fibrillar mucoid content. Basal cells were occasionally present beneath the secretory cells, and displayed focal myofilamentary differentiation in the cytoplasm (Fig 9, top). They were connected to each other and to the inner secretory cells by desmosomes. A continuous basement membrane ensheathed the outer aspects of each cyst's wall, which also exhibited a thick collagenous adventitial envelope with blood vessels.
DISCUSSION Cystic lesions of the eyelids are very common, and are typically epidermal inclusion cysts or pilar canal ectasias,
Fig 1. Top left, multiple bilateral lower eyelid cysts, Fig 2. Top right, the cysts have a vascularized wall, and their upper poles contain a yellowishwhite content. Fig 3. Second row left, excised specimen of one of the cysts displays homogeneous eosinophilic material within the lumen (hematoxylineosin; original magnification, X20). Fig 4. Second row right, most of the cyst wall is lined by a double layer of cuboidal epithelium. The upper portion of the lining toward the right displays plumper cells with apical expansions, so-called snouts of decapitation secretion. Toward the bottom in the stroma are multiple profiles of a contiguous apocrine gland (hematoxylin-eosin; original magnification, X200). Fig 5. Third row left, a double layer of llattened epithelial cells lines the cyst wall below. The eosinophilic material of the cyst displays clefting artifacts and vacuoles (hematoxylin-eosin; original magnification, X200). Fig 6. Third row right, a portion of the cyst lining contains cells with cytoplasmic vacuoles; strands of cytoplasm at the apex break off into the lumen (hematoxylin-eosin; original magnification, X200). Fig 7. Bottom, a region of the cyst lining demonstrating papillary projections (hematoxylin-eosin; original magnification, X200).
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Fig 8. Transmission electron micrograph of a portion of the cyst wall. Top. the lumen (L) is present toward the left, and multiple surface microvilli (mv and arrows) project into this central cavity. In this segment of the wall, the lining cells, which are secretory in character, rest directly on the basement membrane (BM and arrowheads) without an intervening myoepithelial layer. The cytoplasm contains numerous large secretory granules (sg) that are typical of apocrine type cells. A blood vessel (BY), shown in longitudinal section in the connective tissue portion of the wall of the cyst, possesses distorted erythrocytes (original magnification, XII ,5(0). Bottom. a higher power electron micrograph of the same cells displays to better advantage the cytoplasmic organelles and intercellular relationships. In addition to the dominant secretory granules (sg), also present are many mitochondria (M) and lamellae of the Golgi apparatus (G). The intercellular zone manifests intercellular canaliculi (ICC), into which villi (v) foca11y project. The apical regions of adjacent cells are sealed by tight junctions (tj and arrow) and intercellular desmosomes (parentheses) (original magnification,
X23,OOO).
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Fig 9. Top, the cells from another portion of the epithelial lining contain numerous mitochondria (M), profiles of the Golgi apparatus (G), short profiles of rough-surfaced endoplasmic reticulum (rER), and a swirl of smoothsurfaced endoplasmic reticulum (sER). Desmosomes (parentheses) are present around a dilated portion of the intercellular zone and intercellular canaliculus (ICC). A basal cell (BC) exhibits focal myofilamentary differentiation (mf and small arrows). Basement membranes (BM) and arrowheads (original magnification, X27,OOO). Bottom, an inner secretory cell possesses apical villi. The cyst cavity contains decapitated cytoplasmic debris (CD) and associated surviving remnants of a cell membrane (large arrow). The intercellular regions of the inner secretory cells manifest tight junctions (tj and small arrow) as well as subadjacent desmosomes (parentheses). Typical secretory granules (sg), many mitochondria (M), a phagolysosome (PL), and mucous granules (mg) with a floccular content are also identified. The basal cells (BC) in this region are connected to each other by desmosomes (parentheses), but do not show myofilamentary differentiation. BM and arrowheads-basement membrane (original magnification, X23,OOO).
