Ocular surface squamous neoplasia

SURVEY OF OPHTHALMOLOGY VOLUME 39, NUMBER6. MAY-JUNE 1995

MAJOR REVIEW

Ocular Surface Squamous Neoplasia GRAHAM A. LEE, MBBS, AND LAWRENCE W. HIRST, MD

Division of Ophthalmology, Department of Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Abstract. Ocular surface squamous neoplasia presents as a spectrum from simple dysplasia to carcinoma in situ to invasive squamous cell carcinoma involving the conjunctiva as well as the cornea. It is a distinct clinical entity, although it has been known by a variety of different names thorughout the literature. Most commonly it arises in the limbal region, occurring particularly in elderly males who have lived in geographic areas exposed to high levels ofultraviolet-B radiation. Symptoms range from none to severe pain and visual loss. The development of preoperative diagnostic techniques, such as impression cytology, are of value in clinical decision making and follow-up management. Simple excision with adequate margins is currently the best established form of treatment despite trials of other modalities. The course of this disease may be evanescent, but is more frequently slowly progressive and may require/e~enteration and occasionally may lead to death. (Surv Ophthalmol 39"429-450, 1995)

Key words, carcinoma in situ 9 conjunctival intraepithelial neoplasia 9 dysplasia, limbus 9 ocular surface epithelial dysplasia 9 ocular surface squamous neoplasia 9 squamous cell carcinoma 9 ultraviolet light

Squamous cell carcinoma of the conjunctiva and c o r n e a has been long established in the literature, described as early as 1860 by yon Graefe u n d e r the n a m e epithelioma. 37 T h e nomenclature ofdysplasia and carcinoma in situ, however, is somewhat m o r e varied (Table 1). Nicholls 115in 1939 reviewed a condition called epithelial plaque, characterized by local hyperplasia and cornification. O t h e r names that have been used previously in the literature are tyloma, keratosis and conjunctival callosities. T h e r e was no specific r e f e r e n c e to dysplasia, but to a so-called "precanCerous" condition. In 1942, McGavic 99 described five lesiojns showing histopathologic changes similar to that of Bowen's disease of the skin, i.e., cellular variation and unrest (poikilokaryonosis) without violation o f the basement m e m b r a n e . T h e s e changes had also been n o t e d earlier in the

G e r m a n literature. 2a'65 McGavic suggested the terms "intraepithelial epithelioma" (Bowen's disease) and "Bowenoid epithelioma" to describe lesions not fully characteristic o f Bowen's original description. Later that year, Ash and Wilder 4 published a series of 93 epithelial tumors o f the limbus, which included 17 so-called epidermalization and dyskeratoses, 48 carcinoma and 28 papilloma. T h e y concluded that epidermalization was an i m p o r t a n t p r e c u r s o r to d e v e l o p m e n t o f t u m o r and that some basic factors such as Vitamin A deficiency, drying, or chronic irritation were responsible for this metaplasia. J a n e r t vl in 1956, differentiated Bowen's disease as epithelial hyperplasia with dyskeratosis as opposed to leukoplakia with hyperkeratosis. Lugossy 91 and Winter and Kleh ~72 p r e f e r r e d the term "precancerous" epithelioma o f the limbus. This was

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based on the theory that carcinoma develops by gradual thickening and transition in the limbal epithelium. O n e of the largest single series was Irvine's 68 study of 104 dyskeratotic epibulbar tumors. H e observed that there was little correlation between the microscopic criteria of degrees of dyskeratosis and clinical behavior and d o u b t e d the potential for metastasis. Z i m m e r m a n 176 in 1964 stated that leukoplakia should only be used as a clinical descriptive t e r m to describe an o p a q u e white placoid lesion in a mucous m e m b r a n e . H e also stated that Bowen's disease, as a specific histologic entity, is quite rare and should not be s y n o n y m o u s with in situ carcinoma. Carroll and Kuwabara 15 in 1965 differentiated the tumors into four distinct cell types and correlated this with r e c u r r e n c e rate. An i m p o r t a n t observation was that no progression of histologic severity in r e c u r r e n t lesions was noted. T h e t e r m conjunctival intraepithelial neoplasia (CIN) was coined by Pizzarello a n d Jakobiec 125 in 1978, paralleling the gynecological pathology t e r m for cervical intraepithelial neoplasia. Waring et a1166 ext e n d e d the t e r m to include the cornea and Erie et al < f u r t h e r e x t e n d e d it to include invasive neoplasia. We have suggested the use of the "umbrella" term ocular surface epithelial dysplasia (OSED), 83'84 but now feel that ocular surface squamous neoplasia (OSSN) is a better terminology. Ocular surface denotes involvement of the conjunctiva or cornea; squamous excludes other epithelial cells such as basal cells and melanocytes and neoplasia includes both dysplastic and carcinomatous lesions. We still r e c o m m e n d the terms dysplasia, carcinoma in situ and invasive carcinoma for the individual histopathologic entities) 3 These lesions also have been extensively studied in cattle. TM I. Epiderniology A. INCIDENCE OSSN is u n c o m m o n . T e m p l e t o n TM studied tribal groups in U g a n d a between 1961 and 1966, finding an average incidence of 0.13/100,000. More recently, o u r study of Metropolitan Brisbane, Australia, over the period 1980-1989 estimated an incidence of 1.9/100,000. 83 No significant increase in the n u m b e r of cases per year was observed over the ten-year period. This rate was m u c h lower than for squamous cell carcinoma of the skin (600/100,000) for the same geographic area. This t u m o r is also u n c o m m o n c o m p a r e d to o t h e r oculo-orbital tumors (Table 2). T h e findings of previous population surveys, 3'5'9'1~176176

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114,120,121,142,147,148,154 have shown the n u m b e r of cases of OSSN relative to all oculo-orbital tumors range between 4% to 29%, with an average of 14%. In the older population, OSSN is the third most c o m m o n ocular t u m o r after m e l a n o m a and lymphoma. B. RACIAL A N D GEOGRAPHIC DISTRIBUTION

Several large studies have f o u n d a predominance in Caucasians ranging from 90-100%. 5'41' 68,125 However, d a r k e r skinned populations in tropical climates closer to the e q u a t o r than 30 ~ latitude, do develop O S S N . 20'108'114'120'154 Ni et al 1~4 noted the age of onset at latitudes closer to the equator than 30 ~ was y o u n g e r than at latitude 45 ~ (53 years vs 64 years). Caucasian populations at latitudes closer to the e q u a t o r than 30 ~ are t h e r e f o r e at particular ocular risk. C. AGE A N D SEX D I S T R I B U T I O N

OSSN p r e d o m i n a n t l y occurs in older males (76%, range 56-97% [Table 3]). 4'15'20'41'49'64'67'68'83' 84,103,114,120,125,154,172 T h e average age of o c c u r r e n c e is 56 years with a wide age range from 4-96 years old. T h e youngest cases r e p o r t e d were a 4-yearold Caucasion female who developed an inferior palpebral conjunctival lesion one year after strabismus surgery 67 and 13-year-old N e g r o female, who was otherwise healthy22 T h e o t h e r y o u n g e r g r o u p of cases are in children with x e r o d e r m a pigmentosum. 66'67'12~T h e results of several studies have shown the average age of carcinoma in situ patients to be 5-9 years y o u n g e r than the invasive squamous cell carcinoma patients. 41'114 T h e researchers suggest that this may indicate that progression takes place from dysplasia to carcinoma. II. Etiology A. LIMBAL T R A N S I T I O N ZONE/STEM CELL T H E O R Y

T h e limbus is an area of transition from conjunctival to corneal epithelium. It is akin to other areas such as the uterine cervix which are predisposed to dysplasia. 125 T h e stem cell concept was reviewed by T s e n g 168 in 1989. Stem cells located in the limbal region characteristically are longlived and have great potential for clonagenic cell division. T h e y have the responsibility for corneal epithelial replacement. Clinically, excessive conjunctival growth or conjunctivalization of the cornea can be f o u n d in several ocular surface disorders. Histopathologically, these diseases carry the features of overgrowth of conjunctival

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epithelium with associated goblet cells, accompanied by neovascularization, disruption of the basement membrane and inflammatory cell infiltrates. In addition, the alteration of the microenvironment with respect to cell-cell and/or cellmatrix interactions, is likely to result in an altered regulatory mechanism of the limbal stem cell function leading to abnormal epithelial phenotypes. OSSN may represent the abnormal maturation of corneal and conjunctival epithelium as a result of a combination of factors such as ultraviolet-B irradiation and human papillomavirus. B. ULTRAVIOLET-B LIGHT

Exposure to excessive ultraviolet-B light (UVB) has been identified by numerous previous studies as a major etiologic factor in the development of O S S N . 5'8'20'41'68's4'103'125'149A study in Sudan ~~ found a predilection for squamous cell carcinoma and other epithelial lesions of the conjunctiva in the North, in contradistinction to the much lower frequency in the South. They ascribed this trend to various environmental factors such as the presence of clouds, rain, the thick equatorial forests and shaded valleys which reduce the effect of UV-B in the South. In our recent case control study, s4 we identified risk factors for the development of OSSN, which include phenotypic features such as pale skin, pale iris and propensity to sunburn, and spending > 50% of the time outdoors in the first six years of life while living at closer to the equator than 30 ~ latitude. History of actinic skin lesions such as squamous cell carcinoma and solar keratoses was also strongly positively associated with the development of these conditions. 4'99 Ultraviolet light is thought to cause DNA damage and the formation of pyrimidine dimers. 16~Failure or delay in DNA repair may lead to somatic nmtations and the development of cancerous cells, such as occurs in xeroderma-pigmentosa patients. C. HUMAN PAPILLOMAVIRUS TYPE 16

H u m a n papillomavirus (HPV) Type 16 has recently been demonstrated in association with conjunctival neoplasia. 95-9s In their recent reviews, McDonnell et al used in vitro gene amplification with the polymerase chain reaction to identify HPV 16 DNAin as many as 37 out of the 42 biopsies. However, HPV was present in clinically uninvolved eyes and the infection persisted for many years despite successful eradication of the lesions. Odrich et al 1~9 described three patients with bilateral tumors all associated with

