Journal of Cutaneous Pathology 1977: 4: 134-145
Sebaceous Carcinoma of the Eyelid with Pagetoid Involvement of the Bulbar and Palpebral Conjunctiva SIONG CHUAN LEE' AND LAWRENCE M. ROTH' ' Resident in Dermatology, Department of Dermatology, Wayne State University Sehool of Medieine, Detroit, Michigan and ' Professor of Pathology and Director of Surgical Pathology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. A ease of sebaceous carcinoma with pagetoid involvement of the palpebral and bulbar eonjunetival epithelium was studied by light and eleetron microscopy. Ultrastructurally, the neoplastic cells within the conjunctival epithelium were identical to those in the underlying invasive sebaceous eareinoma. Evidence of gradual transformation of eonjunctival epithelial cells to the neoplastic sebaceous ceUs or transitional forms between conjunctival epithelial cells and sebaeeous eells was not eneountered. The evidenee thus supports the theory that the neoplastic cells in the eonjunctival epithelium are the result of secondary invasion by the underlying sebaeeous carcinoma. (Received for publication F'ebruary 18, 1977)
Paget's disease of the nipple and extramammary Paget's disease of the vulva were first described by Sir James Paget (1874) and Dubreuilh (1901) respeetively. Since then this phenomenon has also been noted in areas other than the nipple and the vulva, sueh as the axilla (Cawley 1957), external ear canal (Fligiel & Kaneko 1975), eyelid (Whorton & Patterson 1955, Knauer & Whorton 1963) and perianal areas (Pinkus & Gould, 1939, Helwig & Graham 1963). Paget's disease of the skin of the nipple and areola is practically always associated with adenoeareinoma of the duets of the mammary gland (Muir 1935, Inglis 1946), but by no means all cases in an extramammary location are assoeiated with demonstrable underlying carcinoma of either apocrine or eccrine sweat glands. Concerning the histogenesis, controversy still exists as to whether the Paget eells arise from epidermal basal cells or whether they are the result of migration or metastasis from an underlying
adenoeareinoma. The purpose of this study is to discuss this question in relationship to a case in which a sebaceous adenoeareinoma of the eyelid was associated with Paget-like histologie features in the adjoining eonjunctiva. Case Report A 77-year-old Caucasian woman was referred from the Ophthalmology Department to the Otorhinolaryngology Department because of a tumor mass in the right lower eyelid as well as a metastatic tumor in the right parotid area. The physical examination in the Ophthalmology Department revealed a tumor nodule at the lower eyelid with epithelial thickening of the inferior bulbar and tarsal conjunctiva and subepithelial scarring, A nodule was palpable in the right parotid area. A biopsy of the thickened portion of the bulbar conjunctiva at the lower temporal selera revealed numerous atypical cells with enlarged pleomorphie, hyperchromatic nuclei
SEBAGEOUS GARGINOMA and abundant vacuolated cytoplasm irregularly infiltrating the surface epithelium. A histologic diagnosis of Paget's disease with possible underlying sebaceous carcinoma was made. The patient was subsequently referred to the Otorhinolaryngology Service and a cotnplete resection of the lower eyelid with right superficial parotidectomy was performed. The pathologic diagnosis was invasive poorly differentiated sebaceous adenocarcinoma of meibomian gland origin with pagetoid invasion of the conjunctival epithelium and metastasis to a lymph node in the right parotid gland. The postoperative course was uncomphcated and the patient was discharged in good condition. Materials and Methods
Tissue for light microscopy frotTi various portions of the neoplasm and conjunctiva was fixed in neutral buffered formalin, dehydrated, and embedded in paraffin, sectioned at 5 yUm and stained with hematoxylin and eosin, alcian blue, mucicarmine and periodic acid-Schiff reaction (PAS) with and without predigestion by diastase. Tissue cut from frozen section of the neoplasm was stained by oil red 0 stain. Selected portions of tutnor as well as the conjunctiva were
135
fixed in 4% phosphate buffered gluteraldehyde solutions, post-fixed in 1% osmium tetroxide, dehydrated through a graded series of alcohol and propylene oxide and embedded in epon 812, according to the tnethod of Luft (1961). Sections of 1 fjim thickness were cut, stained with toluidine blue, and examined by light microscopy for proper selection of cells for ultrastructural examination. Ultrathin sections were then cut with an LKB ultratome III ultramicrotome, stained with uranyl acetate and lead citrate and exatnined with a Philips 300 electron microscope. Results
Pathologic Findings Gross observations: The biopsy specitnen of the lower temporal scleral bulbar conjunctiva was very stnall measuring only 1.0 mm in diameter. The specimen removed in the subsequent operation included the right lower eyelid and the right parotid gland and a lymph node. There was a firtii, welldemarcated, but nonencapsulated yellow tumor nodule on the conjunctival surface. This nodule measured 6 mm in diameter (Fig. 1). The cut surface of the nodule had a bright yellow color. Hemorrhage and
Fig. 1. A solid, spherical and well-demareated tutnor arising from the lower eyelid.
