MULTICENTRIC SEBACEOUS ADENOCARCINOMA O F T H E MEIBOMIAN GLAND H. DWIGHT CAVANAGH, M.D., W. RICHARD GREEN, M.D., HERMAN K. GOLDBERG, M.D. Baltimore,
The importance of early recognition and prompt, adequate surgical excision of seba ceous gland carcinoma masquerading as extraocular inflammatory disease has previ ously been emphasized by Boniuk and Zim merman1 in their comprehensive review of 88 cases from the Registry of Ophthalmic Pathology. They reported orbital invasion in 17% of 88 patients, lymph node metastases in 2 1 % of 74 patients, and estimated the five-year tumor death rate to be nine of 30 cases or 30%. The following case report ap pears to represent the first histopathologic example of multicentric primary origin in a single eyelid of this highly lethal tumor.
Maryland being the anterior eyelid margin. The Bard-Parker No. IS knife then cut through conjunctiva and tar sus down to and part way through orbicularis fibers; and tissue margins of 1 mm were excised from the nasal side, the temporal side, and the apex of the trapezoid. All of these specimens were tu mor-free on frozen section. The initial nasal margin was at first felt to contain some dysplastic epithelial changes, and we examined an additional 2-mm fragment of nasal margin. The dysplastic changes proved to be due to probable crush injury when the permanent sections were obtained. The remaining trapezoidal section of eyelid containing the tumor
CASE REPORT A 63-year-old, moderately hypertensive, insulindependent diabetic white man was first evaluated clinically in September 1971 for a persistent for eign-body sensation beneath his right upper eyelid of four months' duration. A small, nodular inflam matory mass was on the conjunctival surface of the right upper eyelid. With a clinical diagnosis of chalazion, the lesion was curretted, only to recur promptly two months later. H e had a second currettage with recurrence again in February 1972. A biopsy resulted in a diagnosis of sebaceous adenocarcinoma of the meibomian gland. T h e patient's general physical condition was good. His medica tions included methyldopa (Aldomet) and isophane insulin suspension, and he had an additional history of an active duodenal ulcer successfully treated with a bland diet. The patient was admitted to the Wilmer Insti tute, and on Feb. 16, 1972, under local anesthesia, underwent a radical wedge resection and plastic re construction with primary closure of his right up per eyelid. Although the lesion was clinically quite small (Fig. 1), only large resection rendered ade quate tumor margins (Fig. 2 ) . With the right eye lid everted, an approximately 1-cm trapezoid-shaped margin was marked off around the lesion, the base From the Eye Pathology Laboratory, Wilmer In stitute, Johns Hopkins University School of Medi cine and Hospital, Baltimore, Maryland. Reprint requests to W. Richard Green, M.D., Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins Hospital, Baltimore, M D 21205. 326
Fig. 1 (Cavanagh, Green, and Goldberg). P r e operative clinical appearance of the lesion of mei bomian carcinoma.
Fig. 2 (Cavanagh, Green, and Goldberg). Surgical excision specimen : a 26-mm (nasal) X 22-mm (tem poral) X 2.5-mm (apex) X 12-mm (base) trapezoid of eyelid tissue the conjunctival surface of which contains a 12 X 12 X 12-mm triangular portion of full-thickness eyelid circumscribing the tumor, and the remaining borders containing eyelid muscle and skin only.