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HPV type 16. Their conclusion was that progression of this conjunctival inflammatory condition to a dysplastic or neoplastic condition in the presence of HPV DNA can only be suggested by comparison with the gynecologic evidence for neoplastic progression from condylomata to carcinoma in situ in the cervix. Thus HPV apparently does not act alone in development of OSSN, but in combination, for example with UVB exposure. A direct role of HPV has yet to be proven. The bovine papillomavirus (BPV) has also been implicated in the development of bovine ocular squamous cell carcinoma. A recent review, however, using DNA probes and electron microscopy, failed to detect the direct involvement ofBPV DNA] 35 It was concluded that BPV may contribute to induction of precursor lesions or events leading to carcinogenic transformation, without being relevant for the maintenance of the tumor. Other authors have suggested alternative etiologic factors. These include dust, wind, lid closure causing trauma, 9, chemical exposure such as trifluridine, ~~ arsenicals, beryllium, 125 ocular surface injury, 4'~25 Vitamin A deficiency,4 exposure to petroleum products and cigarette smoke, u2 and possibly other viruses such as the herpes simplex virus type I. 4s

III. Clinical Findings A. CLINICAL PRESENTATION

Benign dysplasia, carcinoma in situ and invasire squamous cell carcinoma are difficult to distinguish on clinical appearances alone (Figs. 13). The lesions are described as being slightly elevated, variably shaped, relatively sharply demarcated from the surrounding normal tissues, accompanied by feeding blood vessels and colored from pearly gray to reddish gray depending on the vascularity of the tumor. They most commonly straddle the nasal or temporal limbus between the palpebral fissures (Table 3). Lesions restricted to the conjunctiva or cornea alone are rarer, with the corneal variant potentially a more aggressive form 41 (Fig. 4). Pizzarello and Jakobiec 125and Erie et a141have described the macroscopic appearance as being either gelatinous, velvety or papilliform or leukoplakic (Fig. 5). The gelatinous lesion, with characteristic tufted superficial vessels, is the most common appearance (Fig. 4). Two other appearances, nodular and diffuse have also been described. 9The nodular type is circumscribed, rapidly growing, invading adjacent conjunctiva (Fig. 3) and may

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Fig. 1. A: External photograph of nasal limbal dysplasia with mild opacification of cornea evident. B: Characteristic deep epithelial polycystic appearance of dysplastic corneal epithelium (note vessels on right of photo just in advance of limbus).

Fig. 2. External photograph of carcinoma in situ showing typical leukoplakic appearance of corneal lesion and vascularization extending towards the lesion.

Fig. 3. External photograph ofinvasive squamous cell carcinoma recurrence after original removal (see lamellar transplant in periphery of cornea). Recurrence is typified by a firm nodular excresence with overlying conjunctival vessels.

Fig. 4. Extensive carcinoma in situ with typical corkscrew vascular tufts which is restricted to the conjunctiva alone and no corneal involvement.

Fig. 5. Invasive squamous cell carcinoma showing leukoplakia and extensive feeder vessels.

have an increased tendency for metastasis to regional l y m p h nodes. T h e diffuse type is the least c o m m o n (Fig. 6) a n d is difficult to diagnose in its early stages, m a s q u e r a d i n g as chronic conjunctivitis. G9'136This type of lesion is unusual in that it is chronic and that tumefaction occurs later in the disease process. L a r g e r lesions with fixation to

u n d e r l y i n g tissues are suggestive of malignancy; however, generally the clinical a p p e a r a n c e does not help to differentiate benign from malignant lesions. OSSN most often presents as a growth on the ocular surface or as a foreign b o d y sensation, redness or irritation.lV~ Presentation with dimin-

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Fig. 6. A: External photograph of total corneal and limbal involvement by dysplastic lesion with very raised gelatinous vascular tufting. B: Superficial lamellar keratectomy and conjunctival removal which demonstrates no

recurrence four months later.

Fig 7. A: External photograph of a non-pigmented limbal lesion from the nine to ten o'clock position which is an amelanotic nevus in a thirteen-year-old child. B: A raised gelatinous conjunctival lesion on the bulbar conjunctiva which is non-pigmented and on biopsy proved to be melanoma of the conjunctiva. C: External photograph of eye

which has had previous limbal excision for extensive dysplasia now shows a pyogenic granuloma at the five to six o'clock position. D: External photograph shows a lightly pigmented gelatinous lesion extending onto the cornea in which there are multiple clear cysts, representing a conjunctival nevus.

ished vision is m u c h less c o m m o n . In o u r study of 117 cases, d u r a t i o n of s y m p t o m s r a n g e d f r o m two weeks to eight years, with an a v e r a g e of three months. Eighty-six (73.5%) p r e s e n t e d within the first six m o n t h s of s y m p t o m s . T h e r e was no correlation o f the severity of the lesion to rapidity of s y m p t o m onset.

B. DIFFERENTIAL DIAGNOSIS T h e different stages o f OSSN are difficult to distinguish clinically, with an accuracy of diagnosis by e x p e r i e n c e d clinicians of a p p r o x i m a t e l y 40%, s q u a m o u s cell c a r c i n o m a being the most difficult to identify (30% accuracy) in o u r study. T h e most c o m m o n misdiagnoses clinically of this

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condition include pterygium, papilloma, pingueculum, dyskeratosis and nevus r14'125'~29 (Fig. 7). Other differential diagnoses include malignant melanoma, especially in cases of racial melanosis, i pyogenic granuloma,'~ dermoid, phthisis, I14 orbital cellulitis, 1:~3 lympho-proliferative processes, viral keratitis, 3~ keratoacanthoma, or pseudo-epitheliomatous hyperplasia, ~65 corneal pannus from any cause, filtering cicatrix of the cornea, Mooren's ulcer, fatty degeneration of the cornea and epithelial dystrophy of the cornea. 99 The following have been described by Pizzarello and Jacobiec ~25 as distinguishing features. 9 Malignant melanoma has a regular smooth surface, lacks gelatinous or leukoplakic surface disturbances and may become ulcerated. 9 Papilloma may occur anywhere on the conjunctiva, may be sessile or pedunculated, has a punctate vascular pattern, occurs in younger patients, but ultimately may only be difterentiated by histologic examination. 9 Benign nevi tend to occur in the interpalpebral zone, from the limbus to the caruncle, to occur in younger patients, and to have distinctive cysts on slit-lamp examination. Poorly pigmented lesions near the limbus may simulate a dysplastic process. 9 Pseudo-epitheliomatous hyperplasia (PEH) is a benign reactive or pseudocancerous lesion of the conjunctiva which tends to develop rapidly over several weeks to several months. PEH occurs anywhere on the conjunctiva, has a whitish rather than gelatinous appearance and may rarely have crater-like centers filled with keratin, resembling a keratoacanthoma. Histologically, other lesions may have similar features. These include pseudoepitheliomatous hyperplasia, poorly pigmented melanocytic lesions growing in a pagetoid fashion and pagetoid sebaceous cell carcinoma spread radially from lid or caruncular lesions] 25Pyogenic granuloma has also been described as simulating a squamous cell carcinoma. 109 C. RELATED DISEASES

The role of pterygia in the development of OSSN is unclear. The two conditions both arise commonly within the interpalpebral fissure at the limbus. They may occur together or contralaterally and both show collagen degeneration on microscopy. ~4 Cases of OSSN arising in the epithelium of an overlying pinguecula or pterygia have occurred, 14~ but are quite rare. Sevel and Sealy's s t u d y 14~ of 12 squamous cell carcinoma and 17 carcinoma in situ arising in 100 pterygia,

LEE, HIRST found that it can be difficult to distinguish a "reactive pterygium" from carcinoma in situ. Malignant change should be considered in a pterygium if there is unusual evidence of invasion or extension, or if it becomes particularly vascular. Other eye diseases thought to be related to UV-B exposure also have a high association with OSSN. In our follow-up study (unpublished) of 55 OSSN patients, a high proportion had pterygium (12), pingueculum (42), climatic droplet keratopathy (12), cataract (26) or corneal degeneration (10). No increased incidence of other organ malignancies have been found in these diseases as is characteristic of patients with Bowen's disease of the skin. 41'6s'12~ Several specific malignancies, however, have been documented. Awan6 described a 54-year-old male with chronic lymphocytic leukemia who underwent extensive chemotherapy and treatment with systemic steroids. He postulated that in chronic lymphocytic leukemia, the lymphocytes are so abnormal that tumor specific antibody response is diminished. Increased cancer susceptibility may also be related to genetically linked factors and chromosomal abnormalities induced by immunosuppressive agents such as azathoprine or methotrexate. Squamous cell carcinoma arising in a 36-year-old female with nodular malignant lymphoma has also been described. 8~One of the patients in our series was a 79-year-old female with non-Hodgkins lymphoma. This patient presented with a two-week history of an irritated left eye. As 8 mm multilobar, highly vascular limbal lesion extending from nine o'clock to twelve o'clock was found. This patient also had a history of multiple basal cell carcinomas and squamous cell carcinomas removed from her nose and cheek as well as a pterygium removed from the opposite eye. After simple excision, she had a recurrence six months later which was treated with excision and irradiation. She died six months later at age 80 years old. Xeroderma-pigmentosum has been associated with particularly young patients with O S S N . 52'66'67 Gaasterland 52 described a particularly severe case of a 37-year-old female with bilateral, poorly differentiated squamous cell carcinoma. The lesions were characterized by early recurrence and invasion despite radiation treatment, finally leading to exenteration of one of her eyes. Cells from most persons with xeroderma-pigmentosum are unable to repair UV damaged DNA as rapidly as normal celts, j13 Major photopigments of UV irradiation of DNA are

OCULAR SURFACE SQUAMOUS NEOPLASIA pyrimidine dimers which distort t h e DNA strand. The use of UV impenetrable glasses should be stressed in these patients. OSSN has also been associated with the human immunodeficiency virus (HIV). Winward and Curtin 173described a 44-year-old male who had a three-month history of a pigmented squamous cell carcinoma of his nasal limbus. Squamous cell carcinoma is the third most commonly described malignancy associated with HIV, primarily in the oral cavity and anal rectum. The unusual features in this case were the patient's young age, the rapid tumor growth and a particularly malignant histologic appearance. One patient in our review was a 55-year-old male who was HIV seropositive. He presented with a nine-month history of redness in his right eye. A 4 mm nasal lirabus squamous cell carcinoma was diagnosed and simply excised. There was no recurrence, however, and the patient died 21 months later as a result of his HIV infection. In unusual presentations of OSSN with no obvious cause, HIV infection should be suspected. It has been proposed that chronic irritation of the basement membrane may stimulate the oncogenic potential of the overlying basement epidermal cells, giving rise to squamous cell carcinoma of the conjunctiva. 143This may be an etiologic factor in cases of benign mucous membrane pemphigoid 14~and in exogenous insult s, as mentioned previously.