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necrosis were not present. The parotid gland measured 7 X 6 X 2 cm. On sectioning, the parotid gland appeared grossly normal; however, there was a well circumscribed nodule present at one end of the gland measuring 1.2 cm in diameter. On sectioning, the cut surface also had a yellow color resembling the one described in the lower eyelid. Light Microscopic Observations These sections of the bulbar conjunctiva over the temporal selera showed a stratified squamous epitheliutn which contained many intraepithelial atypical cells, either isolated or in clusters, with enlarged pleomorphic, hyperchromatic nuclei and vacuolated cytoplasm (Fig. 2). These neoplastic cells were present at different levels of the epithelium but were most numerous in the basal portion. Glandular formation was not seen. The mucicarmine, alcian blue and periodic acidSchiff (PAS) stains with and without diastase were negative. Sections from the right lower eyelid showed the tumor to extend beneath the conjunctival epithelium (Fig. 3). The
tumor consisted of numerous round to irregularly shaped interconnecting nests or cords of cells separated by delicate fibrovascular septa with focal infiltrates of lymphocytes. The tumor cells generally had variable amounts of vacuolated eosinophilic cytoplasm. The nuclei of the neoplastic cells varied somewhat in size and shape. The chrotnatin was dense and irregularly clear. A few cells had small nucleoli. Numerous tnitotic figures were present. There was no evidence of squamous differentiation or formation of lutnina. The overlying conjunctival epithelium showed focal areas of attenuuation and, on one side, simOar neoplastic cells were present in the epithelium for a distance of at least 5 mm from the margin of the nodule (Figs. 4 and 5). The appearance of the neoplastic cells within the conjunctival epithelium was identical to those described previously. Sections of the yellow nodule within the parotid lymph node revealed an epithelial neoplasm. The histopathologic picture was identical to the tumor in the lower eyelid except that at the center of
jmr* 1 ""5&^'>'--'-'"^ ^ ^ ^ ^ H B H H w I P S
_
Fig. 2. A photograph of the bulbar eonjunctival epithelium shows numerous isolated or smaU nests of atypical eells with hyperehromatic nuclei and vacuolated eytoplasm present mostly in the lower portion of the epithelium. H & E X 400.
SEBAGEOUS GARGINOMA
137
Fig. 3. Low magnifieation photomicrograph of the eyelid shows a well-circumscribed but non-encapsulated tumor adjacent to nutnerous nortnal sebaceous glands (tneibotnian glands). Arrows show invading tumor eells in the adjacent conjunetival epitheliutn. H & E X 100.
Fig. 4. A high magnification photomicrograph at the junction of the tutnor and the adjacent conjunctival epitheliutn (in Fig. 3) shows tutnor cells (arrows) invading the palpebral eonjunetival epithelium. H & E XIOO.
F;;?. 5. A high magnification photomicrograph from the distal portion of the palpebral conjunctival epithelium (in Fig. 3) shows more tumor cells (arrows) present within the epithelium. H & E X 205.
'S^-M^jM
Fig. 6. Section of the metastatie tumor shows cords of polygonal tutnor cells with progressive sebaceous differentiation in the central portion. H & E X 200.
SEBACEOUS CARCINOMA many lobules there was a progressive sebaceous differentiation of the tutnor cells as they were transformed from undifferentiated tumor cells at the periphery towards the large sebaceous cells with abundant foamy cytoplasm (Fig. 6). The neoplastic cells in the lower eyelid tumor as well as those in the conjunctival epithelium and the metastatie tumor in the parotid node were strongly positive to the oil red 0 stain.
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tumor cells (Fig. 9). The tumor cells within the epithelium resembled the tumor cells in the primary and metastatie tumors. Varying numbers of lipid droplets were present as well as large aggregates of glycogen particles. The mierovilli on the cell surface were more conspicuous and occasionally simple desmosomal attachments were formed between the tumor cells and adjacent squamous cells. The squamous epithelial cells were distinguished from the tumor cells by the presence of abundant bundles of tonofilaments, numerEleetron Microscopic Observations By electron microscopy, the cells in the ous desmosomal complexes and the absence primary and metastatie tumor showed fea- of lipid droplets. tures of epithelial cells with a varying degree of sebaceous differentiation. In general, they Discussion resembled normal immature and partially mature sebaceous cells (Ellis & Henrikson Although sebaceous glands are abundant on 1963, Ellis 1967, Hibbs 1969). Sotne tumor the body and face, sebaceous carcinomas cells were separated from each other by a arising from these areas are relatively rare. In narrow intercellular space into which numer- fact, the majority of the sebaceous carcinous mierovilli extended. Occasional desmo- omas (MiUer & White 1967, Rulon & Helwig somes joined mierovilli from adjacent cells. 1974) reported in the literature are from the A few strands of tonofilaments were present sebaceous glands or modified sebaceous close to the attachment sites. The most glands (meiboniian glands) of the eyelid striking feature was the presence of relatively (Ginsberg 1965, Boniuk & Zimmerman large lipid droplets of variable size in the 1968). The reason for this is not clear. In cytoplasm of the more differentiated tumor spite of its identical morphology, the biocells (Figs. 7 and 8), suggesting that they logical behavior of sebaceous carcinoma of arose asynchronously. The outline of the the eyelids in terms of propensity of recurlipid droplets was smooth. In the majority rence and distant metastasis, is worse than of tumor cells, free ribosomes were dispersed those arising from the body and face (Boniuk throughout the cytoplasm. Scattered strands & Zimmerman 1968). of granular endoplasmic reticulum were Sebaceous carcinoma reportedly reprepresent. Earge aggregates of glycogen sents 1% of carcinoma of the eyelids particles occurred within the cytoplasm and (Ginsberg 1965). In the series studied by were more abundant in the less differentiated Boniuk & Zimmerman (1968), orbital invatumor cells. The Golgi complex was promin- sion occurred in 17% of 88 patients, and ent (Eig. 8). The mitochondria were large, lymph node metastasis developed in 28.4% spherical to ovoid and randomly distributed of 74 patients. Ten patients died with probin the cytoplasm. The cristae were usually able or proved metastasis. Sebaceous carcinoriented perpendicular to the long axis. The oma arising in extraocular areas showed a nucleus was large in the less differentiated more favourable prognosis. A review of the tumor cells. When lipid droplets were present, previously reported cases revealed recurrence the nuclear membrane was frequently in- in 11 cases out of 59, and 8 cases showed dented. The ehromatin was mostly peripher- metastasis (Rulon & Helwig 1974). ally located. The present case might be mistaken for a Ultrastruetural examination of the con- poorly differentiated squamous cell carcinjunctival epithelium showed that the squa- oma with secondary invasion into adjacent mous epithelial cells were displaced by the conjunctival epithelium (Borst phenomenon)
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LEE AND ROTH
Fig. 7. An electron mierograph of the neoplastie eells from the invasive tumor shows several lipid droplets (E) of varying size displaeing the eytoplasm. Intereellular spaces eontaining mierovilli are seen (arrow). Lead acetate and uranyl acetate X 7,800.
