Eye Cytology

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Editors: Koss, Leopold G.; Melamed, Myron R.

Title: Koss' Diagnostic Cytology and Its Histopathologic Bases, 5th Edition
Copyright ©2006 Lippincott Williams & Wilkins
> Table of Contents > II - Diagnostic Cytology of Organs > 41 - The Eyelids, Orbit, and Eye
41
The Eyelids, Orbit, and Eye
Cytologic diagnosis of various disorders of the eyelids and the external eye has been in use for many years (Kimura
and Thygeson, 1955). Naib (1972, 1981) was a major contributor to this knowledge. Cytologic sampling of the orbit,
its adnexa, and the eye became possible with the developments of imaging modalities, such as the computed
tomography (CT) and precision ultrasound. With the use of small caliber needles under imaging guidance, the
aspiration of these organs became safe and accurate (Jakobiec and Chattock, 1978; Czerniak et al, 1983, 1985; Koss
et al, 1992; Glasgow and Foos, 1993). In this chapter, the application of cytologic techniques to the external eye,
the orbit and its contents will be discussed.
ANATOMIC AND HISTOLOGIC RECALL

The eye is located within the bony structure of the skull, the orbit. The eye is connected to the brain by the optic
nerve and to the orbit by a number of striated muscles that control its movements. Besides the eye and the
muscles, the orbit is filled with loose connective tissue that contains nerves, vessels, and small deposits of
lymphocytes.
The anterior surface of the eye, a transparent to light lens-like structure, the cornea, is lined on its surface by a
transparent, stratified, nonkeratinized squamous epithelium (Fig. 41-1A). Laterally, the cornea becomes the
sclera, a fibrous structure that encloses the eye. The eye is protected anteriorly by the eyelids which, on the
surface facing the eye, are lined by a stratified epithelium containing numerous mucus-producing goblet cells. This
epithelium is in continuity with the squamous epithelium lining the cornea; the transition occurs at the limbus,
where the peripheral cornea merges with the anterior sclera. The outer surface of the eyelids is formed by skin. The
eyelids contain numerous mucus-producing glands, the largest and most important being the meibomian glands.
Smaller glands are known as glands of Zeis and Moll. Extending from the eyelids into the orbit are the lacrimal
glands, similar in structure to serous salivary glands, which, by a series of canals, secrete tears that lubricate the
eye and the eyelids.
The internal structure of the eye is extremely complex and beyond the scope of this chapter, thus only the key
structures will be mentioned. The interior of the eye is divided into two chambers: the anterior aqueous chamber,
located between the cornea and the transparent crystalline lens, and the posterior chamber, filled with transparent
viscous vitreous (vitreous body), demarcated anteriorly by the lens and posteriorly by the retina. The anterior
chamber contains a contractile pigmented structure, the iris, forming the pupil of the eye and regulating the input
of light. All parts of the eye serve the primary purpose of processing light signals by multilayered sensory complex
neuronal tissue, the retina. The retina can become the site of a malignant tumor of childhood, the retinoblastoma.
On the outer, orbital side, the retina is supported by a layer of melanin-containing pigment epithelium that
extends anteriorly into the iris. In turn, the pigmented epithelium is separated from the sclera by an intermediate
layer, the uvea, composed
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of connective tissue containing blood vessels, nerves, and melanocytes. The uvea is divided into three distinct
anatomic segments: the choroid, which surrounds most of the eye and transits anteriorly into the ciliary body, and
the iris. The most common malignant tumors of the eye, malignant melanomas, develop in the uvea, particularly in
the choroid but also, less commonly, in the ciliary body and the iris. The optic nerve may be the site of formation
of orbital gliomas and meningiomas. For a detailed description of the histology of the eye, the reader is referred to
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a simple, yet detailed and accurate account by Stevens and Lowe (1992).
Figure 41-1 A. Normal corneal epithelium. Note orderly epithelium of squamous type without surface
keratinization. B. Normal conjunctival scrape smear. Cuboidal and columnar epithelial cells and goblet cells.
THE EYELIDS AND EXTERNAL SURFACE OF THE EYE
Sampling Techniques
The external surface of the eye and the eyelids are accessible to simple cytologic procedures, within the reach of
any ophthalmologist and any laboratory of cytology. Scraping the surface of the lesion under local anesthesia with
an appropriate small instrument and preparation of alcoholfixed or air-dried smears is sufficient for the diagnosis
of inflammatory disorders and some malignant lesions, such as carcinoma of the cornea and conjunctiva, or
carcinomas of the eyelid (Naib et al, 1967; Dykstra and Dykstra, 1969; Spinak and Friedman, 1977; Naib, 1970,
1981; Koss et al, 1992). Tsubota et al (1990) and Kobayashi et al (1991) advocated the use of a modified small
endocervical brush with short, soft bristles (S-Brush, Medscan, Malmö, Sweden) for securing material from the
conjunctiva. Instead of smears, these authors advocated the use of a cytocentrifuge and, more recently, ThinPrep
(Cytyc Corp, Boxborough, MA) for processing of the samples (Kobayashi et al, 1997). Another brush with a spherical
tip (Acellon-M) was used for the same purpose by Fujihara et al (1997).
Nolan et al (1994, 1997, 2001), described an ingenious technique named “impression cytology” for the study of
conjunctival samples. Following local anesthesia, a cellulose acetate strip is placed on the surface of the cornea
using gentle pressure, carefully peeled off, fixed in alcohol, and stained with Papanicolaou stain. The technique was
used by other investigators with impressive results (Dart, 1997; Divani et al, 1997).
Normal Cells in Conjunctival and Corneal Scrape Smears