the latter associated with the eyelid cilia or vellous hairs elsewhere on the eyelid. Next most common are the sweat gland cysts, which include both apocrine and eccrine origins. Eccrine cysts are also called sudoriferous cysts and arise from the sweat-producing eccrine glands scattered
throughout the eyelid; when multiple, small, and translucent, they are termed milia. Less common, but also encountered in clinical practice, are apocrine cysts, which arise only from the glands of Moll at the eyelid margin. The glands of Moll are associated with the cilia and empty
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their secretions into the pilar canals of these structures. 21 Finally, rare solid adenomas and carcinomas may arise from the glands of Moll.5,6 We report this case because we believe that it offers diagnostic clinical findings, including restriction of the cysts to the eyelid margin. The presence of yellowish material in the apical regions of the cyst contents probably represents cellular debris attendant upon the decapitation secretion, which is lipid-rich and rises to the top of the cyst, much in the manner that fat rose to the top of a milk bottle before the era of homogenization. The electron microscopic findings in this case are the first reported of apocrine cysts of the glands of Moll, and will be compared with the ultrastructure of normal apocrine glands31 and that of apocrine cystadenomas appearing elsewhere throughout the integument. 22,28 Reports of multiple apocrine cysts have been uncommon; our patient had a total of 13 cysts on both lower eyelids. Smith and Chernoskyll reported a dermatologic series of 42 patients with apocrine cysts: one patient had four lesions, one had three lesions, and three had two lesions. Grinspan et al 32 described one patient with six lesions, and Hassan et al28 reported over 40 lesions on the face and ears of one patient. In their review, it was calculated that 93% of apocrine cysts are solitary, 89% occur on the head and face and approximately 50% are pigmented in appearance. The lesions are asymptomatic, and there is no seasonal variation in their size. 7,1O,1I,17,27 Eccrine cysts, on the other hand, enlarge during hot seasons when sweating is increased. Apocrine cysts are most common during the later years oflife, although they are occasionally encountered in young persons. 7,11 The origin of the bluish color seen in about 50% of lesions, but not observed in our case, remains unclear. Some authors I 1,28 explain it as a Tyndall effect, the color being caused by light scattering in a colloidal system with the resultant reflection of blue light created by the presence of particles less than one-twentieth the wavelength of light. 33 The darker blue and black colors are probably due to the same pigments that cause apocrine chromhidrosis. 28 Carotenoids, melanin, hemoglobin, and porphyrins are not implicated in the chromhidrosis of apocrine cystS. 26,34 Prominent lipofuscins have been found in apocrine secretions. These latter heterogenous pigments are derived from lipoproteins and lipids, the various colors of which are dependent on the degree of exudation, which could explain the various hues of apocrine cysts. 12 Our light microscopic findings are consistent with previous descriptions of apocrine cystadenomas from cutaneous regions other than the eyelids. The lesions are located in the dermis and harbor several cystic spaces into which may extend papillary projections. The inner surface of the cyst wall and the papillary projections are lined by a double row of cuboidal to high columnar secretory epithelial cells, which have round nuclei at their bases, and which display the "decapitation" secretion characteristic of apocrine cells. The apocrine nature of the secretion of the luminal cells is confirmed not only by the presence of numerous large periodic acid-Schiff (PAS)-positive,