SEBACEOUS CARCINOMA f^
141
«...
Fig. 8. High magnification electron micrograpli of two neoplastic cells from the invasive portion of the tumor shows small desmosomes with a few strands of tonofilaments (arrows), lipid droplets (L), a proininent Golgi apparatus (G), large aggregate of glycogen particles (Gly) and abundant free ribosomes. Lead acetate and uranyl acetate X 13,600.
Fig^. 9. Election micrograph of the eonjunetival epithelium shows two squamous eells (Sq) sunounded by three neoplastic cells. The neoplastic cells are identical to those in the primary and metastatic tumors. They contain large lipid droplets (L) and aggregates of glycogen particles. The surrounding squamous cells contain abundant tonofilaments and microvilli (Lead eitrate and uranyl acetate X 6,600). Inset: 1 Aim epon section of conjunctival epithelium shows that the squamous cells have been replaced partially by tumor cells (arrows). Toluidine blue X 425.
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(Borst 1904). However, the absence of indivi- conneetions between epidermal keratinodual eell keratinization and keratin pearl cytes and Paget cells. However, the normal formation, inconspicuous intercellular cells of intraepidermal adnexal units also are bridges, the presence of vacuolation and a bound to surrounding epidermal cells by foamy appearance of the cytoplasm, and the desmosomes and contain tonofilaments and strongly positive oil red 0 stain excluded this often keratohyalin granules. possibility. The sebaceous differentiation The diseussion of Helwig & Graham within the neoplasm was substantiated by (1963) supported the idea that the Paget's ultrastructural findings including the disease and the underlying adnexal carcipresence of numerous lipid droplets and noma could occur concomitantly or sepabundant glyeogen particles, whereas tono- arately; they said, 'Since apocrine cells or filaments and keratohyaline granules were their precursors are normally located in the scanty (Ellis & Henrikson 1963, Hibbs 1969, epidermis, it is our interpretation that these Weigent & Staley 1976). According to eells are autochthonously affeeted by an unZimmerman (1971), pagetoid involvement known agent that causes extramammary occurs rather frequently in association with Paget's disease.' This suggestion comes very sebaceous carcinoma of the eyehds. How- close to the data used by Inglis (1936, ever, to the best of our knowledge, this 1946) to support the Unitarian concept of phenomenon has not been studied and sub- Paget's disease. Inglis (1936) demonstrated stantiated ultrastructurally. in careful work the origin of the Paget eells Classical Paget's disease of the nipple is in the most superficial portion of the lactialways assoeiated with underlying adeno- ferous duct, the part homologous to the eareinoma of the breast (Muir 1935, 1939, intraepidermal sweat duct unit (acroToker 1961). Extramammary Paget's disease syringum). This possibility has also been prohas been described in the vulva (Knauer & posed by Pinkus (1962) to explain extraWhorton 1963), perianal area (Helwig & mammary cases in which no underlying Graham 1963), axilla (Cawley, 1957), eyelids tumor mass can be demonstrated. (Whorton & Patterson 1955), external ear It seems that our case sheds some light on eanal (Fligiel & Kaneko 1975), and serotum the subject from a different angle. It does (Helwig & Graham 1963) and is often asso- not fulfill all the criteria of extramammary ciated with adjacent or underlying adeno- Paget's disease beeause it did not involve eareinoma. For those authors (Koss & skin and did not have the clinical eharacterBrockunier 1969, Ferenczy & Riehart 1972) istic of eezematous dermatitis. Neither did it who subscribe to the proposition that the fulfni the strict histogenic concept of Inglis intraepidermal Paget eells originate from (1936) and other Unitarians who exclude extraepidermal cancers by migration, metas- any case in which the intraepidermal cells tasis or eontinuous growth, these cases appear to have come from invasive cancer need no special explanation. On the other eells in the dermis. It did however, exhibit hand, those authors (Sagami 1963, Fether- the Paget phenomenon: colonization of the ston & Friedrich 1972, Medenica & Sahihi epidermis by non-keratinizing extraepi1972, Parmley et al. 1975) who favored the dermal eaneer cells. There also was an underview that the epidermal lesions and the lying adnexal adenoeareinoma. underlying carcinoma originated each in its The interesting facts are that this carcinown locus, have involved unknown carcino- oma was a sebaceous meibomian gland genie field effeets or have pointed to transi- eareinoma and that the affected stratified tional eell forms between epidermal keratino- epithelium was conjunctiva, the only ectocytes and Paget cells. The latter approach dermal squamous epithelium, normally conhas become more fashionable since the intro- taining some mucin-produeing goblet cells. If duction of electron microscopy. It is often an unknown earcinogenic stimulus was resbased on the demonstration of desmosomal ponsible for simultaneous but independent
