Primary Intraepithelial Sebaceous Gland Carcinoma of the Palpebral Conjunctiva

CLINICOPATHOLOGIC REPORT

SECTION EDITOR: W. RICHARD GREEN, MD Primary Intraepithelial Sebaceous Gland Carcinoma of the Palpebral Conjunctiva

Santosh G. Honavar, MD; Carol L. Shields, MD; Marlon Maus, MD; Jerry A. Shields, MD; Hakan Demirci, MD; Ralph C. Eagle, Jr, MD

ebaceous gland carcinoma usually arises from meibomian or Zeis glands deep within the eyelid, but it can rarely arise within the conjunctival epithelium without a deep component. We describe a woman with a history of chronic blepharoconjunctivitis unre- sponsive to topical medications. Examination disclosed confluent papillary hypertro- phyS of the upper palpebral conjunctiva and deposits of white flaky material. Tarsoconjunctival punch biopsy revealed intraepithelial sebaceous gland carcinoma. Management consisted of frozen section– controlled complete tumor excision with removal of the entire posterior lamella of the right upper eyelid, cryotherapy to the margins, and reconstruction. Histopathologic analysis confirmed primary sebaceous gland carcinoma localized to the conjunctival epithelium without involvement of underlying meibomian or Zeis glands or the caruncle. Patients with unexplained chronic unilateral blepharoconjunctivitis or papillary hypertrophy of the palpebral conjunctiva should be considered for biopsy to rule out neoplasia, even when there is no sign of an underlying eyelid mass. Arch Ophthalmol. 2001;119:764-767

Sebaceous gland carcinoma of the ocular fined to and presumably arising primar- adnexa is a relatively rare tumor that arises ily within the conjunctival epithelium from the meibomian glands, Zeis glands, without underlying glandular or invasive or sebaceous glands in the caruncle or eye- component is uncommon.8-10 Herein, we brow.1-7 It is estimated that this cancer rep- describe one such case with supportive resents 1% to 6% of all eyelid malignant histopathologic findings. neoplasms.4 The clinical presentation of sebaceous gland carcinoma depends on its site of origin. Sebaceous gland carcinoma REPORT OF A CASE of meibomian gland origin usually pre- sents as a slowly enlarging, deep tarsal mass A 33-year-old white woman developed that may simulate a chalazion.4 The Zeis contact lens intolerance, conjunctival hy- gland tumor appears as a well-circum- peremia, and irritation in her right eye for scribed mass near the eyelid margin.3 Some 1 year. She had been treated with topical patients have unilateral chronic blepha- medications for chronic blepharoconjunc- roconjunctivitis before the tumor is clini- tivitis without relief. Her only medical cally obvious, leading to delay in diag- problem was idiopathic thrombocytope- nosis.8 Patients with this presentation nic purpura, treated with varying doses of generally manifest conjunctival intraepi- oral corticosteroids for 14 years. There was thelial invasion of sebaceous gland carcino history of radiotherapy to the face or noma (pagetoid spread) from a primary fo- systemic malignancy. On examination, her cus of tumor in the meibomian or Zeis visual acuity was 20/20 OU. The left eye glands.4,8 Sebaceous gland carcinoma con- was unremarkable. The right eye revealed diffuse hyperemic papillary hyper- From the Oncology Service (Drs Honavar, C. L. Shields, J. A. Shields, and Demirci), trophy of the entire upper palpebral con- Oculoplastics Service (Dr Maus), and Department of Pathology (Dr Eagle), Wills Eye junctiva and scattered deposits of white Hospital, Thomas Jefferson University, Philadelphia, Pa; and Oncology Service, flaky material (Figure 1A). There was no L.V. Prasad Eye Institute, Hyderabad, India (Dr Honavar). evident eyelid mass or madarosis. Mini-

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Figure 1. A, Conjunctival primary intraepithelial sebaceous gland carcinoma manifesting as diffuse papillary hypertrophy of the upper palpebral conjunctiva. B, An intraoperative photograph showing the entire tarsus and the palpebral conjunctiva up to the superior fornix being excised. Margins were uninvolved by frozen section biopsy examination.