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diastase-resistant granules in the secretory cells, 11,22 but also by the electron microscopic findings. 28,35 An electron microscopic study31 of the normal apocrine glands of the eyelids (glands of Moll) has shown a layer of inner secretory cells with apical villi projecting into the lumens, which contain cytoplasmic debris. An outer layer of myoepithelial cells, possessing filaments and fusiform densities, is separated from the interstitial connective tissue by a thick basement membrane; myoepithelial cells are present only in the secretory region and not among the ductal cells. 31 Two ultrastructural studies of apocrine cysts28 ,35 demonstrated abundant, moderately dense secretory granules contained within the inner secretory cells, particularly of their luminal portions. Normal apocrine decapitation secretion,28 with numerous secretory granules in the detaching apical cap, has been demonstrated in apocrine cysts36 ; abnormal mitochondria with increased matrical density have also been noted. 28,35 Hassan et al28 observed fewer myofilaments in cystadenomas than in normal apocrine gland secretory cells; among the basal cells in our case, we discovered focal cytoplasmic evidence of myofilamentary differentiation that was not pronounced. Our study did not reveal the annulate lamellae observed by Gross,35 but not confirmed by Hassan et al. 28 In the classic paper by Robinson,37 the tenet was established that hidrocystomas are retention cysts, often multiple, seasonal in their occurrence, and commonly found on the faces of women who become exposed to moist heat and who are inclined to hyperhidrosis. His observations, however, were made on cysts of eccrine origin which are retention cysts; in contrast apocrine cysts are from their inception a proliferative disorder. In an effort to underscore the truly proliferative nature of apocrine cystic lesions, Mehregan22 redesignated the apocrine hidrocystoma a cystadenoma, based on the findings of papillary projections into the lumens of the cystic spaces. Although the term hidrocystoma is still preferable for eccrine cysts, it remains in use in most standard texts for lesions of apocrine origin. 7,17,21 Considerable additional data indicate that apocrine cysts are not merely retention cysts. 12,17,22 Application of nitric acid to axillary apocrine gland orifices produces cystic dilatation of the duct without affecting the deeper secretory coil region. 34 In addition to the secretory lining of high columnar cells with areas of papillomatous hyperplasia extending centrally, apocrine cystadenomas have a surrounding well-organized adventitial fibrous stroma, characteristic of adnexal tumors but not of retention cystS. IO- 12,22 For the foregoing reasons, we recommend the adoption within ophthalmic pathology of the term apocrine cystadenoma for the lesions we have described in this report. The current case of multiple bilateral inferior lid apocrine cystadenomas must be distinguished from the recently reported syndrome of bilateral apocrine cysts of all four eyelids associated with hypodontia, palmar-plantar hyperkeratosis, and onychodystrophy (i.e., an ectodermal dysplasia syndrome).38 None of these additional features was present in our patient, nor were all four eyelids involved as in this syndrome.
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REFERENCES 19. 1. Jakobiec FA. Tumors of the lids. In: Symposium on Diseases and Surgery of the Lids, Lacrimal Apparatus, and Orbit: Transactions of the New Orleans Academy of Ophthalmology. St. Louis: CV Mosby, 1982; 264-307. 2. Ni C, Dryja TP, Albert DM. Sweat gland tumors in the eyelids: a clinicopathological analysis of 55 cases. Int Ophthalmol Clin 1982; 22(1): 1-22. 3. Zimmerman LE, Sobin L. Histological typing of tumors of the eye and its adnexa. In: Zimmerman LE, Sobin L (eds). International Histological Classification of Tumors. No. 24, Geneva, World Health Organization, 1980. 4. Aurora AL, Blodi FC. Lesions of the eyelids: a clinicopathological study. Surv Ophthalmol1970; 15:94-104. 5. Jakobiec FA, Austin P, Iwamoto T, Trokel SL, Marquardt MD, Harrison W. Primary infiltrating signet ring carcinoma of the eyelids. Ophthalmology 1983; 90:291-9. 6. Jakobiec FA, Streeten BW, Iwamoto T, Harrison W, Smith B. Syringocystadenoma papilliferum of the eyelid. Ophthalmology 1981; 88: 1175-81. 7. Luckasen JR, Goltz RW. Clinical Dermatology. Vol. 4, Unit 22-1. Hagerstown, Maryland: Harper & Row, 1979. 8. Reese AB. Discussion of "common tumors of the eyelids." JAMA 1936; 107:937-8. 9. O'Brien CS, Braley AE. Common tumors of the eyelids. JAMA 1936; 107:933-7. 10. Srnith JD, Chernosky ME. Hidrocystomas. Arch Dermatol1973; 108: 676-9.
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