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malignant transformation of the meibomian gland and the conjunctival epithelium, one would reasonably expect the latter to produce a muein-producing carcinoma similar to eases of extramammary Paget's disease. The 'Paget cells' in our ease, however, were lipidized eells, identical by light and eleetron microscopy to the cells of the underlying carcinoma. The presenee of some desmosomal conneetions between intraepithelial tumor eells and surrounding squamous cells does not constitute evidenee of transition between epithelial cells and tumor cells. The tumor cells in the stroma also possessed some desmosomes and tonofilaments. No other souree of potentially sebaceous cells is present in the conjunctiva. The intraepithelial cells were also morphologically similar to the cells in the metastatic tumor in the parotid node. These observations lead us to think that the atypical cells in the conjunctival epithelium were the result of secondary invasion from the subjacent sebaceous carcinoma. To the best of our knowledge neither primary intraepithelial nor intraepidermal sebaeeous carcinoma has ever been deseribed in the English literature. Since Pagetoid involvement by sebaceous-type cells has never been noted without underlying sebaceous eareinoma, nor has the mueinous type extramammary Paget's disease ever been described in conjunctival epithelium, the observations do not support the conversion of undifferentiated basal cells in the stratum germinativum by unknown carcinogenic agents into neoplastic cells (Sagami 1963, Fetherston & Friedrieh 1972, Medenica & Sahihi 1972). If the Paget cells do not arise de novo from the epidermis, one may stUl eonsider the mode of metastasis or migration of tumor cells into the surface epithelium by the neoplastic cells from subjacent sebaceous carcinoma. In fact, a case of sebaceous carcinoma with direct invasion into the conjunctival epithelium showing Pagetoid phenomenon has been convincingly demonstrated by Boniuk & Zimmerman (1968). In the present case, histopathologically, we were not able to convincingly demonstrate the course of migration or invasion of the
neoplastie cells into the conjunctival epithelium. However, owing to close apposition of the tumor to the overlying conjunctival epithelium, direct invasion seems to be the most likely explanation. Situations somewhat similar to our case have been reported by others in connection with other types of carcinoma. Eversole (1952) reported a case of eareinoma of the bladder with Paget-like invasion of the epithelium. Pinkus & Gould (1939) saw clinically and histologically typical perianal Paget's disease in a case of reetal mueinous carcinoma with widespread metastasis to other organs. Pinkus & Mehregan (1963) reported a ease of ulcerating eccrine eareinoma of the foot with widespread intradermal lymphatic metastasis in whieh multiple nodular lesions with pagetoid structure resulted from upward invasion of the epidermotropic carcinoma. These and our case demonstrate beyond reasonable doubt that extraepidermal adenoeareinoma can be epidermotropic and that cancer cells can invade stratified ectodermal epithelium and colonize it. They support the alternate eoncept of extramammary Paget's disease being, in most instanees, the result of direct invasion or extension of adenoeareinoma that arises from the intraepidermal sweat gland unit, intradermal sweat duet, sweat gland or in some occasional cases from extraepidermal carcinoma of other type.
Acknowledgement
The authors wish to thank Dr. Hermann Pinkus, Emeritus Professor of Dermatology, Wayne State University, School of Medicine for his comtnents and suggestions on the manuseript and to Dr. Raleigh E. Lingeman, Professor and Chairman, Department of Otorhinolaryngology, Indiana University School of Medicine, for his kind contribution of this case. References
Boniuk, M. & Zimmerman, L. E. (1968) Sebaceous carcinoma of the eyelid, eyebrow, caruncle
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and orbit. Transactions of the American Acad- Luft, J. H. (1961) Improvements in epoxy resin embedding methods. Journal of Biophysics, emy of Ophthalmology and Otolaryngology 72, Biochemistry and Cytology 9, 409-414. 619-642. Borst, M., (1904) Ueber die Moglichkeit cineraiis- Medenica, M. & Sabihi, T. (1972) Ultrastructural study of a case of extramammary Paget's disease gedehnten intraepidcrmalen Verbreitung des of the vulva. Arehives of Dertnatology 105, Hautkrebses. Verhandlutigcn der deutsehen 236,241. pathoiogilichen Gesellsehaft 7, 118-123. Cawley, L. P., (1957) Extramammary Paget's Miller, R. E. & White, J. J. (1967) Sebaceous gland carcinoma. American Journal of Surgery 114, disease; Report of a case. Attieriean Journal of 958-961. Clinieal Pathology 27, 559-566. Dubreuilh, W., (1901) Paget's disease of the vulva. Muir, R. (1935) The pathogenesis of Paget's disease of the nipple and associated lesions. British British Journal of Dermatology 13, 407-413. Journal of Surgery 22, 128-T31. Ellis, R. A. (1967) Eccrine, sebaceous and apociine glands. In Ultrastrueture of Nortnal and Ab- Muir, R. (1939) Further observations on Paget's disease of the nipple. Journal of Pathology and normal Skin, ed. Zelickson, A. S., pp. 132-162. Bacteriology 41, 299-312. Philadelphia, Lea & Febigcr. Ellis, R. A. & Henxikson, R. C. (1963) The ultra- Paget, J. (1874) On disease of mammary areola preceding cancer of mammary gland. St. structure of the sebaceous glands of man. In Bartholomew's Hospital Report 10, 87-89. Advances in Biology of Skin, IV, ed. Montagna, W. & Silver, R. A., p. 94. New York, Porgamon Parmley, T. H., Woodruff, J. D. & Julian, C.G. (1975) Invasive vulvar Paget's disease. Obstetrics Press. and Gynecology 46, 341-346. Eversole, J. W. (1952) Extramammary Paget's disease. Discussion of Pathogenesis. Southern Pinkus, H. (In discussion of Murrell, T. W. Jr. & MeMullan, F. H.) (1962) Extramammary Paget's Medical Journal 45, 28-30. disease. Archives of Dermatology 85, 600-613. Ferenczy, A. & Richai-t, R. M. (1972) Ultrastructure of perianal Paget's disease. Cancer 29, Pinkus, H. & Gould, S. E. (1939) Extramammary Paget's disease and intraepidermal carcinoma. U41-1149. Archives of Dermatology 39, 479-502. Fetherston, W. B. & l'riedrich, E. G., Jr. (1972) Tlie origin and significance of vulvar Paget's Pinkus, H. & Mehregan, A. H. (1963) Epidermotropic eccrine carcinoma: Case combining feadisease. Obstetrics and Gynecology 39, Ti5tures of eccrine poroma and Paget's dermatosis. 