IV. P r e o p e r a t i v e D i a g n o s i s A. EXFOLIATIVE CYTOLOGY Use of exfoliative cytology was first studied by Larmande and Timsit in 1954. s2 They used a sterile platinum spatula to obtain the specimen, fixed it with 95% alcohol and stained it using a Papanicolaou technique. More recently a small cytobrush, similar to that used for endocervical sampling, has been used by Tsubota et al. 164The cytologic characteristics have been reviewed by s e v e r a l authors. 3s'56'144 9 Dysplasia: enlarged nuclei with fine to coarse granulation of the nuclear chromatin, irregular nuclear bordersl scanty cytoplasm, background clean. 9 Carcinoma in situ: variable number ofdysplastic cells with an admixture of intact and well preserved malignant cells, scanty cytoplasm < 1 nuclear diameter in width, enlarged nuclei with neoplastic features of hyperchromatism, irregular thickening or crusting of nuclear membranes, abnormal clearing or condensation of nuclear chromatin and large acidophilic nucleoli, back-

437 ground clean. 9 Invasive squamous cell carcinoma: Grades 1-2 -

marked cytologic aberrations, bizarre malignant cells including tadpole cells with cytoplasmic tails, fiber or spindle cells, hyperkeratinized cells with opaque refractile red or orange cytoplasm and malignant nuclei; Grades 3-4 - cytoplasm scanty, nonkeratinized and maybe partially destructed or completely lost, large-to-huge pleomorphic nuclei; with deeper invasion and ulceration, 'tumor diasthesis' background - n e c r o t i c tumor cells, debris, blood and leukocytic exudate. The specimen must be taken from one or more appropriate areas and examined by an experienced histopathologist. Its advantages include: 1) diagnosis of corneal and conjunctival tumors; 2) exclusion of diagnosis of cancer in patients with persistent or resistant unilateral epibulbar inflammation, particularly if they refuse biopsy and it is an important guide to therapy and especially if non-surgical intervention is indicated; 3) evaluation of changes in the tumor during treatment, and 4) follow-up of patients after treatment, particularly for detection of recurrences. It is, however, a difficult technique to practice. It may be uncomfortable for the patient, it requires an experienced pathologist to interpret the specimens reliably (with problems of cellular overlap), and it does not localize the lesion or indicate the degree of tumor invasion.

B, IMPRESSION CYTOLOGY Impression cytology is the use of cellulose acetate filter paper sheets, which are gently placed in contact with the ocular surface] 61 The paper, on removal from the surface, samples the most superficial epithelial cells which can then be fixed and stained with a Papanicolaou stain (Fig. 8A). It is a simple relatively noninvasive and repeatable test and has been evaluated for the specific study of O S S N . 117 Dysplastic cells are characterized by enlarged, irregular and hyperchromatic nuclei (Fig. 8B). Carcinoma in situ demonstrating syncytia-like cell groupings, i.e., loss of cellular borders and irregularly arranged enlarged nuclei (Fig. 8C) and invasive lesions having the additional features of inflammatory cells and sheets of abnormal cells with macronucleoli (Fig. 8D). Cytology was found to be positive in 77% of histologically confirmed cases. The main advantage is that it allows relatively easy collection of the epithelial samples with minimal discomfort to the patient and enables more precise localization of the area studied with the advantage of assessing cell to cell relationships.

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Fig. 8. A: Impression cytology of normal conjunctival epithelium with goblet cells (Papanicolaou stain, x 400). B:

Impression cytology of mild dysplasia showing atypical cells with enlarged, irregular and hyperchromatic nuclei (Papanicolaou stain, • C: Impression cytology of carcinoma in situ showing syncytial-like groupings of irregularly arranged, enlarged nuclei (Papanicolaou stain, x 400). D: Impression cytology of invasive squamous cell carcinoma showing abnormal cells with macronucleoli and inflammatory cell infiltrate (Papanicolaou stain, x 400).

Two other methods have been used experimentally to study these conditions. Weissman et a1167described the use ofbromodeoxyuridine, a thymidine analog to analyze conjunctival epithelial cell cycling. This analog can be stained immunohistologically and has been used to demonstrate an increased proliferation of basal epithelial cells and suprabasal cell DNA synthesis. It has been claimed to be a more sensitive examination than enumeration of mitoses per high-powered field by microscopy. The findings suggest a possible benefit from the local use of anti-cycling agents for treatment of dysplasia. Similarly, nucleolar organizer regions (NORs) which are composed of genes coding for RNA, can be detected by a silver staining technique showing as intranuclear black dots. ~ The authors claim this can be used to distinguish dysplasia and neoplasia, as there is a statistically significant increase in AgNOR counts in neoplasia and may reflect the degree of malignant potential. However, the method is time-consuming

and thus not practical for routine diagnostic histopathology.

V. Histopathology OSSN presents as a spectrum of histologic severity which can be classified as follows. 63'125 9 Dysplasia:

Mild - less than a third thickness occupied by atypical cells (Fig. 9A) Moderate - three quarters thickness occupied by atypical cells (Fig. 9B) Severe -- nearly full thickness occupied by atypical cells (Fig. 9C) 9 Carcinoma in situ: as above with loss of the normal surface layer (Fig. 9D) 9 Invasive squamous cell carcinoma: as above when the basement membrane of the basal epithelial layer has been breached and invasion of the substantia propria has occurred. (Fig. 9E) The histologic appearance of the atypical cells or keratinocytes have also been classified with varying nomenclature.~5'114,125

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Fig. 9. A: Light photomicrograph of mild dysplasia

highlighting atypical basal cells extending for less than one-third of the epithelial thickness (H&E, x 100). B: Light photomicrograph of moderate dysplasia revealing extensive cellular atypia occupying less than three quarters of the corneal epithelial thickness (H&E, x 100). C: Light photomicrograph of severe dysplasia revealing almost full thickness cellular atypia with a small area of stratified epithelial cells on the surface (H&E, x 100). D: Light photomicrograph of carcinoma in situ revealing full thickness epithelial involvement by atypical cells (H&E, x 50). E: Light photomicrograph of invasive squamous cell carcinoma showing intrastromal extension by atypical cells with overlying mild to moderate dysplasia (H&E, x 50).

9 spindle cell/small cell/basal cell: small uniform cells with elliptical and moderately chromatic nuclei without prominent nucleoli; scant, slightly basophilic cytoplasm; poorly defined cellular borders; frequent mitotic figures 9 epidermoid cell/squamous cell/large cell/prickle cell/pavement celt: large, polyhedral cells with large, hyperchromatic, and often pleomorphic nuclei with prominent nucleoli; abundant eosinophilic cytoplasm (containing glycogen), variable degrees of hyperkeratosis and parakeratosis; infrequent mitotic figures 9 clear cell: small cells with hyperchromatic nuclei; scant, clear, slightly basophilic cytoplasm

with occasional melanin pigment granules 9 muco-epidermoid/goblet cell: cuboidal cells with mucicarmine-positive, intracytoplasmic droplets; cells arranged in nests and cords with secreted pools of mucin in the extracellular spaces.

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Of these, the spindle cell is the most common cellular type with the epidermoid cell less common (5%) and the other variants even less common. Distinction between the cell types, however, is not absolute, as lesions may have mixtures of both types or have cells of intermediate type, for example, "spindle squamous. ''125 Proliferation of atypical cells commence in the basal region of the epithelium and tend to be orientated perpendicular to the basement membrane. There is generally a sharp vertical or oblique demarcation between the dysplastic cells and adjacent normal epithelial cells. However, lateral spread in one to two layers immediately above the basement membrane region can occur without manifest thickening of the conjunctiva. McGavic in 194299 compared five cases of carcinoma in situ of the conjunctiva to Bowen's disease of the skin. Certain histologic features of OSSN may resemble that of Bowen's disease which is characterized by large atypical epidermoid cells with bizarre nuclei and vacuolated cytoplasms. OSSN is different from dyskeratosis which implies abnormal keratin formation deep to the epithelial surface, particularly within individual epithelial cells and is not suggestive of malignancy. 114 The electron microscopy of OSSN has been studied by several investigators? ~ Features include: excessive number of organelles including mitochondria, endoplasmic reticulum and tonofilaments; reduction in the n u m b e r of desmosomes; microcysts containing disintegrating cytoplasmic debris and organelles (apoptotic bodies~4); and, alteration of the basement membrane - deposition of fibrillogranular material between the basement membrane and Bowman's layer. Rare variants of squamous cell carcinoma include muco-epidermoid, 12'53'63'127'1~9 pigmente d 72'136'154 and spindle cell. 22'63'174 The cardinal histologic features of muco-epidermoid carcinoma are the presence of mucus-secreting elements, initially seen as cystoid spaces containing mucin and cells with clear vacuolated cytoplasm and eccentric nuclei (signet-ring cells). The diagnosis is facilitated with special stains such as PAS, Alcian blue and mucicarmine. The mucoid element may either be detected only in the primary lesion or conversely found only in the recurrent lesion.l a9The muco-epidermoid carcinoma is important to recognize in that it has an increased capacity for local invasion, and aggressive surgical management, such as early enucleation for treatment of primary lesions has been recom-