mal bulbar conjunctival conges- and hyperchromatic nuclei, focally Conjunctival intraepithelial se- tion and diffuse superficial punc- vacuolated cytoplasm, and promi- baceous gland carcinoma typically tate keratopathy were noted. There nent mitotic activity (Figure 2A-B). arises from an underlying primary was no obvious involvement of the The cells stained positively with oil- meibomian or Zeis gland carci- bulbar or inferior palpebral conjunc- red-O confirming the presence of in- noma that secondarily invades the tiva. The clinical differential diag- tracytoplasmic lipid (Figure 2C). Im- conjunctival epithelium by a cen- nosis included squamous or seba- munohistochemical analysis showed tripetal or radial migration of tu- ceous neoplasia of the conjunctiva that the cells were strongly immu- mor cells.8 This has been correlated as well as atypical conjunctival in- noreactive for BRST-2, focally posi- with poor ocular and life progno- fection. A deep tarsoconjunctival tive for cytokeratin marker CAM 5.2, sis.6,7 Three histopathologic pat- punch biopsy revealed purely in- and minimally immunoreactive for terns are exhibited by intraepithe- traepithelial sebaceous gland carci- epithelial membrane antigen, con- lial conjunctival sebaceous gland noma without an underlying tarsal sistent with the diagnosis of seba- carcinoma—the bowenoid, paget- component. Map biopsy specimens ceous gland carcinoma. Step sec- oid, and papillary types.6-8 The from 9 other sites on the bulbar and tions showed that the tumor was bowenoid type is characterized by lower palpebral conjunctiva were confined to the palpebral conjunc- full-thickness replacement of the negative for malignancy. The tu- tiva without deep involvement of the epithelium by tumor cells that are mor management involved com- meibomian glands or Zeis glands. large and pleomorphic and exhibit plete excision of all sebaceous units The margins of the excised area pro- prominent mitotic activity. The pag- of the upper eyelid using frozen sec- cessed for frozen sections were nega- etoid type is characterized by scat- tion–controlled excision of the en- tive for tumor. The final diagnosis tered individual tumor cells or nests tire posterior lamella including the was primary intraepithelial seba- of tumor cells within the epithe- eyelid margin (Figure 1B) and cryo- ceous gland carcinoma of the pal- lium that are devoid of intercellular therapy to the margins. The defect pebral conjunctiva. bridges. The papillary pattern is rare was reconstructed with a free tarso- and manifests with intraepithelial conjunctival graft from the oppo- COMMENT confluent cells resembling carci- site upper eyelid. Healing was ex- noma in situ.8 In our case, the pat- cellent and all permanent margins In 1967, Theodore11 and Irvine12 de- tern of conjunctival involvement was were free of tumor. The patient was scribed a “masquerade syndrome” of the bowenoid type. free of tumor recurrence 1 year af- characterized by chronic blepharo- It has been estimated that ap- ter the surgery. conjunctivitis due to an unsus- proximately 5% of patients with con- The surgical specimen was re- pected conjunctival intraepithelial junctival intraepithelial sebaceous ceived as a single piece of fresh un- squamous cell or sebaceous gland gland carcinoma show no detect- fixed tissue. A segment of the speci- carcinoma. Although the originally able eyelid nodule at initial presen- men was submitted for frozen described neoplasms were squa- tation.8 However, this has not been sections and staining for the lipid mous cell carcinomas, in retro- histopathologically proven with step with oil-red-O stain. The remain- spect, many of the tumors produc- or serial sections in most cases.8-10 der of the specimen was fixed in for- ing this clinical picture may have Freeman and associates15 described malin, sectioned perpendicular to been sebaceous gland carcino- 2 such cases but the histopathologic the lid margin in a bread-loaf fash- ma.13,14 Others have also empha- evidence was inadequate. Margo and ion, and submitted for routine light sized that tarsoconjunctival inflam- associates9 reported one case of a 65- microscopy. The palpebral conjunc- mation is common in patients with year-old woman whose exentera- tiva was thickened and replaced by intraepithelial sebaceous gland car- tion specimen showed intraepithe- tumor cells that had pleomorphic cinoma of the conjunctiva.8-10 lial sebaceous gland carcinoma