744. Arehives of Dertnatology 88, 597-606. Fligiel, Z. & Kaneko, M. (1975) Extramammaiy Paget's disease of the external ear canal in asso- Rulon, D. B. & Helwig, E. B. (1974) Cutaneous sebaceous neoplasms. Cancer 3, 82-102. ciation with ceruminous gland carcinoma: a Sagami, S. (1963) Electron microscopic .studies in ease report. Caneer 36, 1072-1076. Paget's disease. Medieal Journal of Osaka Ginsberg, J. (1965) Present status meibomian gland University 14, 173-187. carcinoma. Arehives of Ophthalmology 73, Toker, C (1961) Some observations on Paget's disease of the nipple. Caticer 14, 653-672. Helwig, E. B. & Graham, J. H. (1963) Anogenital (extramammary) Paget's disease: a clinieopatho- Weigent, C. E. & Staley, N. A. (1976) Meibomian gland eareinoma: report of a case with electron logical study. Cancer 16, 387-403. microscopic findings. Human Pathology 7, Hibbs, R. G., (1969) Electron microscopy of human 231-234. axillary sebaceous glands. Jotirnal of InvestigaWhorton, C M. & Patterson, J. B. (1955) Carcinoma tive Dermatology 39, 329-336. of Moll's glands with extramammary Paget's Inglis, K. (1936) Paget's Disease of the nipple and disease of the eyelid. Cancer 8, 1009-1015. its relation to surface cancers and Precaneerous states in General. London, OxtoTd University Zimmerman, L. E. (1971) Ophthalmologie Pathology In: Pathology, Sixth edition, ed. Anderson, Press. W. A. D., pp. 998-1047 St. Louis, CV. Mosby Inglis, K. (1946) Paget's disease of the nipple. With Company. Special Reference to the Changes in the Ducts. American Journal of Pathology 22, 1 - 2 L Knauer, W. B. Jr. & Whorton, C M. (1963) Extra- Address: mammary Paget's disease originating in Moll's Siong Chuan Lee, M.D, glands of the lids. Transactions of the American Department of Dermatology Academy of Ophthaltnology and Otolarytxgo- Wayne State University School of Medieine logy 67, 829-833. Koss, L. G. & Broekunier, A. Jr. (1969) Ultrastruc- 540 Bast Canfield Avenue tural aspects of Paget's disease of the vulva. Detroit, Michigan 48201 U.S. A. Arc/lives of Pathology 87, 592-600.
Sebaceous Carcinoma of the Eyelid with Pagetoid Involvement of the Bulbar and Palpebral Conjunctiva SIONG CHUAN LEE' AND LAWRENCE M. ROTH' ' Resident in Dermatology, Department of Dermatology, Wayne State University Sehool of Medieine, Detroit, Michigan and ' Professor of Pathology and Director of Surgical Pathology, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. A ease of sebaceous carcinoma with pagetoid involvement of the palpebral and bulbar eonjunetival epithelium was studied by light and eleetron microscopy. Ultrastructurally, the neoplastic cells within the conjunctival epithelium were identical to those in the underlying invasive sebaceous eareinoma. Evidence of gradual transformation of eonjunctival epithelial cells to the neoplastic sebaceous ceUs or transitional forms between conjunctival epithelial cells and sebaeeous eells was not eneountered. The evidenee thus supports the theory that the neoplastic cells in the eonjunctival epithelium are the result of secondary invasion by the underlying sebaeeous carcinoma. (Received for publication F'ebruary 18, 1977)
Paget's disease of the nipple and extramammary Paget's disease of the vulva were first described by Sir James Paget (1874) and Dubreuilh (1901) respeetively. Since then this phenomenon has also been noted in areas other than the nipple and the vulva, sueh as the axilla (Cawley 1957), external ear canal (Fligiel & Kaneko 1975), eyelid (Whorton & Patterson 1955, Knauer & Whorton 1963) and perianal areas (Pinkus & Gould, 1939, Helwig & Graham 1963). Paget's disease of the skin of the nipple and areola is practically always associated with adenoeareinoma of the duets of the mammary gland (Muir 1935, Inglis 1946), but by no means all cases in an extramammary location are assoeiated with demonstrable underlying carcinoma of either apocrine or eccrine sweat glands. Concerning the histogenesis, controversy still exists as to whether the Paget eells arise from epidermal basal cells or whether they are the result of migration or metastasis from an underlying
adenoeareinoma. The purpose of this study is to discuss this question in relationship to a case in which a sebaceous adenoeareinoma of the eyelid was associated with Paget-like histologie features in the adjoining eonjunctiva. Case Report A 77-year-old Caucasian woman was referred from the Ophthalmology Department to the Otorhinolaryngology Department because of a tumor mass in the right lower eyelid as well as a metastatic tumor in the right parotid area. The physical examination in the Ophthalmology Department revealed a tumor nodule at the lower eyelid with epithelial thickening of the inferior bulbar and tarsal conjunctiva and subepithelial scarring, A nodule was palpable in the right parotid area. A biopsy of the thickened portion of the bulbar conjunctiva at the lower temporal selera revealed numerous atypical cells with enlarged pleomorphie, hyperchromatic nuclei
SEBAGEOUS GARGINOMA and abundant vacuolated cytoplasm irregularly infiltrating the surface epithelium. A histologic diagnosis of Paget's disease with possible underlying sebaceous carcinoma was made. The patient was subsequently referred to the Otorhinolaryngology Service and a cotnplete resection of the lower eyelid with right superficial parotidectomy was performed. The pathologic diagnosis was invasive poorly differentiated sebaceous adenocarcinoma of meibomian gland origin with pagetoid invasion of the conjunctival epithelium and metastasis to a lymph node in the right parotid gland. The postoperative course was uncomphcated and the patient was discharged in good condition. Materials and Methods