The normal cell population in scrape smears consists of squamous cells of corneal origin and cuboidal to columnar
epithelial cells of conjunctival origin. Goblet cells may be present (Fig. 41-1B). In about 20% of the patients,
squamous cell nuclei may display a central chromatin bar, similar to the appearance of Anitschkow cells, first
observed by Marner (1980). On scanning electron microscopy, the bars form a ridge in the nucleus, whereas in
transmission electron microscopy, a tortuous folding of the nuclear membrane was observed (Kobayashi et al, 1992,
1998). Similar squamous cells have been observed in the oral cavity (see Chap. 21 and Fig. 21-1). Kumar and
Manabati (1998) also observed nuclear protrusions in the form of nipples in conjunctival cells, a common finding
in endocervical cells, discussed at length in Chapter 8. These nuclear variants may occur in health and disease and
have no diagnostic significance.
Inflammatory Lesions
Viral Infections
Viral infections are very common and cause painful inflammation of the conjunctiva and the cornea. Their
identification may be of substantial assistance in the clinical management of the patient. Naib et al (1967, 1972,
1981) have given excellent descriptions of cytologic findings in eye disorders caused by viruses. These are
summarized in Table 41-1. The morphologic manifestations of various viral infections were described and illustrated
in Chapters 10 and 19. Olding-Stenkvist and Brege (1975) applied immunofluorescent techniques for the diagnosis of
herpetic conjunctivitis.
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There are now several other diagnostic techniques available, such as polymerase chain reaction (PCR) for viral
identification.
TABLE 41-1 CYTOLOGIC CHANGES IN VIRAL INFECTIONS OF THE EYE AND ADNEXA
Inclusion: Descriptive
Disease Ocular Site Location of Inclusions Features Remarks
Trachoma Cornea and Cytoplasmic in Multiple small Clusters of

(chlamydia) conjunctiva mature cells (0.5 µm), inclusions from
basophilic with necrotic cells
halos
Inclusion Cytoplasmic in Same as above Clusters of

conjunctivitis mature cells inclusions
(frequent in
newborn
infants)
Adenovirus Conjunctiva Intranuclear in Multiple, small Few cells involved

small cells eosinophilic,
becoming
coalescent,
basophilic with
halos
Vaccinia Conjunctiva Cytoplasmic Single, large,

eosinophilic
Herpes, Conjunctiva Intranuclear, Enlarged In herpes zoster

simplex and and cornea often in “ground-glass” multinucleated
zoster multinucleated nuclei forming cells and
cells with nuclear eosinophilic eosinophilic
molding inclusions inclusions are rare
Measles Conjunctiva Multinucleated Multiple

giant cells eosinophilic
cytoplasmic
inclusions with
sharp halos
(Modified from Naib ZM, et al. Exfoliative cytology as an aid in the diagnosis of ophthalmic lesions. Acta
Cytol 11 :295-303, 1967; and Naib ZM. Cytology of ocular lesions. Acta Cytol 16:178-185, 1972.)
Chlamydial Infections
Conjunctival infection, caused by the bacterium, Chlamydia trachomatis, results in trachoma, the most widespread
cause of blindness in the developing world. The infection, usually transmitted by human contact, leads to
opacification of the upper part of the cornea and can be diagnosed by cytologic scraping. Besides trachoma,
chlamydia may lead to various other less dangerous infections, such as chronic inclusion conjunctivitis,
characterized by formation of lymphoid follicles in the conjunctiva and lower part of the cornea. As discussed above,
Kobayashi et al (1991) advocated the use of the S-brush for the diagnosis of chlamydial infection.
The cytology of the chlamydial infection of the eye is identical to the infections in the female genital tract,
described and illustrated in Chapter 10. Naib (1972) stressed the presence of numerous small (0.5 µm) basophilic
cytoplasmic inclusions with halos as the characteristic cytologic finding (see Table 41-1). A number of staining
techniques documenting this infection in infants was discussed and illustrated by Duggan et al (1986).
Other Inflammatory Processes

Allergic conjunctivitis, a common disorder, is characterized in smears by a large number of eosinophils mixed with
other inflammatory cells. Rivasi et al (1992) also observed an increase in goblet cells and the presence of various
foreign materials, presumably of plant or mineral origin.
Bacterial infections result in acute conjunctivitis characterized by a dominance of neutrophils in smears.