LEE, HIRST m e n d e d ?3 The pigmented variety of OSSN was first described by Noyes as early as 1879.1~'~ It has been found to occur particularly in pigmented individuals. 7~'13<~54Abnormal proliferation of melanocytes, however, is a common feature in dysplasia, occurring in pigmented individuals. 2~ Findings on transmission electron microscopy include melanosomes within squamous epithelium, melanocytes, and macrophages, with squamous cells being the only cells of malignant nature. The condition needs to be clinically distinguished from the more ominous nodular conjunctival melanoma, but this can be difficult and may not be possible without a histologic examination. 7~'~3~This variant has a clinical course similar to that of nonpigmented squamous cell carcinoma. The spindle cell variant is extremely rare, characterized by pleomorphic spindle cells with variably shaped nuclei (in comparison to the uniformity of the more common spindle cell). It is important to identify because of its propensity for recurrence; 22'6~'j74 excision with a wide margin is recommended. The lesion may be mistaken for an early pterygium, an amelanotic melanoma, or an atypical fibrous xanthoma. OSSN arising from the cornea alone is uncommon, but has been well documented (Table 4). 11'13'14'26''H'41'55'60'61'88'93'124'131'15I'159'166'I75 The etiology is controversial. Some authors advocate a de novo dysplastic process in the cornea, 55 while others suggest the centripetal sliding of subsequently neoplastic cells from the limbus. 1:~ Its clinical presentation varies from limbal and conjunctival lesions, in that reduced visual acuity due to growth across the visual axis is more common. 26'13~Reduced sensation over the tumor may also be a feature suggesting the role of neurotrophic keratitis. ~3'5~'~3~Macroscopically it is of an opaque, grayish, avascular appearance with timbriated margins/66 It may not be detected on just cursory biomicroscopic examination and has been mistaken for lesions of allergic or Vitamin A deficiency origin, s8'~ Histologically, these corneal lesions have histology similar to that of limhal and conjunctival lesions. 1-~ Waring et al ~66 reviewed the electron micoscopic features. These features include decreased desmosomal cellular attachments, widened intercellular spaces which give the tissue a spongy appearance, absent epithelial basement membrane and intact Bowman's zone, multilobular nuclei with invagination of membranes, coarse clumping of chromatin, multiple irregular nucleoli and cytoplasmic

441

OCULAR SURFACE SQUAMOUS NEOPLASIA TABLE 4

Corneal Ocular Surface Squamous Neoplasia

Ash, 19505 Locke, 195693 Taylor, 1974153 Cruess et al, 198126 Roberson, 1984 TM Erie et al, 198641 Lee et al, (unpublished data)

Total 11 6 5 7 5 5

Age Range 63-78 31-73 34-68 -

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4

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tonofilament bundles s u r r o u n d i n g the nucleus. Apoptosis has also been noted. ~4T h e i m p o r t a n c e of corneal dysplasia is its particular t e n d e n c y to recur. 26'55'131 This may be related to inadequate corneal scraping, thereby leaving an intact abn o r m a l basal cell layer, predisposing to dysplasia of the overlying epithelium, or to remaining abn o r m a l limbal stem cells. 55

VI. Treatment A. SURGERY Excision of the lesions is the most accepted m e t h o d of t r e a t m e n t for squamous neoplasia of the ocular surface (Table 5). Dissection of all abn o r m a l tissue within a wide surgical margin of 2-3 m m will suffice to ensure removal of the majority l e s i o n s . 67'7~ Rose bengal staining may help aid the delineation of the extent of abnormal tissue TM (Fig. 10). Deep corneal invasion may require deep lamellar keratoplasty and scleroplasty. ~77 Variations of these techniques have been described/~'5~ T h e m e t h o d used by F r e e d m a n and R o h m 5~ consists of an incision m a d e in clear cornea just b e y o n d the furthest area of t u m o r invasion into the u p p e r third of the corneal stroma. A plane is then f o u n d at this level and the dissection continued b e n e a t h the invading t u m o r to the limbus. T h e dissection then becomes superficial and a wide excision of the conjunctiva containing the t u m o r mass is und e r t a k e n (Fig. 1 1). Frozen section of lesions can be used to assess the adequacy of excision margins, particularly if invasion is suspected. However, the disparity between apparently clear surgical margins and rec u r r e n c e emphasizes the limitations o f standard frozen section control of t u m o r margins, is Frozen section is quite accurate to delineate horizontal t u m o r spread, especially with a small surgical

specimen, but is p o o r for sampling the deep surface. Another m e t h o d of microscopic t u m o r margin surveillance, an adaptation of Mohs' micrographic technique for cutaneous tumors, was r e p o r t e d by Buuns et al. 12aT h e m e t h o d involves removal of the gross mass o f the t u m o r with a lateral resection margin of 2 mm. T h e specimen is then carefully orientated and processed by p e r m a n e n t section within 24 hours. If margins showed evidence of t u m o r cells, the patient ret u r n e d for a second stage excision usually within 3-4 days. An additional 2 rnm of tissue was excised from the conjunctival edge c o r r e s p o n d i n g to the involved edge of the specimen. In all patients, the tumor-free conjunctival defect was allowed to heal by secondary intention. During 6-60 months o f follow-up of 19 patients, no recurrences were d o c u m e n t e d . Excision of intraocular invasive tumors may occasionally be successful. Char et al ~8 described a patient with a 7 m m intraocular squamous cell carcinoma whose eye they were able to save by p e r f o r m i n g a modified iridocyclochoroidectomy with adjunctive cryotherapy. A p p a r e n t surgical clearance of extensive squamous cell carcinoma, however, may not ensure total intraocular clearance, as residual t u m o r may be r e m o t e from the original t u m o r site. In o u r study, one of the patients, a 73-year-old male who had a 5 m m intraocular squamous cell carcinoma, u n d e r w e n t a wide corneoscleral tissue resection with a large u n d e r l y i n g iridocyclectomy. Pathologic examination which included aqueous and vitreous cytology, d e m o n s t r a t e d a p p a r e n t t u m o r clearance. Despite this evidence, squamous cell carcinoma r e c u r r e d four m o n t h s later and an exenteration had to be p e r f o r m e d . 58 Extensive corneal limbal resection in h u m a n s can be replaced by grafting limbal tissue from the

442

Surv Ophthalmol 39 (6) May-June 1995

LEE, HIRST

Fig. 10. A: External photograph of extensive corneal and conjunctival dysplasia revealing typical tnfted, superficial conjunctival vessels. B: Same eye as in Fig. 10A revealing the extensive rose bengal staining over the tun:or area.

opposite eye. ~4'75These grafts consist of sectors of tissue of approximately 0.5-1.0 mm of clear cornea, the limbus and 2 m m o f b u l b a r conjunctiva and extending about four clock hours. T h e autograft can then be transferred to the recipient eye and secured in an anatomically appropriate position with 10-0 nylon at the corneal margin and 8-

0 absorbable suture at the conjunctival margin. Either a soft contact lens bandage or a marginal tarsorraphy can be used to protect the graft and the subsequently resurfacing epithelium. Topical corticosteroids and antibiotics in m o d e r a t e doses are applied and topical cycloplegics and/or u n p r e s e r v e d lubricants may be used until re-

Fig. 11. A: External pre-operative photograph of a 360 ~ limbal carcinoma in situ extending close to the central cornea from superiorly. B: Intraoperative photograph of diamond lamellar dissection underneath superior tumor. C: External photograph three weeks post-surgery showing residual central full thickness corneal stroma and epithelium and 360~ lamellar dissection and conjunctival excision. D: Post-operative external photograph five

months after tumor removal showing minimal vessel conjunctival overgrowth onto cornea.

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epithelialization is complete (usually within 7-21 days) and postoperative inflammation resolved. No problems were e n c o u n t e r e d with infection, limbal graft failure, or sloughing of the graft. 75 Enucleation or, more rarely, exenteration are required in instances o f i n t r a o c u l a r or intraorbital extension. 7'14~Partially excised tumors tend to recur with a more aggressive behavior. 4I'I14'1~7 This may be due to disruption of the integrity of Bowman's m e m b r a n e and the densely packed sclera d u r i n g multiple surgical procedures, theoretically enhancing the ability of t u m o r cells to enter the eye. ]14 Gonioscopy is r e c o m m e n d e d to ensure that the t u m o r has not physically invaded the angle or anterior chamber. Recurrence rates for OSSN following excision range from 15-52%, with an average of approximately 30% for the studies having adequate follow-up (Table 5). Inadequacy of excision margins has been identified as a major risk factor for r e c u r r e n c e f l '~25 Erie et al 4] showed that excised lesions with free surgical margins had a recurrence rate of 5%, as opposed to a 53% recurrence rate in those lesions that were incompletely excised. Pizzarello and Jakobiec v-'~ similarly found that if dysplastic tissues were left at the surgical margin there was a 69% recurrence. T h e use of 193 n m argon-fluoride excimer laser for the removal of r e c u r r e n t corneal intraepithelial dysplasia has recently been reported. 2~ This technique offers the advantage of a sharply defined photoablation of the cornea and is relatively simpler and safer than lameltar or penetrating keratectomy. However, no histologic examination can be p e r f o r m e d on the ablated tissue and assessment of adequate excision margins is not possible. B. RADIOTHERAPY

Radiation therapy has been reviewed by several g r o u p s 16':~9'44'74'94'1:~sand has been in use since the 1930S. 42'46'47'76'105 TWO types of radiation sources have been utilized. Strontium-90 is a beta source which delivers a h u n d r e d percent of its dose in the most superficial layers of the tum o r location, j6 A cup-shaped applicator is used to apply this directly to the ocular surface. Cerezo et aP 6 r e c o m m e n d s for small lesions less than 1 m m or postoperative lesions, a dose of I x 60GY or 3 x 20GY, whereas lesions greater than 1 mm, 4-7 • 20GY are r e c o m m e n d e d at weekly intervals. G a m m a radiation has also been studied using radium as a source. 5~'~:~ Recurrence rates range from 2% to 47%, with an average of 18%. 16'44'74'94'1!28 Complications have been