Tissue for light microscopy frotTi various portions of the neoplasm and conjunctiva was fixed in neutral buffered formalin, dehydrated, and embedded in paraffin, sectioned at 5 yUm and stained with hematoxylin and eosin, alcian blue, mucicarmine and periodic acid-Schiff reaction (PAS) with and without predigestion by diastase. Tissue cut from frozen section of the neoplasm was stained by oil red 0 stain. Selected portions of tutnor as well as the conjunctiva were
135
fixed in 4% phosphate buffered gluteraldehyde solutions, post-fixed in 1% osmium tetroxide, dehydrated through a graded series of alcohol and propylene oxide and embedded in epon 812, according to the tnethod of Luft (1961). Sections of 1 fjim thickness were cut, stained with toluidine blue, and examined by light microscopy for proper selection of cells for ultrastructural examination. Ultrathin sections were then cut with an LKB ultratome III ultramicrotome, stained with uranyl acetate and lead citrate and exatnined with a Philips 300 electron microscope. Results
Pathologic Findings Gross observations: The biopsy specitnen of the lower temporal scleral bulbar conjunctiva was very stnall measuring only 1.0 mm in diameter. The specimen removed in the subsequent operation included the right lower eyelid and the right parotid gland and a lymph node. There was a firtii, welldemarcated, but nonencapsulated yellow tumor nodule on the conjunctival surface. This nodule measured 6 mm in diameter (Fig. 1). The cut surface of the nodule had a bright yellow color. Hemorrhage and
Fig. 1. A solid, spherical and well-demareated tutnor arising from the lower eyelid.
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necrosis were not present. The parotid gland measured 7 X 6 X 2 cm. On sectioning, the parotid gland appeared grossly normal; however, there was a well circumscribed nodule present at one end of the gland measuring 1.2 cm in diameter. On sectioning, the cut surface also had a yellow color resembling the one described in the lower eyelid. Light Microscopic Observations These sections of the bulbar conjunctiva over the temporal selera showed a stratified squamous epitheliutn which contained many intraepithelial atypical cells, either isolated or in clusters, with enlarged pleomorphic, hyperchromatic nuclei and vacuolated cytoplasm (Fig. 2). These neoplastic cells were present at different levels of the epithelium but were most numerous in the basal portion. Glandular formation was not seen. The mucicarmine, alcian blue and periodic acidSchiff (PAS) stains with and without diastase were negative. Sections from the right lower eyelid showed the tumor to extend beneath the conjunctival epithelium (Fig. 3). The
tumor consisted of numerous round to irregularly shaped interconnecting nests or cords of cells separated by delicate fibrovascular septa with focal infiltrates of lymphocytes. The tumor cells generally had variable amounts of vacuolated eosinophilic cytoplasm. The nuclei of the neoplastic cells varied somewhat in size and shape. The chrotnatin was dense and irregularly clear. A few cells had small nucleoli. Numerous tnitotic figures were present. There was no evidence of squamous differentiation or formation of lutnina. The overlying conjunctival epithelium showed focal areas of attenuuation and, on one side, simOar neoplastic cells were present in the epithelium for a distance of at least 5 mm from the margin of the nodule (Figs. 4 and 5). The appearance of the neoplastic cells within the conjunctival epithelium was identical to those described previously. Sections of the yellow nodule within the parotid lymph node revealed an epithelial neoplasm. The histopathologic picture was identical to the tumor in the lower eyelid except that at the center of
jmr* 1 ""5&^'>'--'-'"^ ^ ^ ^ ^ H B H H w I P S
_
Fig. 2. A photograph of the bulbar eonjunctival epithelium shows numerous isolated or smaU nests of atypical eells with hyperehromatic nuclei and vacuolated eytoplasm present mostly in the lower portion of the epithelium. H & E X 400.
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Fig. 3. Low magnifieation photomicrograph of the eyelid shows a well-circumscribed but non-encapsulated tumor adjacent to nutnerous nortnal sebaceous glands (tneibotnian glands). Arrows show invading tumor eells in the adjacent conjunetival epitheliutn. H & E X 100.
Fig. 4. A high magnification photomicrograph at the junction of the tutnor and the adjacent conjunctival epitheliutn (in Fig. 3) shows tutnor cells (arrows) invading the palpebral eonjunetival epithelium. H & E XIOO.
F;;?. 5. A high magnification photomicrograph from the distal portion of the palpebral conjunctival epithelium (in Fig. 3) shows more tumor cells (arrows) present within the epithelium. H & E X 205.
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Fig. 6. Section of the metastatie tumor shows cords of polygonal tutnor cells with progressive sebaceous differentiation in the central portion. H & E X 200.
SEBACEOUS CARCINOMA many lobules there was a progressive sebaceous differentiation of the tutnor cells as they were transformed from undifferentiated tumor cells at the periphery towards the large sebaceous cells with abundant foamy cytoplasm (Fig. 6). The neoplastic cells in the lower eyelid tumor as well as those in the conjunctival epithelium and the metastatie tumor in the parotid node were strongly positive to the oil red 0 stain.