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was then excised and submitted for permanent sec tions (Fig. 2). Additional tissue was also biopsied from suspicious areas near a dilated vessel at the apex of the trapezoid and from the lacrimal gland area just lateral to the main eyelid lesion. All of these specimens were tumor-free. There were no clinical lymph node or orbital metastases at the time of operation, and the patient has remained appar ently tumor-free and in good health for 17 months after operation. METHODS
The principal pathologic specimen con sisting of the whole full-thickness portion of eyelid circumscribing the tumor was step-sec tioned at 0.5-mm intervals six times from the nasal margin before encountering the first tumor cells. T h e block was then serially sec tioned until no further tumor was seen. Sec tions were routinely stained with hematoxylin-eosin with each tenth section remaining unstained. Stained sections were examined under a microscope equipped with an ocular micrometer, and tumor locations from each section were then transcribed to scale on sheets of graph paper. A carefully con structed montage demonstrated tumor loca tions (Fig. 3 ) . RESULTS
It is strikingly apparent that there are sev eral unconnected sites of tumor foci: three anteriorly situated and one large posterior focus (Fig. 3 ) . These sites appear to meet
Straatsma's 2 criteria for establishing tumor origin from a meibomian gland. The tumors arise in the sharply demarcated tarsal por tion of the eyelid and show either direct con tinuity with or conspicuous proximity to a meibomian gland, and histologically resemble normal meibomian gland (Fig. 4 ) . T h e tu mor foci contained areas of relatively in situ tumor in direct continuity with normal gland adjacent to tumor actively invading different sebaceous ducts (Fig. 5 ) . T h e most anteri orly situated tumor focus actively invaded a sebaceous duct that opened onto the surface at the eyelid margin (Fig. 6 ) . In the area of posterior tumor, considerable amounts of scar tissue and foreign body material were the result of previous surgery (Fig. 4 ) . Dis tinctive histopathologic features of the tu mor included the arrangement of large tumor cells with vacuolated cytoplasm in a lobular pattern (Fig. 7 ) . There was no pagetoid in vasion 3 of overlying epithelium. DISCUSSION
Meibomian carcinoma is a rare but appar ently highly lethal tumor. Welch and Duke 4 estimated its incidence to be 0.2% of all eye lid tumors. Morax 5 and Ziangirova 6 esti mated its frequency at about 1.9% of all ma lignant evelid cancers, while Kwito, Roniuk, and Zimmerman 7 found only seven sebaceous
POSTERIOR TARSAL MARGIN RIGHT EYE
w \ 120
140 160 180 SECTION NOSlaij)
ANTERIOR LID MARGIN
Fier. 3 (Cavanagh, Green, and Goldberg). Montage showing multicentric tumor foci demonstrated by serial sections.
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Fig. 4 (Cavanagh, Green, and Goldberg). Low-power histologic section demonstrat ing anterior tumor foci near the eyelid margin and a pos terior focus at the margin of the tarsal plate. Scarring is present at the posterior site of previous surgery ( S ) (hematoxylin and eosin, X16).
Fig. S (Cavanagh, Green, and Goldberg). Posterior tumor focus. Most of the tumor, which is arranged in an acinar pattern, remains in situ and is connected with normal lobules of meiboinian gland. Other contiguous portions have invaded a posteriorly situated sebaceous duct (hematoxylin and eosin, XlOO).
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carcinomas in 550 malignant eyelid tumors (1.3%). Ginsberg8 reported an incidence of 1% of all eyelid malignancies in his series of 142 documented cases up to 1963. As in our patient, this tumor characteristically develops late in life with the most vulnerability be tween the age of 40 and 80 years8"11 and an average age of 61.6 years. 1 Rare exceptions have been reported by Knapp 12 and Lazarescu and associates,13 who observed its occurrence in two children aged 3.5 and 11 years. Some authors14'15 believe the disease involves both sexes about equally; however, Sweebe and Cogan9 found a female to male ratio of 1.7, Ginsberg8 a ratio of 1.3, and Boniuk and Zimmerman1 have similarly reported an ap parent female predilection in their series of 57 females to 37 males (1.5:1). The tumor occurs with worldwide distribution and in all although Orientals may be affected races,
disproportionately.1 The upper eyelid is in volved twice as often as the lower in most series,1'2'8 probably because of the greater number of glands, but both eyelids may often be involved simultaneously.1 More rarely, the caruncle and eyebrow are primary sites or origin.1 As the present case illustrates, the tumor characteristically presents as a slow-grow ing, yellow elevation on the tarsus of the eyelid which may be initially quiet and be nign in appearance,1'17 but most commonly presents an inflammatory picture typical of a chalazion.1'9 Thirty of the 78 eyelid tumors reviewed by Boniuk and Zimmerman1 pre sented initially as a chalazion, and 16 of these had a history of previous multiple op erations for chalazion, as did our own pa tient. All cases of persistent or recurrent unilateral ocular inflammatory disease should
Fig. 6 (Cavanagh, Green, and Goldberg). Low-power histologic section, demonstrating tumor invasion into a sebaceous gland duct that opens onto the surface of the eyelid margin. The epithelium adjacent to and overlying the area of the duct displays parakeratosis and hyperkeratosis without definite pagetoid invasion. There is an area of focal hemorrhage at the opening of the duct (hematoxylin and eosin, X50).