LEE, HIRST stated to be relatively u n c o m m o n , but they include: moderate to severe conjunctivitis immediately postirradiation; dry eye, cataract, especially following gamma radiation; telangiectasis; scarring; persistent scleral ulceration; symblepharon; and, corneal rupture, v-'~ T h e study by Kearsley et al TM over the period 1950-1985, reported a r e c u r r e n c e rate much lower than other previous treatments and an apparently low number of recurrences. O u r own review of the same area from 1972-1991, yielded 18 patients who u n d e r w e n t excision and irradiation, seven of whom later had a r e c u r r e n c e according to the records of the treating ophthalmologist. Generally, irradiation alone is not r e c o m m e n d e d ; however, it may be used for diffuse or spreading lesions, for which initial excision would be too extensive. C. CRYOTHERAPY

Cryotherapy is a n o t h e r modality commonly employed. ~':~5':~6'4:~484~)'I~2T h e most recent review by Peksayar et a1122 r e c o m m e n d s excision of the t u m o r plus 2 mm of apparently healthy surr o u n d i n g conjunctiva or superficial sclerectomy in a d h e r e n t areas. 4"~A nitrous oxide cryoprobe is used to form an iceball extending 2 mm for the conjunctiva, 1 mm for the episcleral tissues and limbus, and 0.5 mm for the cornea. An end-toend closure of the wound with 6-0 or 8-0 silk sutures is p e r f o r m e d and then cryotherapy is repeated in the same m a n n e r at the end of the surgery. Postoperatively, corticosteroids and antibiotics four times a day for two to three weeks is r e c o m m e n d e d . Liquid nitrogen can also be used as a freezing agent, :~6but is technically more difficult to apply, with associated storage and instrument difficulties. Recurrence rates range from 7-22%, with an average of 12%. 25":~''':~< 43.48.4!LI22 Cryotherapy is thought to act by destroying cells initially by its thermal effect and later by obliteration of the microcirculation, resuiting in ischemic infarction of both normal and t u m o r tissues. Cryotherapy may also act via an immunologic response to liberated t u m o r antigens, which may play a late role in ongoing policing of residual or r e c u r r e n t t u m o r cells at a cellular level); Repeated rapid freeze and a slow thaw is r e c o m m e n d e d to get adequate cellular destruction. T h e most important area to freeze is the limbus. 4~ In areas of inadequate dissection, it is r e c o m m e n d e d to freeze three times. T h e probe should never be applied for more than three seconds. Early side effects include iritis, altered intraocular pressure, either increased or

OCULAR SURFACE SQUAMOUS NEOPLASIA

445

decreased, thermic inflammatory edema and later corneal scarring, sector iris atrophy, ablation of the peripheral retina, ectropion and, uncommonly, corneal hemorrhage and superficial corneal vascularization. :~<~22These complications increase with more extensive freezing.

nique is simple and has few side effects, it is quite intensive and has the major problem of poor compliance with the use of the drops. Topical mitomycin C 0.02% applied four times daily for 10-22 days has been used to treat corneal intraepithelial neoplasia. 5~"The three patients reported showed resolution of their lesions within nine weeks of the beginning of drug administration and did not have a recurrence during the 4-12 months of follow-up. Adverse reactions included hyperemia, ocular pain and blepharospasm, but these symptoms disappeared after the drug was discontinued. As the group was small, no definite dosage of mitomycin C or the duration of treatment could be concluded. The longterm efficacy of this treatment is yet to be established. Tretinoin ~2 has been used in nonocular dysplasia and carcinoma, but not in ocular conditions. Tretinoin reverses squamous metaplasia and has been used in various dry eye disorders. Its treatment may be beneficial in early dysplastic lesions. Thiotepa has also been used in the treatment ofOSSN. 41 In our study, it was used on four patients, one with a recurrent lesion. There were no recurrences in these four patients. It is hard to draw conclusions from this small number of cases.

D. IMMUNOTHERAPY AND CHEMOTHERAPY Five other types of treatment have been advocated in the literature. Perry et al used immnnotherapy with dinitrochlorobenzene (DNCB) on a 24-year-old male who had had six previous surgical excisions, fulguration, cryotherapy and localized thiotepa application25 This kind of therapy requires systemic sensitization before tumor treatment by applying 2000 micrograms of DNCB to the skin of the forearm. Delayed hypersensitivity is indicated by a spontaneous "flare" reaction and measurement of lymphocyte production of migration inhibitory factor (MIF). Minute amounts of concentrated DNCB solution in acetone are applied to the surface of the tumor. Five applications over a number of weeks resulted in tumor regression in Perry's case. The patient was tumor-free after three years of follow-up. In a discussion following Perry's report, however, Dr. Irving Leopold comments that the selection of patients best suited for immunotherapy is difficult. Treatment favors patients with small or debulked tumors and those with normal immunocompetence. The need for continuous clinical monitoring and frequent application make this type of therapy difficult in most cases of OSSN. Urea treatment has been trialled in a study of nine patients, four with tarsal conjunctival squamous cell carcinoma and five with scleral conjunctival squamous cell carcinoma2 7 The treatment involves application of sterilized urea powder to the tumor surface which is allowed to dilute with tears and repeated 3-4 times in the one session. This is repeated every second or third day, depending on the degree of inflammation. Five to seven treatments for small or medium sized tumors are required. Combining urea with scrapings is recommended for larger lesions. After disappearance of the tumor, 4-6 drops of 10% urea solution in normal saline are installed into the eye 5-8 times daily for 2-3 weeks, gradually decreasing to 3 drops 3 times a day for about one year. Complications observed included 2~t weeks of transient corneal edema and redness due to contact by the urea. Two recurrences in this series of nine were probably a result of lack of compliance. Although this tech-

VII. Clinical Course Carcinoma of the ocular surface is generally regarded as low-grade malignancy.5,41,67,68,114,125 Even when cells rupture through the basement membrane, they usually invade only superficially into the stroma. 7~ Dysplasia and carcinoma in situ are considered to be precancerous conditions. 91'~72 However, although this kind of progression to carcinoma has been observed in carcinoma in situ of the cervix, it has not been observed in ocular lesions. Also, recurrent lesions tend to be of the same histologic grade as the primary tumor and generally do not demonstrate progressive malignant change. The potential for malignant behavior, however, argues against simple observation of even lesser grades of dysplasia] 72 Recurrences have generally been found to be d e p e n d e n t on the status of surgical margins 4I'I25'L72rather than on any particular patient characteristic or clinical appearance of the lesion. The more severe grades of OSSN tend to recur at higher rates, although the evidence in support of this view is less certain. Erie et a141 found conjunctival intraepithelial neoplasia (24%) to have a lower recurrence rate than squamous cell carci-

446

Surv Ophthalmol 39 (6) May-June 1995

noma (41%). We found, in our study, the recurrence rate for dysplasia (17%) to be much lower than CIS (40%) and SCC (30%). Irritation as a presenting symptom as well as corneal location was also identified as risk factors for recurrence. Most lesions tend to recur within the first two years, but they have been r e p o r t e d up to seven years laterJ 5 O u r study of 67 r e c u r r e n t lesions showed similar r e c u r r e n c e times across the spect r u m of OSSN. T w e n t y (31%) had a second recurrence (recurrence time ranging from three months to five years, mean one year) and five (8%) had more than two recurrences. Follow-up of these lesions thus should be most intensive d u r i n g the first two years. Intraocular invasion 9'32'47'58'62'67'69'89'90'116'I28'146' 169,176 and m e t a s t a s i s 41'67'1~ a r e uncomm o n occurrences (Table 5). T u m o r cells are thought to enter the eye t h r o u g h the canals for perforating vessels at the limbus. 146T h e cells can then invade Schlemm's canal, the trabecular meshwork, the anterior chamber, the suprachoroidal space, the ciliary body, iris and choroid. These intraocular lesions may be associated with inflammation, iritis, glaucoma, retinal detachment, and scleral thinning and may progress to spontaneous globe rupture. 99Tabbara et al I49 reviewed 10 patients from Saudi Arabia with regional and distal metastases. All lesions were greater than 2 cm. ~ Sites of metastasis included preauricular lymph nodes, submandibular lymph nodes and cervical lymph nodes, parotid gland, lungs, and bone. T h e major factor for this type of spread was delay in seeking medical treatment. Interestingly, the development of regional metastases was not necessarily related to poor prognosis, but more often local invasion was related to tumor-related mortality. 14'jNodal develo p m e n t was noted to precede the development of systemic dissemination, thus regular neck examination is r e c o m m e n d e d so potential curative radical neck dissection may be u n d e r t a k e n before the onset of distal metastases. Only nine known deaths have been d o c u m e n t e d as directly related to OSSN and were mostly due to local invasion. 67,114,154.172.176

VIII.

Summary

Ocular surface squamous neoplasia (OSSN) is a spectrum of disease with the potential for visual loss and metastasis. It is a distinct clinical entity, although it has been known by a variety of different names t h r o u g h o u t the literature. Most commonly it arises in the limbal region, occurring

LEE, HIRST particularly in elderly males living closer to the equator than 30 ~ latitude. Excess exposure to UV-B radiation is the major etiologic factor; however, h u m a n papillomavirus may play a role. Preoperative diagnostic techniques such as impression cytology are of great value in clinical decision-making and the follow-up management. Simple excision with adequate margins is currently the best established form of treatment despite trials of other modalities. Emphasis should be placed on the prevention of this disease t h r o u g h the use of ultraviolet light protective devices such as sunglasses and hats.