139
tumor cells (Fig. 9). The tumor cells within the epithelium resembled the tumor cells in the primary and metastatie tumors. Varying numbers of lipid droplets were present as well as large aggregates of glycogen particles. The mierovilli on the cell surface were more conspicuous and occasionally simple desmosomal attachments were formed between the tumor cells and adjacent squamous cells. The squamous epithelial cells were distinguished from the tumor cells by the presence of abundant bundles of tonofilaments, numerEleetron Microscopic Observations By electron microscopy, the cells in the ous desmosomal complexes and the absence primary and metastatie tumor showed fea- of lipid droplets. tures of epithelial cells with a varying degree of sebaceous differentiation. In general, they Discussion resembled normal immature and partially mature sebaceous cells (Ellis & Henrikson Although sebaceous glands are abundant on 1963, Ellis 1967, Hibbs 1969). Sotne tumor the body and face, sebaceous carcinomas cells were separated from each other by a arising from these areas are relatively rare. In narrow intercellular space into which numer- fact, the majority of the sebaceous carcinous mierovilli extended. Occasional desmo- omas (MiUer & White 1967, Rulon & Helwig somes joined mierovilli from adjacent cells. 1974) reported in the literature are from the A few strands of tonofilaments were present sebaceous glands or modified sebaceous close to the attachment sites. The most glands (meiboniian glands) of the eyelid striking feature was the presence of relatively (Ginsberg 1965, Boniuk & Zimmerman large lipid droplets of variable size in the 1968). The reason for this is not clear. In cytoplasm of the more differentiated tumor spite of its identical morphology, the biocells (Figs. 7 and 8), suggesting that they logical behavior of sebaceous carcinoma of arose asynchronously. The outline of the the eyelids in terms of propensity of recurlipid droplets was smooth. In the majority rence and distant metastasis, is worse than of tumor cells, free ribosomes were dispersed those arising from the body and face (Boniuk throughout the cytoplasm. Scattered strands & Zimmerman 1968). of granular endoplasmic reticulum were Sebaceous carcinoma reportedly reprepresent. Earge aggregates of glycogen sents 1% of carcinoma of the eyelids particles occurred within the cytoplasm and (Ginsberg 1965). In the series studied by were more abundant in the less differentiated Boniuk & Zimmerman (1968), orbital invatumor cells. The Golgi complex was promin- sion occurred in 17% of 88 patients, and ent (Eig. 8). The mitochondria were large, lymph node metastasis developed in 28.4% spherical to ovoid and randomly distributed of 74 patients. Ten patients died with probin the cytoplasm. The cristae were usually able or proved metastasis. Sebaceous carcinoriented perpendicular to the long axis. The oma arising in extraocular areas showed a nucleus was large in the less differentiated more favourable prognosis. A review of the tumor cells. When lipid droplets were present, previously reported cases revealed recurrence the nuclear membrane was frequently in- in 11 cases out of 59, and 8 cases showed dented. The ehromatin was mostly peripher- metastasis (Rulon & Helwig 1974). ally located. The present case might be mistaken for a Ultrastruetural examination of the con- poorly differentiated squamous cell carcinjunctival epithelium showed that the squa- oma with secondary invasion into adjacent mous epithelial cells were displaced by the conjunctival epithelium (Borst phenomenon)
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Fig. 7. An electron mierograph of the neoplastie eells from the invasive tumor shows several lipid droplets (E) of varying size displaeing the eytoplasm. Intereellular spaces eontaining mierovilli are seen (arrow). Lead acetate and uranyl acetate X 7,800.
SEBACEOUS CARCINOMA f^
141
«...
Fig. 8. High magnification electron micrograpli of two neoplastic cells from the invasive portion of the tumor shows small desmosomes with a few strands of tonofilaments (arrows), lipid droplets (L), a proininent Golgi apparatus (G), large aggregate of glycogen particles (Gly) and abundant free ribosomes. Lead acetate and uranyl acetate X 13,600.
Fig^. 9. Election micrograph of the eonjunetival epithelium shows two squamous eells (Sq) sunounded by three neoplastic cells. The neoplastic cells are identical to those in the primary and metastatic tumors. They contain large lipid droplets (L) and aggregates of glycogen particles. The surrounding squamous cells contain abundant tonofilaments and microvilli (Lead eitrate and uranyl acetate X 6,600). Inset: 1 Aim epon section of conjunctival epithelium shows that the squamous cells have been replaced partially by tumor cells (arrows). Toluidine blue X 425.