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 orbital exenteration. The meibo- A mian and Zeis glands showed no carcinoma but were completely replaced by lipogranulomatous inflammation. Our case was unique in several respects. The tumor oc- curred in a young patient aged 33 years who had been receiving oral corticosteroids. Immunosuppres- sion may have contributed to the young age at onset of sebaceous neoplasia, as the patient had no other known predisposition, such as radia- tion exposure.16 In addition, there was no histopathologic evidence of inflammation, scarring, or tumor in the underlying sebaceous glands. The lack of underlying tarsal tumor on B histopathologic examination is ex- tremely unusual and raises specula- tion as to the source of the malignant cells. The origin of primary conjunctival intraepithelial sebaceous gland carcinoma without deep involvement has been debated.8-10 One ar- gument is that the conjunctival epithelium has the potential to spawn sebaceous gland carcinoma.8 From an embryologic point of view, this is understandable, as the sebaceous glands of the tarsus and caruncle arise from invaginations of the em- bryonic conjunctival epithelium.17 To support this hypothesis, 2 cases C of papillomas of the tarsal conjunctival epithelium with focal sebaceous differentiation have been iden- tified.8 Another theory suggests that glandular sebaceous neoplasms could give rise to intraepithelial spread on the ocular surface fol- lowed by spontaneous involution of the glandular component, leaving only intraepithelial disease.10 Last, it should be realized that the presence of a focus of microinvasive or deep glandular tumor cannot fully be eliminated, even by step section- ing of the specimen, as the tumor is known to have skip areas. Figure 2. A, The excised tarsoconjunctival lamina showing full-thickness replacement of conjunctival epithelium by sebaceous gland carcinoma. Note the absence of deep focus in the meibomian glands or The optimal method of treat- an invasive component (hematoxylin-eosin, original magnification ϫ20). B, Large anaplastic cells ing intraepithelial sebaceous gland with vacuolated cytoplasm and large vesicular nuclei, diagnostic of sebaceous gland carcinoma carcinoma is controversial. Sug- (hematoxylin-eosin, original magnification ϫ200). C, Frozen section of the palpebral conjunctiva showing positive oil-red-O staining indicating the presence of intracellular lipid (oil-red-O, original gested modalities include careful magnification ϫ200). observation, cryotherapy, radiotherapy, complete excision, and or- involving the inferior tarsal and bul- mian and Zeis glands showed no bital exenteration.4,8-10 We chose bar conjunctiva, with one small fo- clear-cut source of tumor. Margo and complete excision with frozen sec- cus of invasive tumor of the bulbar Grossniklaus10 later reported 2 simi- tion control and cryotherapy after conjunctiva. There was extensive lar cases in a 58-year-old woman and map biopsies disclosed no tumor in scarring of the tarsus but the meibo- a 71-year-old man, both treated with the remainder of the conjunctiva.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 In conclusion, we describe a pa- Ophthalmic Pathology, Wills Eye Hos- Tumors. Birmingham, Ala: Aesculapius Publish- tient with primary sebaceous gland pital, Philadelphia, Pa (Dr Eagle). ing Co; 1978:461-476. 8. Jakobiec FA. Sebaceous tumors of the ocular ad- carcinoma of the conjunctival epithe- Corresponding author and re- nexa. In: Albert DM, Jakobiec FA, eds. Principles lium without evidence of involvement prints: Carol L. Shields, MD, Oncol- and Practice of Ophthalmology. Vol 3. Philadel- of the tarsus, Zeis glands, caruncle, or ogy Service, Wills Eye Hospital, 900 phia, Pa: WB Saunders; 1994:1745-1770. othersitesofnormalsebaceousglands. Walnut St, Philadelphia, PA 19107. 