References 1. Adefule AO, Mordi VPN: Squamous cell carcinoma of the limbal conjunctiva with corneal involvement and racial melanosis in a Nigerian woman. AmJ Ophthalmol 96:106-107, 1983 2. Angervall L, Tornquist R: Bowen's disease of the cornea and conjunctiva. Acta Ophthalmol (Copenh) 39:808816, 1961 3. Ajaiyeoba IA, Pindiga HU, Akang EEU: Tumours of the eye and orbit in Ihadan. East Aft Med J 69:487-489, 1992 4. AshJE, Wilder HC: Epithelial tumors of the limbus. Am ] Ophthalmol 25:926-932, 1942 5. Ash JE: Epibulbar tumors. AmJ Ophthalmol 33:12031219, 1950 6. Awan KJ: Intraepithelial epithelimna (Bowen's Disease) of the conjunctiva and chronic lymphocytic leukemia. Ann Ophthalmol 4:781-783, 1978 7. Bartley GB, Garrity JA, Waller RR, et al: Orbital exenteration at the Mayo Clinic, 1967-1986. Ophthalmology 96:468-473, 1989 8. Birge HL: Cancer of the eyelids. 1. Basal cell and mixed basal cell and squamous cell epithelioma. Arch Ophthaltool 19:700-708, 1938 9. Blodi FC: Squamous cell carcinoma of the conjunctiva. Doc Ophthalmol 34:93-108, 1973 10. Bowen JT: Precancerous dermatoses: a study of two cases of chronic atypical epithelial proliferation. J Cut Dis 30:241-255, 1912 11. Brown HH, Glasgow BJ, Holland GN, Foos RY: Keratinizing corneal intraepithelial neoplasia. Cornea 8:220224, 1989 12. Brownstein S: Mucoepidermoid carcinoma of the conjunctiva with intraocular invasion. Ophthalmology 88: 1226-1230, 1981 12a.Buuns DR, Tse DT, Folberg R: Microscopically controlled excision of conjunctival squamous cell carcinoma. Am J Ophthalmol 117:97-102, 1994 13. Cameron JA, Hidayat AA: Squamous cell carcinoma of the cornea. Am J Ophthalmol 111:571-574, 1991 14. Campbell RJ, Bourne WM: Unilateral central corneal epithelial dysplasia. Ophthalmology 88:1231-1238, 1981 15. Carroll JM, Kuwabara T: A classification of limbal epitheliomas. Arch Ophthalmol 73:545-551, 1965 16. Cerezo L, Otero J, Aragon G, et al: Conjunctival intraepithelial and invasive squamous cell carcinomas treated with strontium-90. Radiother Oncot 17:19 i - 197, 1990 17. Cha SB, Shields JA, Shields CL, Wang MX: Squamous cell carcinoma of the conjunctiva. Int Ophthalmol Clin 33:19-24, 1993 18. Char DH, Crawford JB, Howes EL, Weinstein AJ: Resection of intraocular squamous cell carcinoma. Br J Ophthalmol 76:123-125, 1992

OCULAR SURFACE SQUAMOUS NEOPLASIA 19. Chassard JL, Papillon J, Ravkualt MP, et ah Contact X-ray therapy of limbus cornae squamous cell carcinomas. A report of 50 observations.J Eur Radiother 1O:1-7, 1989 20. Clear AS, Chirambo MC, Hutt MSR: Solar keratosis, pterygium and squamous cell carcinoma of the conjunctiva in Malawi. Br J Ophthalmol 63:102-109, 1979 21. Chilova-Atanassova B: On the etiopathogenesis of malignant epithelial epibulbar tumours. Folia Med (Plovdiv) 32:5-9, 1990 22. Cohen BH, Green WR, IliffNT, et al: Spindle cell carcinoma of the conjunctiva. Arch Ophthabnol 98:18091813, 1980 23. Contino A: Neue Beobachtungen unter Untersuchungen uber die Papillome des Limbus und der Hornhaut. Arch Augenheilkunde 68:366, 1911 24. Copeland RA, Char DH: Limbal autograft reconstruction after conjunctival squamous cell carcinoma. AmJ Ophthalmol 110:412-415, 1990 25. Coop HV: Squamous cell carcinoma of the conjunctiva: case presentation and treatment. Aust N Z J Ophthalmol 15:321-324, 1987 26. Cruess AF, Wasan SM, Willis WE: Corneal epithelial dysplasia and carcinoma in situ. Can J Ophthalmol 16: 171-175, 1981 27. Danopoulos ED, Danopoulou IE, Liarikos SB, Merkuris KM: Effects of urea treatment in malignancies of the conjunctiva and cornea. Ophthalmologica 178:198203, 1979 28. Daoud EH, Osman AA: Conjunctival carcinoma in Northern Sudan. Sudan Med[ 8:82-87, 1970 29. Dausch D, Landesz M, Schroder E: Photodisruptive keratectomy in recurrent corneal intraepithelial dysplasia. Arch Ophthalmol 112:22-23, 1994 30. Dark AJ, Streeten BW: Preinvasive carcinoma of the cornea and conjunctiva. Br J Opbthahnol 64:506-514, 1980 31. Daxecker F, Philipp W, Mikuz G: Corneal carcinoma. Ophthalmologica 198:163-165, 1989 32. De Felice GP, Viale G, Caroli R: Deeply invasive squamous cell carcinoma of the conjunctiva: case report, h~t Ophthalmol 14:241-244, 1990 33. De Luise VP: Peripheral corneal degenerations and tumors. Int Ophthab~loI Clin 26:49-61, 1986 34. Dinolt R, McAdams G: Intra-epithelial carcinoma of the limbus. Am J Opbthalmol 42:630-633, 1956 35. Divine RD, Anderson RL: Nitrous oxide cryotherapy for intraepithelial epithelioma of the conjunctiva. A~rh Ophthalmol 101:782-786, 1983 36. Dutton J j , Anderson RL, Tse DT: Combined surgery and cryotherapy for scleral invasion of epithelial malignancies. Ophthalmic Sung 15:289-294, 1984 37. Duke-Elder S, Leigh AG: Diseasesof the Outer Eye, Vol 7, Part 2, in Duke-Elder S (ed): Systemsof Ophthalmology. St Louis, CV Mosby, 1985, pp I154-1159, 1165-1175 38. Dykstra PC, Dykstra BA: The cytologic diagnosis of carcinoma and related lesions of the ocular conjunctiva and the cornea. Trans Am Aead OphthaImol OtolmTngol 73:979-995, 1969 39. Elkon D, Constable WC: The use of strontium-90 in the treatment of carcinoma in situ of the conjunctiva. AmJ Ophthalmol 87:84-86, 1979 40. Erbakan S, Aksu Y, Slem G: Bowen's disease: Report of two cases. Am J Ophthalmol 55:620-623, 1963 41. Erie JC, Campbell RJ, Liesegang J: Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmology 93:176-83, 1986 42. Esterman B, Laval J, Okrainetz C: Intra-epithelial epitheliomas of cornea and conjunctiva (Bowen's disease). Am J Ophthalmol 30:1537-40, 1947 43. Farris HE, Fraunfelder FT: Cyrosurgical treatment of ocular squamous cell carcinoma of the cattle. J Am Vet Med Assoc 168:213-216, 1976 44. FayosJV, Wildermuth O: Carcinoma of the ocular con-

447 junctiva: its treatment with roentgen irradiation. Radiology 79:582-587, 1962 45. Ferry AP, Meltzen MA, Taub RN: Immunotherapy with dinitrochlorobenzene (DNCB) for recurrent squamous cell tumor of conjunctiva. Trons Am Ophthalmol Soc 74:154-171, 1976 46. FrangoisJ, KluyskensJ, Rolaey M: Intra-epithelioma of the conjunctiva and cornea (Bowen's disease) healed by contact radiotherapy. BrJ Ophthalmo134:360-364, 1950 47. FrangoisJ, Hanssens M, Germen M: Epitheliomas perforates du limbe et de la conjunctive bulbaire. Ann Dacl (Paris) 200:505-521, 1967 48. Fraunfelder FT, Wingfield D: Therapy of intraepithelial epitheliomas and squamous cell carcinoma of the limbus. Trm~s Am Ophthahnol Soc 79:290-300, 1980 49. Fraunfelder FT, Wingfield D: Management of intraepithelial conjunctival tumors and squamous cell carcinomas. Am J Opbtholmol 95:359-363, 1983 50. F r e e d m a n , , Rohm G: Surgical management and histopathology of invasive tumours of the cornea. BrJ Ophthalmol 63:632-635, 1979 51. Friedlaender MH Smolin G: Corneal degenerations. Ann Opbtholmol 11:1485-1495, 1979 51a.Frucht-Pery J, Rozenman Y: Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 117: 164-168, 1994 52. Gasterland DE, Rodrigues MM, Moshell AN: Ocular involvement in xeroderina pigmentosum. Ophthalmology 89:980-986, 1982 53. Gamel JW, Eiferman tL~_, Guibor P: Mucoepidermoid carcinoma of the conjunctiva. Arch Ophthalmo1102:730731, 1984 54. Garner A: Tumors of the cornea and conjunctiva. Curt Opin Ophthalmol 4:41-46, 1993 55. Geggel HS, Friend J, Boruchoff SA: Corneal epithelial dysplasia. Ann Ophthalmol 17:27-31, 1985 56. Gelender H, Forster RK: Papanicolaou cytology in the diagnosis and management of external ocular tumors. Arch Ophthalmol 98:909-112, 1980 57. Gill EG, Harris RB: Bowen's disease (intraepithelial epithelioma). Am J Ophthalmol 43:111-114, 1957 58. Glasson WJ, Hirst LW, Axelsen RA, Moon M: Cinicopathologic case report: invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol 112:1342-1345, 1995 59. GoldbergJR, Becket SC, Rosenbaum HD: Gamma radiation in the treatment of squamous cell carcinoma of the limbus. Am J Ophthalmol 55:811-815, 1976 60. Grayson M: Intraepithelial epithelioma of the cornea. AmJ Ophthalmol 55:1246-1248, 1963 61. Greaves DP: Bowen's disease of the cornea. Trans Ophthahnol Soc UK 75:311-314, 1955 62. Greer CH: Limbal epithelioma with intraocular invasion. Br J Ophthalmol 46:306-307, 1962 63. Grossniklaus HE, Green WR, Lukenback M, Chan CC: Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 6:78-116, 1987 64. Harrison M, Glasson W: Conjunctival and limbal tumours. Aust N Z J Ophthalmol 13:193-194, 1985 65. Heilbrun K: Ein Beitrag zur Kenntnis der Neubildungen am Limbus Corneae. Arch f Ophthalmol 77:54l, 1910 66. Hertle RW, Durso F, Metzler JP, Varsa EW: Epibulbar squamous cell carcinomas in brothers with xeroderma pigmentosa.J Pediatr Ophthalmol Strabismus 28:350-353, 1991 67. IliffwJ, Marback R, Green WR: Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol 93:119122, 1975 68. Irvine AR, Jr: Dyskeratotic epibulbar tumors. TransAm Ophthalmol 8oe 61:243-273, 1963 69. Irvine AR, Jr: Diffuse epibulbar squamous cell epithelioma. Am J Ophthalmol 64:550-554, 1967 70. Irvine AR, Jr: Epibutbar squamous cell carcinoma and