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Fig. 7 (Cavanagh, Green, and Goldberg). Large tumor cells with vacuolated cytoplasm (hematoxylin and eosin, x28S). thus be viewed with a high index of suspi cion for a possible underlying malignancy. Differential diagnosis must include basal or squamous carcinoma, granulomatous inflam mation due to syphilis, tuberculosis, or sarcoid, metastatic tumors to the eyelid and tu mors arising from adjacent pilosebaceous structures and sweat glands. Difficulty in di agnosis of these tumors may arise when the cellular pattern is relatively anaplastic and when cases of basal cell epithelioma and squamous cell carcinoma demonstrate seba ceous metaplasia.18 The usual long interval between initial symptoms and pathologic diagnosis may ac count for this tumor's high mortality. In the present case this was at least ten months. Straatsma2 reported a period between onset of growth and definitive treatment that varied between five months and seven years with an average of three years. Ginsberg8 noted an average delay of one year, while Sweebe and
Cogan9 reported a two-year average delay with a range of five months to five years. Al though meibomian carcinoma metastasizes late,11'19 extensive delay undoubtedly contrib utes to the high recurrence rate of 32% re ported by Ginsberg,8 who also found the rate of ipsilateral lymph node metastases to be 17% and an orbital invasion and death rate of at least 6%. Gowey and Kern 19 reviewed 16 cases with known metastases, and at the time of publication, seven of their patients had died of metastatic disease. Of the eight patients reported by Sweebe and Cogan,9 two died probable tumor deaths, while Spaeth's 20 observation of one tumor death in his three cases prompted his statement that this tumor was "the most malignant of all the epithelial tumors of the eye." It is significant that these findings also appear to apply to other types of sebaceous gland carcinoma. Excluding car cinomas of the meibomian glands, less than 80 cases of histologically malignant sebaceous
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gland neoplasms have been recorded.21'22 Constant and Leahy-1 and Batsakis, Littler, and Leahy22 recently described four patients with histologically proved sebaceous car cinoma—two died tumor deaths, one died of an associated antral squamous carcinoma, and one was alive ten years after surgical re moval. These authors similarly emphasized delay in diagnosis, inadequate excision, fre quency of metastases, and underestimation of malignant potential in dealing with this tumor. Adequate therapy for meibomian gland tu mors thus appears dependent on three im portant factors. First, the malignancy must always be suspected in cases of recurrent chalazia or persistent unilateral ocular inflam mation, and biopsy promptly initiated. Sec ond, even if the lesion is small as in the pres ent case, adequate tumor margins must be carefully obtained on frozen sections before surgery is terminated. Incomplete excision accelerates the malignant process and rate of metastasis.'-'"'23 This was particularly im portant in our patient who had multicentric tumor foci, and would also be equally critical if there was diffuse disease in both eyelids simultaneously.1 Third, local recurrence and lymphatic metastases must be antici pated and dealt with adequately. Orbital in vasion necessitated exenteration in 15 cases of 88 reported by Boniuk and Zimmerman,1 who also found nine living patients who had been treated for lymphatic metastases by either ipsilateral radical neck surgery or irra diation or both. Careful attention to these points should result in improved survival rates for this rare but highly malignant tu mor. SUMMARY
A 63-year-old white man developed a small nodular inflammatory mass on the tarsal surface of the right upper eyelid, which was twice incised and curetted. After the second recurrence, biopsy revealed an adenocarcinoma of the meibomian gland, a rare tumor, the malignant potential of which is