SEBACEOUS CARCINOMA
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(Borst 1904). However, the absence of indivi- conneetions between epidermal keratinodual eell keratinization and keratin pearl cytes and Paget cells. However, the normal formation, inconspicuous intercellular cells of intraepidermal adnexal units also are bridges, the presence of vacuolation and a bound to surrounding epidermal cells by foamy appearance of the cytoplasm, and the desmosomes and contain tonofilaments and strongly positive oil red 0 stain excluded this often keratohyalin granules. possibility. The sebaceous differentiation The diseussion of Helwig & Graham within the neoplasm was substantiated by (1963) supported the idea that the Paget's ultrastructural findings including the disease and the underlying adnexal carcipresence of numerous lipid droplets and noma could occur concomitantly or sepabundant glyeogen particles, whereas tono- arately; they said, 'Since apocrine cells or filaments and keratohyaline granules were their precursors are normally located in the scanty (Ellis & Henrikson 1963, Hibbs 1969, epidermis, it is our interpretation that these Weigent & Staley 1976). According to eells are autochthonously affeeted by an unZimmerman (1971), pagetoid involvement known agent that causes extramammary occurs rather frequently in association with Paget's disease.' This suggestion comes very sebaceous carcinoma of the eyehds. How- close to the data used by Inglis (1936, ever, to the best of our knowledge, this 1946) to support the Unitarian concept of phenomenon has not been studied and sub- Paget's disease. Inglis (1936) demonstrated stantiated ultrastructurally. in careful work the origin of the Paget eells Classical Paget's disease of the nipple is in the most superficial portion of the lactialways assoeiated with underlying adeno- ferous duct, the part homologous to the eareinoma of the breast (Muir 1935, 1939, intraepidermal sweat duct unit (acroToker 1961). Extramammary Paget's disease syringum). This possibility has also been prohas been described in the vulva (Knauer & posed by Pinkus (1962) to explain extraWhorton 1963), perianal area (Helwig & mammary cases in which no underlying Graham 1963), axilla (Cawley, 1957), eyelids tumor mass can be demonstrated. (Whorton & Patterson 1955), external ear It seems that our case sheds some light on eanal (Fligiel & Kaneko 1975), and serotum the subject from a different angle. It does (Helwig & Graham 1963) and is often asso- not fulfill all the criteria of extramammary ciated with adjacent or underlying adeno- Paget's disease beeause it did not involve eareinoma. For those authors (Koss & skin and did not have the clinical eharacterBrockunier 1969, Ferenczy & Riehart 1972) istic of eezematous dermatitis. Neither did it who subscribe to the proposition that the fulfni the strict histogenic concept of Inglis intraepidermal Paget eells originate from (1936) and other Unitarians who exclude extraepidermal cancers by migration, metas- any case in which the intraepidermal cells tasis or eontinuous growth, these cases appear to have come from invasive cancer need no special explanation. On the other eells in the dermis. It did however, exhibit hand, those authors (Sagami 1963, Fether- the Paget phenomenon: colonization of the ston & Friedrich 1972, Medenica & Sahihi epidermis by non-keratinizing extraepi1972, Parmley et al. 1975) who favored the dermal eaneer cells. There also was an underview that the epidermal lesions and the lying adnexal adenoeareinoma. underlying carcinoma originated each in its The interesting facts are that this carcinown locus, have involved unknown carcino- oma was a sebaceous meibomian gland genie field effeets or have pointed to transi- eareinoma and that the affected stratified tional eell forms between epidermal keratino- epithelium was conjunctiva, the only ectocytes and Paget cells. The latter approach dermal squamous epithelium, normally conhas become more fashionable since the intro- taining some mucin-produeing goblet cells. If duction of electron microscopy. It is often an unknown earcinogenic stimulus was resbased on the demonstration of desmosomal ponsible for simultaneous but independent
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malignant transformation of the meibomian gland and the conjunctival epithelium, one would reasonably expect the latter to produce a muein-producing carcinoma similar to eases of extramammary Paget's disease. The 'Paget cells' in our ease, however, were lipidized eells, identical by light and eleetron microscopy to the cells of the underlying carcinoma. The presenee of some desmosomal conneetions between intraepithelial tumor eells and surrounding squamous cells does not constitute evidenee of transition between epithelial cells and tumor cells. The tumor cells in the stroma also possessed some desmosomes and tonofilaments. No other souree of potentially sebaceous cells is present in the conjunctiva. The intraepithelial cells were also morphologically similar to the cells in the metastatic tumor in the parotid node. These observations lead us to think that the atypical cells in the conjunctival epithelium were the result of secondary invasion from the subjacent sebaceous carcinoma. To the best of our knowledge neither primary intraepithelial nor intraepidermal sebaeeous carcinoma has ever been deseribed in the English literature. Since Pagetoid involvement by sebaceous-type cells has never been noted without underlying sebaceous eareinoma, nor has the mueinous type extramammary Paget's disease ever been described in conjunctival epithelium, the observations do not support the conversion of undifferentiated basal cells in the stratum germinativum by unknown carcinogenic agents into neoplastic cells (Sagami 1963, Fetherston & Friedrieh 1972, Medenica & Sahihi 1972). If the Paget cells do not arise de novo from the epidermis, one may stUl eonsider the mode of metastasis or migration of tumor cells into the surface epithelium by the neoplastic cells from subjacent sebaceous carcinoma. In fact, a case of sebaceous carcinoma with direct invasion into the conjunctival epithelium showing Pagetoid phenomenon has been convincingly demonstrated by Boniuk & Zimmerman (1968). In the present case, histopathologically, we were not able to convincingly demonstrate the course of migration or invasion of the
neoplastie cells into the conjunctival epithelium. However, owing to close apposition of the tumor to the overlying conjunctival epithelium, direct invasion seems to be the most likely explanation. Situations somewhat similar to our case have been reported by others in connection with other types of carcinoma. Eversole (1952) reported a case of eareinoma of the bladder with Paget-like invasion of the epithelium. Pinkus & Gould (1939) saw clinically and histologically typical perianal Paget's disease in a case of reetal mueinous carcinoma with widespread metastasis to other organs. Pinkus & Mehregan (1963) reported a ease of ulcerating eccrine eareinoma of the foot with widespread intradermal lymphatic metastasis in whieh multiple nodular lesions with pagetoid structure resulted from upward invasion of the epidermotropic carcinoma. These and our case demonstrate beyond reasonable doubt that extraepidermal adenoeareinoma can be epidermotropic and that cancer cells can invade stratified ectodermal epithelium and colonize it. They support the alternate eoncept of extramammary Paget's disease being, in most instanees, the result of direct invasion or extension of adenoeareinoma that arises from the intraepidermal sweat gland unit, intradermal sweat duet, sweat gland or in some occasional cases from extraepidermal carcinoma of other type.
Acknowledgement
The authors wish to thank Dr. Hermann Pinkus, Emeritus Professor of Dermatology, Wayne State University, School of Medicine for his comtnents and suggestions on the manuseript and to Dr. Raleigh E. Lingeman, Professor and Chairman, Department of Otorhinolaryngology, Indiana University School of Medicine, for his kind contribution of this case. References
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