448

Surv Ophthalmol

39 (6) M a y - J u n e 1995

related lesions, lnt Ophlhalmol Clin 12:71-83, 1972 71. Janert H: Zur pracancerose der cornea und conjunctiva. Von GraefesArch Ophthalmol 157:380-396, 1956 72. Jauregui HO, Klintworth GK: Pigmented squamous cell carcinoma of cornea and conjunctiva. Cancer 38: 778-788, 1976 73. Kaae S: Carcinoma at the corneal limbus treated with strontium-90 applicator. Acta Ophghalmol (Copenh) 32: 69-75, 1954 74. Kearsley JH, Fitchew RS, Taylor RGS: Adjunctive radiotherapy with strontium-90 in the treatment of conjunctival squamous cell carcinoma. Int J Radiat Oncol Biol Pkys 14:435-443, 1988 75. Kenyon KR, Tseng SCF: Limbal autograft transplantation for ocular surface disorders, ophthalmology 96:709722, 1989 76. Khanolkar V: Bowen's disease of the conjunctiva. AmJ Ophlhahnol 29:515-519, 1946 77. Kimura SJ, Thygeson P: The cytology of external ocular disease. Am J OphthalmoI 39:137-145, 1955 78. Kinoshita S, Kiorpes TC, Friend J, Thoft RA: Limbat epithelium in ocular surface wound healing. Invest Ophthalmol Vis Sci 23:73-80, 1982 79. Koch PS, Rodriguez-Sains RS: Conjunctival dysplasia and squamous cell carcinoma. J Dermatol Surg Oncol 7:602-605, 1981 80. Kushner FH, Mushen RL: Conjunctival squamous cell carcinoma combined with malignant lymphoma. AmJ Ophthalmol 80:503-506, 1975 8I. Landolt E: Zur Dyskerstose des Hornhautepithels. Klin MonatsbI Augenheilkd 172:527-530, 1978 82. Larmande A, Timsit E: L'interet du cyto-diagnostique en ophtalmologie; communication preliminaire a propos de neuf cas de tumeurs du limbe sclerocorneen. Bull Soc ophlalmol Fr 19:415-419, 1954 83. Lee GA, Hirst LW: Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol 110:525-527, 1992 84. Lee GA, Williams G, Hirst LW, Green AC: Risk factors in the development of ocular surface epithelial dysplasia. Ophlhabnology 101:360-364, 1994 85. Lennart A, Tornquist R: Bowen's disease of the cornea and conjunctiva. Acta Ophthalmol (Copenh) 39:305-316, 1961 86. Levin PS, Dutton J j: A 20-year series of orbital extenteration. Am J Ophthalmol 112:496-501, 1991 87. Lew HR, Sheppard CL: Variations in management of adnexal tumours. Aust NZ J Ophthalmol 13:189-191, 1985 88. Lewis EL, Turtz AI: Bowen's disease of the cornea. AmJ OphlhaImol 48:527-528, 1959 89. Li WW, Pettit TH, Zakka KA: Intraoeular invasion by papillary squamous cell carcinoma of the conjunctiva. Am J Ophlhah72oI 90:697-701, 1980 90. Lindenmuth KA, Sugar A, Kincaid MC, et al: Invasive squamous cell carcinoma of the conjunctiva presenting as necrotizing scleritis with scleral perforation and uveal prolapse. Surv Ophthalmol 33:50-54, 1988 91. Lugossy G: Precancerous conditions of the bulbar conjunctiva. Am J Ophthalmol 42:112-125, 1956 92. Linwong M, Herman SJ, Rabb MF: Carcinoma in situ of the corneal limbus in an adolescent girl. Arch Ophthalmol 87:48-51, 1972 93. Locke J: Bowen's disease (intraepithelial epithelioma) of the cornea and conjunctiva: clinicopathologic study. Am J Ophthalmol 4I:801-809, 1956 94. Lommatzsch P: Beta-ray treatment of malignant epithelial tumors of the conjunctiva. Am J Ophthalmol 81:198-206, 1976 95. McDonnellJM, McDonnell PJ, Mounts P, et al: Demonstration of papillomavirus capsid antigen in h u m a n conjuntival neoplasia. Arch Ophthalmol 104:1801-1805, 1986 96. McDonnell JM, Mayr AJ, Martin WJ: DNA of human

LEE, HIRST

97.

98.

99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111.

112. 113. 114. 115. 116. 117.

118.

119.

120. I21.

papillomavirus type 16 in dysplastic and lnalignant lesions of the conjunctiva and cornea. N E~lgl J Med 320:1442-1446, 1989 McDonnell JM, Wagner D, Ng ST, Bernstein G, Sun YY: Human papillomavirus type 16 DNA in ocular and cervical swabs of women with genital tract condylomata. am J Ophthalmol 112:61-66, 1991 McDonnellJM, McDonnell PJ, Sun YY: Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia. J hzvest Ophthalmol Vis Sci 33:184-189, 1992 McGavic JS: Intraepithelial epithelioma of the cornea and conjunctiva (Bowen's disease). Am J Ophlhalmol 25:167-176, 1942 Maertens K, Blodi EC: Epibulbar lesions among Bantus. Am J Ophthalmol 74:680-687, 1972 Mahoney MC, Burnett WS, Majerovics A, Tanenbauln H: The epidemiology of ophthalmic malignancies in New York state. Ophthalmology 97:1143-1147, 1990 Makie EG, Edward JL: A case of Bowen's disease of the eye. Trans Ophthalmol Soc UK 68:539-544, 1948 Malik MOA, El Sheikh EH: Tumors of the eye and adnexa in the Sudan. Cancer 44:293-303, 1979 Margo CE, Groden LR: Squamous cell carcinoma of the cornea and conjunctiva following a thermal burn of the eye. Cornea 5:185-188, 1986 Mascati NT: Bowen's disease. AmJ Ophthalmo138:652655, 1954 Maudal RC, Van Damme B, Missotten L: Corneal epithelial dysplasia after trifluridine use. Albrecht Vo~ Graefes Arch Kiln Exp Ophthalmol 202:6-12, 1983 Mehlum DL, Parker GS, Strom CG, et al: Conjunctival squamous cell carcinoma with parotid gland metastasis. Otolaryngol Head Neck Surg 94:246-249, 1986 Menez B, Landes J, Cornand G: La transformation maligne des tumeurs benignes du limbe sclerocorneen. Bull Soc Ophthalmol Fr 5:575-578, 1982 Minckler D: Pyogenic granuloma of the cornea simulating squamous cell carcinoma. Arch Ophthalmol 97: 516520, 1979 Mork T: Malignant neoplasms of the eye in Norway. Acta Ophthalmol (Copenh) 39:824-831, 1961 Muscara M, Guiffre G, Trombetta CJ, et al: Nucleolar organizer regions (NORs) in dysplastic and neoplastic epithelial lesions of the conjunctiva. Palhologica 83: 281-288, 1991 Napora C, Cohen EJ, Genvert GI, et al: Factors associated with conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surg 21:27-30, 1990 Newsome DA, Kraemer KH, Robbins JH: Repair of DNA in xeroderma pigmentosum conjunctiva. Arch Ophthalmol 93:660-662, 1975 Ni C, SearI SS, Kriegstein HJ, Wu BF: Epibulbar carcinoma. Int Ophthalmol Clin 22:1-33, 1982 Nicholls JV: Epithelial plaques of the conjunctiva and the cornea. Arch Ophthalmol 22:370-376, 1939 Nicholson DH, Herschler J: Intraocular extension of squamous cell carcinoma of the conjunctiva. Arch Ophthalmol 95:843-846, 1977 Nolan GR, Hirst LW, Wright RG, Bancroft BJ: The application of impression cytology to the diagnosis of conjunctival neoplasms. Diagn Cytopathol 11:246-249, 1994 Noyes liD: Report of a case of melanotic epithelioma upon the front of the eye. Extirpation of the tumor and preservation of the globe and of sight. A~rh Ophlhalmol 8:145-163, 1979 Odrich MG, Jakobiec FA, Lancaster WD, et at: A spectrum of bilateral squamous conjunctival tumors associated with human papillomavirus type 16. Ophthalmology 98:628-635, 1991 Olurin O, WilliamsAO: Orbito-ocular tumom's in Nigeria. Ca*zcer30:580-587, 1972 Parsons G, Wilkey IS: Cancers of the eye and orbit in