often underestimated. A large resection was required to excise the lesion and provide tissue margins free of tumor on frozen sec tion. Serial sections were utilized to construct montage that demonstrated four uncon nected sites of tumor. Most important to adequate therapy are early biopsy in cases of persistent or recurrent eyelid inflammation, wide initial surgical excision with careful frozen sections for proved cases, and longterm follow-up due to the frequency of re currences and metastases. REFERENCES 1. Boniuk, M., and Zimmerman, L. E.: Seba ceous carcinoma of the eyelid, eyebrows, caruncle, and orbit. Trans. Am. Acad. Ophthalmol. Otolaryngol. 72.619, 1968. 2. Straatsma, B. R.: Meibomian gland tumors. Arch. Ophthalmol. 56:71, 1956. 3. Hogan, M. J., and Zimmerman, L. E . : Oph thalmic Pathology. Philadelphia, Saunders, 1962, p. 217. 4. Welch, R. B., and Duke, J. R.: Lesions of lids. Statistical note. Am. J. Ophthalmol. 45 :415, 1958. 5. Morax, V.: Cancer de Tappareil visual. Paris, GastonDoin, 1926, p. 101. 6. Ziangirova, G. G.: Precancerous and cancer ous affections of eyelids and conjunctiva. Vestn. Oftalmol. 5:3, 1962. 7. Kwito, M. L., Boniuk, M., and Zimmerman, L. E.: Eyelid tumors witli reference to lesions con fused with squamous cell carcinoma. 1. Incidence and errors in diagnosis. Arch. Ophthalmol. 69 :693, 1963. 8. Ginsberg, J.: Present status of meibomian gland carcinoma. Arch. Ophthalmol. 73 :271, 1965. 9. Sweebe, E. C , and Cogan, D. G.: Adenocarcinoma of the meibomian gland. A pseudochalazion entity. Arch. Ophthalmol. 61 :282, 1959. 10. Scheie, H. G., Yanoff, M., and Frayer, W. C. : Carcinoma of sebaceous glands of the eyelid. Arch. Ophthalmol. 72:800. 1964. 11. Kutty, M. K., and Bhanumathy, N . : Meibo mian carcinoma. A report of a case with a review of the literature. Med. J. Aust. 1:1007, 1970. 12. Knapp, H . : On hypertrophy and degeneration of the meibomian glands. Trans. Am. Ophthalmol. Soc. 10:57, 1903. 13. Lazarescu, D., Lazarescu, E., and Ionescu, E.: A case of epithelioma of the meibomian glands. Br. T. Ophthalmol. 14:588, 1930. 14. Scheerer, R.: Ein Beitrag zur Kenntnis der Geschwulste der Meibomschen Drusen. Klin. Monatsbl. Augenheilkd. 52:86, 1914. 15. Hagedoorn, A.: Adenocarcinoma of meibo mian gland. Arch. Ophthalmol. 12 :850, 1934. 16. .Tain, B. S.: Adenocarcinoma of the meibo mian glands. A case report. Am. J. Ophthalmol. 57: 1050, 1964.
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17. Ward, D. M.: Carcinoma of the meibomian glands. Br. J. Ophthalmol. 51:193, 1967. 18. Taylor, R. P., and Lehman, J. A.: Sebaceous adenocarcinoma of the meibomian gland. Presenta tion of a case and review of the literature. Arch. Ophthalmol. 82:66, 1969. 19. Gowey, R. J., and Kern, W. H.: Metastasizing adenocarcinomas of the tarsal glands. Calif. Med. 103:126,1965. 20. Spaeth, E. B.: Ocular tumors. Arch. Oph
thalmol. 46:421, 1951. 21. Constant, E., and Leahy, M. S.: Sebaceous cell carcinoma. Plast. Reconstr. Surg. 41:433, 1968. 22. Batsakis, J. G., Littler, E. R., and Leahy, M. S.: Sebaceous cell lesions of the head and neck. Arch. Otolaryngol. 85 :151, 1972. 23. Lebensohn, J. E.: Primary carcinoma of the meibomian gland. Am. I. Ophthalmol. 18:552, 1935.
I would not be thy executioner. I fly thee, for I would not injure thee: Thou tell'st me there is murder in mine eye. 'Tis pretty sure, and very probable, That eyes that are the frail'st, and softest things, W h o shut their coward gates on atomies, Should be call'd tyrants, butchers, murderers. Now I do frown on thee with all my heart, And if mine eyes can wound, now let them kill thee: Now counterfeit to swoon, why, now fall down, O r if thou canst not, oh for shame, for shame, Lie not, to say mine eyes are murtherers: Now show the wound mine eye hath made in thee. Scratch thee but with a pin, and there remains Some scar of it: lean but upon a rush, The cicatrice and capable impressure T h y palm some moment keeps: but now mine eyes, Which I have darted at thee, hurt thee not. Now am I sure there is no force in eyes That can do hurt. William Shakespeare As You Like It