9. Margo CE, Lessner A, Stern GA. Intraepithelial sebaceous carcinoma of the conjunctiva and the skin Careful follow-up is necessary as the of the eyelid. Ophthalmology. 1992;99:227-231. primary tumor site may not yet be evi- REFERENCES 10. Margo CE, Grossniklaus HE. Intraepithelial seba- dent. Any patient with unexplained ceous neoplasia without underlying invasive car- asymmetric, chronic blepharocon- 1. Shields JA, Shields CL. Sebaceous gland carci- cinoma. Surv Ophthalmol. 1995;39:293-301. junctivitis or papillary hypertrophy of noma. In: Atlas of Eyelid and Conjunctival Tu- 11. Theodore FH. Conjunctival carcinoma masquer- mors. Philadelphia, Pa: Lippincott Williams & ading as chronic conjunctivitis. Eye Ear Nose the palpebral conjunctiva should be Wilkins; 1999:40-49. Throat Monthly. 1967;46:1419-1420. considered for biopsy to rule out se- 2. De Potter P, Shields CL, Shields JA. Sebaceous 12. Irvine AR. Diffuse epibulbar squamous cell epi- baceous gland carcinoma, even in a gland carcinoma of the eyelids. Int Ophthalmol Clin. thelioma. Am J Ophthalmol. 1967;64:550-554. young patient. 1993;33:5-9. 13. Brownstein S, Codere F, Jackson B. Masquerade 3. Shields JA, Shields CL. Sebaceous adenocarci- syndrome. Ophthalmology. 1980;87:259-262. Accepted for publication September 25, noma of the glands of Zeis. Ophthal Plast Recon- 14. Irvine AR. Epibulbar squamous cell carcinoma and str Surg. 1988;4:11-14. related lesions. Int Ophthalmol Clin. 1972;12:71- 2000. 4. Kass LG, Hornblass A. Sebaceous carcinoma of 83. This work was supported by the the ocular adnexa. Surv Ophthalmol. 1989;33: 15. Freeman LN, Iliff WJ, Iliff NT, Green WR. Extra- Orbis International, New York, NY 477-490. mammary Paget’s disease/pagetoid change of the (Dr Honavar); the Hyderabad Eye Re- 5. Boniuk M, Zimmerman LE. Sebaceous carci- conjunctiva without underlying sebaceous gland noma of the eyelid, eyebrow, caruncle and orbit. carcinoma. Invest Ophthalmol Vis Sci. 1988;29 search Foundation, Hyderabad, In- Int Ophthalmol Clin. 1972;12:225-256. (suppl):321. dia (Dr Honavar); Eye Tumor Re- 6. Rao NA, Hidayat AA, McLean IW, et al. Seba- 16. Lewallen S, Shroyer KR, Keyser RB, Liomba G. search Foundation, Philadelphia, Pa ceous carcinoma of the ocular adnexa: a clinico- Aggressive conjunctival squamous cell carci- (Drs J. A. Shields and C. L. Shields); pathologic study of 104 cases, with five-year fol- noma in three young Africans. Arch Ophthalmol. Paul Kayser International Award of low-up data. Hum Pathol. 1982;13:113-122. 1996;114:215-218. 7. Rao NA, McLean IW, Zimmerman LE. Seba- 17. Ozanics V, Jakobiec FA. Prenatal development of Merit in Retina Research, Houston, Tex ceous carcinoma of the eyelid and caruncle: cor- the eye and its adnexa. In: Jakobiec FA, ed. Ocu- (Dr J. A. Shields); and Noel T. and relation of clinicopathologic features with prog- lar Anatomy, Embryology and Teratology. Phila- Sara L. Simmons Endowment for nosis. In: Jakobiec FA, ed. Ocular and Adnexal delphia, Pa: Harper & Row; 1982:11-96.

From the Archives of the ARCHIVES

A look at the past. . .

. . . when Col Smith introduced his operation for the intracapsular extraction of cataract, ophthalmic surgeons were much struck by the beauty of the operation, and the skill of the originator. Sir John Parsons referred to his visit to St Louis and watching Dr Green operate by the Col Smith method. He was not favorably impressed by the results; at the same time he thought “show opera- tions” were a great mistake, as, under these conditions, it was difficult to fairly assess the value of a particular operation. His own view was that intracapsular methods must of necessity be accompanied by increased dangers to the patient’s eye.

Reference: Dickinson H. The Jullundur operation for cataract. Arch Ophthal- mol. 1925;54:515.

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