OCULAR SURFACE SQUAMOUS NEOPLASIA Papua New Guinea, in Atkinson L, C]azy JK, ReayYoung, et al (eds): Epidemiology of Cancer in Papua New Guinea. Konedobu, Papua New Guinea, Department of Public Health, 1974, pp 126-130 122. Peksayar G, Soyturk MK, Demiryont M: Long-term results of cryotherapy on malignant epithelial tumors of the conjunctiva. Am J Ophthalmol 15:337-340, 1989 123. Philipp W, Daxecker F, Langmayr J, Gottinger W: Spontaneous corneal rupture after strontium irradiation ofa conjunctival squamous cell carcinoma. Ophthalmologica 195:113-118, 1987 124. Pierse D, Steel ADM, Garner A, Tripathi RC: Intraepithelial carcinoma (Bowen's disease) of the cornea. Br J Ophthabnol 55:664-670, 1971 125. Pizzarello LD, Jakobiec FA: Bowen's disease of the conjunctiva: a misnomer, in Jakobiec FA (ed): Ocular and Adnexal Tumors. Birmingham, AL, Aesculapius, 1978, pp 553-571 126. Rajagspalan K, Subramanian KS: Bilateral conjunctiva epithelioma. J Indian Med Assoc 11:430-431, 1971 127 Rao NA, Font RL: Mucoepidermoid carcinoma of the conjunctiva. A clinico-pathologic study of five cases. Cancer 38:1699-1709, 1976 128. Rasteiro A, Cunha-VazJG: Squamous cell carcinoma of the limbus with intraocular invasion. Ophthalmologica 172:332-336, 1976 129. ReedJW, Cashwell F, Klintworth GK: Corneal manifestations of hereditary benign intraepithelial dyskeratosis. Arch Ophthalmol 97:297-300, 1979 130. Reese AB: Tumors of the Eve. New York, Harper and Row, 1976, ed 3, pp 53-58 131. Roberson MC: Corneal epithelial dysplasia. Ann Ophthalmol 16:1147-1150, 1984 132. Rodriguez-Sains RS: Ophthalmologic oncology. Common conjunctival neoplasms. J Dermatol Sung Oncol 7: 195-199, 1981 133. Rootman J, Roth AM, Crawford JB, et al: Extensive squamous cell carcinoma of the conjunctiva presenting as orbital cellulitis: the hermit syndrome. CanJ Ophlhaltool 22:40-44, 1987 134. Russell WO, Wynne ES, Loquvam GA: Studies on bovine squamous carcinoma ("Cancer Eye") 1. Pathological anatomy and historical review. Cancer 9:1-52, 1956 135. Rutten VP, Klein WR, De Jong MA, et al: Search for bovine papilloma virus DNA in bovine ocular squamous cell carcinoma (BOSCC) and BOSCC-derived cell lines. AmJ Vet Res 53:1477-1481, 1992 136. Salisbury JA, Szpak CA, Klintworth GK: Pigmented squamous cell carcinoma of the conjunctiva. A clinicopathologic ultrastructural study. Ophthalmology 90: 1477-1481, 1983 137. Sanders N, Bedotto C: Recurrent carcinoma in situ of the conjunctiva and cornea (Bowen's disease). Am J Ophthahnol 74:688-693, 1972 138. Scale ER: Carcinoma of limbus. Report of 19 cases treated with radium and effect of gamma radiation upon eye. AMA Arch De~watol Syph 68:286-294, 1953 139. Searl SS, Krigstein HJ, Albert DM, Grove AS: lnvasive squamous cell carcinoma with intraocular mucoepidermold features. Arch Ophthalmol 100:109-I 11, 1982 140. Sevel D, Sealy R: Pterygia asnd carcinoma of the conjunctiva. Tram Ophthabnol Soe UK 88:567-568, 1968 141. Shields JA, Shields CL, Suvarnami C, et al: Orbital exenteration with eyelid sparing indications, techniques and results. Ophthalmic Surg 22:292-297, 1991 142. Silva D: Orbital tumours. AmJ Ophthalmol 65:318-339, 1968 143. Sivalingam V, Shields CL, ShieldsJA, PearahJD: Squamous cell carcinoma of the conjunctiva associated with benign mucous membrane pemphigoid. Am Ophthalmol 22:106-109, 1990 144. Spinak M, Friedman AH: Squamous cell carcinoma of the conjunctiva. Value of exfoliative cytology in diagnosis. Surv Ophthalmol 21:351-355, 1977

449 145. Steinhorst U, Von Domarus D: Carcinoma in situ of the cornea. Ophthalmologica 200:107-110, 1990 146. Stokes J J: Intraocular extension ofepibulbar squamous cell carcinoma of the limbus. Trans Am Acad Ophthalmol Otolmyngol 56:143-6, 1955 147. Sunderraj P: Malignant tumours of the eye and adnexa. Ind J Ophthalmol 39:6-8, 1991 148. Swanson MW, Cloud G: A retrospective analysis of primary eye cancer at the University of Alabama at Birmingham, 1958-88. Part 1: eye and orbital cancer. Am Optom Assoc 62:815-819, 1991 149. Tabbara KF, Kersten R, Dauk N, Blodi FC: Metastatic squamous cell carcinoma of the conjunctiva. Ophthalmology 95:318-321, 1988 150. Takahasi T: Bowen's disease at the limbus. Acta Ophthaltool (Copenh) 60:147-15, 1982 151. Tanabe Y, Tanabe S: Electron microscopic studies of corneal cancer. Folia OphthalmolJpn 16:137-146, 1965 152. Tanaka M, Kanei A, Nakajima A: Electron microscope studies of Bowen's disease. Folia OphthalmolJpn 25: 1098-1111, 1974 153. Taylor JN: Some aspects of intra-epithelial carcinoma of the cornea (Bowen's disease). Aust J Ophthalmol 2:148-151, 1974 154. Templeton AC: Tumors of the eye and adnexia in Africans of Uganda. Cancer 20:1689-1698, 1967 155. Theodore FH: Carcinoma of the conjunctiva masquerading as chronic conjunctivitis. Eye Ear Nose Throat Monthly 46:1419-1420, 1967 156. Thygeson P: Observations on conjunctival neoplasms masquerading as chronic conjunctivitis or keratitis. Trans Am Acad Ophthalmol Otolaryngol 73:969-978, 1969 157. Ticho U, Ben-Sira: Clinical and pathologic correlation of nonpigmented tumors of the conjunctiva and pingueculas among Africans. Am J Ophthalmol 70:757-763, 1970 158. Trevor-Roper PD: Intra-epithelial epithelioma (Bowen's disease). BrJ Ophthalmol 41:167-173, 1957 159. Tripathi RC, Garner A: The ultrastructure of preinvasire cancer of the corneal epithelium. Cancer Res 32: 90-97, 1972 160. TroskoJE, Krause D, Isoun M: Sunlight-induced pyrimidine dimers in human cells in vitro. Nature 228:358359, 1970 161. Tseng SCG: Staging ofconjunctival squamous metaplasia by impression cytology. Ophthalmology 92:728-733, 1985 162. Tseng SCG: Topical tretinoin treatment for dry-eye disorders, lnt Ophthalmol Clin 27:47-53, 1987 163. Tseng SCG: Concept and application of limbal stem cells. Eye 3:141-157, 1989 164. Tsubota K, Kajiwara K, Ugajin S, Hasegawa T: Conjunctival brush cytology. Acta Cytol 34:233-235, 1990 165. Waher WL: Pseudo-epitheliomatous hyperplasiaofthe conjunctiva. A lesion simulating squamous-cell carcinoma; a case report. AmJ Ophthalmol 53:999-1003, 1962 166. Waring GO IlI, Roth AM, Ekins MB: Clinical and pathologic description of 17 cases of corneal intraepithelial neoplasia. Am J Ophthalmol 97:547-559, 1984 167. Weissman SS, Char DH, Herbort CP, et al: Alteration of human conjunctival epithelial proliferation. Arch Ophthalmol 110:357-379, 1992 168. Weskamp C: Bowen'sdiseaseofcornea.ArchOphthalmol 31:310-5, 1944 169 Wexler SA, Wallow IH: Squamous cell carcinoma of the conjunctiva presenting with intraocular extension. Arch Ophthalmol 103:1175-1177, 1985 170. Willard R: Bowen's disease. AmJ Ophthalmol 36:17501751, 1953 171. Wilson FM: Rose bengal staining of epibulbar squamous neoplasms. Ophthalmic Surg 7:21-22, 1976 172. Winter FC, Kleh TR: Precancerous epithelioma of the limbus. Arch Ophthalmol 64:208-215, 1960 173. Winward KE, Curtin VT: Conjunctival squamous cell

450

174. 175. 176.

177.

Surv O p h t h a l m o l 39 (6) May-June 1995 carcinoma in a patient with human imnmnodeficiency virus infection. Am J Ophthalmol 107:554-555, 1989 Wise AC: A limbal spindle-cell carcinoma. Surv Ophthaltool 12:244-246, 1967 Wise G: A case of Boweu's disease of the cornea. AmJ OphthahnoI 26:167-171, 1943 Zimmerman LE: Squamous cell carcinoma and related lesions of the bulbar conjunctiva, in Bouiuk M (ed.): Ocular and Adnexal Tumors. St Louis, CV Mosby, 1964, pp 49-74 Zimmerman LE: The cancerous, precancerous and pseudocancerous lesions of the cornea and conjunctiva: The Pocklington Memorial Lecture, in Rycroft PV (ed): Corneoplastic SurgeU. New York, Pergamon Press, 1969, Outline

I. Epidemiology A. Incidence B. Racial and geographic distribution C. Age and sex distribution II. Etiology A. Limbal transiton zone/stem cell theory B. Ultraviolet-B light C. H u m a n papillomavirus type 16 III. Clinical findings A. Clinical presentation

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B. Differential diagnosis C. Related diseases Preoperative diagnosis A. Exfoliative cytology B. Impression cytology Histopathology Treatment A. Surgery B. Radiotherapy C. Cryotherapy D. I m m u n o t h e r a p y and chemotherapy Clinical course Summary

Supported in part by the Queensland Cancer Fund, the University of Queensland, the Prevent Blindness Foundation and the Princess Alexandra Hospital. We would like to thank the 7 pathology laboratories, the 4 hospitals and the 52 Queensland ophthalmologists who kindly allowed us access to their medical records; Ms Glenda Nolan and Dr Roy Axelsen for their reviews of the prediagnostic and histopathologic sections. Reprint Address: Professor Lawrence Hirst, Division of Ophthalmology, Department of Surgery, Princess Alexandra Hospital, Ipswich Road, Brisbane, Queensland 4102, Australia.