Gonorrheal conjunctivitis in newborn infants is a preventable disease with prophylactic treatment with antibiotics.
A related organism, Moraxella (Branhamella) catarrhalis, an encapsulated diplococcus, may cause a purulent
inflammation in adults. Eyelid infections with staphylococci (sty) rarely require cytologic confirmation.
Actinomycosis of the cheek may spread to the orbit.
An occlusion of the meibomian ducts by an inflammatory process, usually secondary to inflammation of the hair
follicles (blepharitis), may cause a granulomatous inflammation and palpable enlargement of the meibomian
glands, known as chalazion. A chalazion may be mistaken for a tumor of the eyelids and, more importantly, tumors
may be mistaken for a chalazion. Needle aspiration biopsy is the ideal diagnostic technique in these situations.
Mycotic infections are uncommon but may lead to a severe corneal disease and loss of vision, particularly with
Phycomycetes (Zygomycetes), such as mucormycosis (Johnson, 2000). These infections may cause sudden blindness
(Downie et al, 1993). Other fungi, such as Candida and Aspergillus species, may be observed (Naib, 1981; Johnson,
2000). The morphology of these fungi is discussed at length in Chapter 19.
Parasites
Acanthamoeba
Corneal infection (keratitis) caused by Acanthamoeba species occurs with increasing frequency, mainly in wearers
of soft contact lenses (Stehr-Green et al, 1989; Moore and McCulley, 1989).
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Corneal scrapings may be used for diagnosis (summary in Karayianis et al, 1988; Rivasi et al, 1995). Against a
background of acute inflammation, trophozoites and the double-walled cysts of the parasite may be identified by
several staining and fluorescent techniques, but also in Papanicolaou stain (Fig. 41-2). An early diagnosis and
aggressive therapy are essential to prevent a loss of vision (Moore and McCulley, 1989; Rivasi et al, 1995).
Figure 41-2 Acanthamoeba in corneal epithelium in a young wearer of contact lenses. Small spherical cysts of
the parasite are stained with Gomori-methenamine silver. (Courtesy of Dr. Pearl Rosenbaum, Montefiore
Medical Center, Bronx, NY.)
Microsporidiosis
Microsporidial keratitis, caused by the tiny intracellular protozoan parasite of the genus Nosema or
Encephalitozoon, previously a rare event observed after corneal trauma in immunologically normal patients, is
becoming increasingly prevalent in HIV-positive, immunosuppressed individuals (Wittner et al, 1993; Weber et al,
1994; Rasterelli et al, 1994; Coyle and Weiss, 1996). The epidemiology and life cycle of the parasite were
summarized by Chen et al (2002). The parasite may be demonstrated in conjunctival smears and biopsies with
various staining techniques or phase contrast microscopy (Fig. 41-3). Identification of specific genus is possible with
electron microscopy, by a specific antibody or genomic analysis.
Figure 41-3 Microsporidia. A. Corneal scrapings from a 34-year-old man who was HIV-positive. The tiny
organisms are present in the cytoplasm, surrounding a central clear area that is the nucleus. B. Biopsy of the
limbal conjunctiva showing the Gram-positive organisms within the cytoplasm of the superficial epithelial
cells. (Brown and Brenn stain.) (Courtesy of Dr. Pearl Rosenbaum, Montefiore Medical Center, Bronx, NY.)
Onchocerciasis (River Blindness)

Onchocerca volvulus is the largest of human filariae, transmitted by blackflies rather than mosquitoes (Ash and
Spitz, 1945). It is the cause of severe dermatitis and river blindness, prevalent in Africa and parts of Central and
South America, caused by numerous filariae accumulating in eye chambers, resulting in sclerosing keratitis. The
disease is curable with appropriate drugs. To our knowledge, cytologic techniques have not been applied to the
diagnosis of this very important disorder.
Echinococcosis
Sodhani et al (1996) described a case of echinococcosis affecting the eye. For description of this parasite, see
Chapters 19 and 38.
Benign Tumors
Scrapings of benign tumors of the skin of the eyelids, such as xanthelasma, molluscum contagiosum (a viral
disorder), and squamous papillomas may sometimes be of diagnostic advantage (Naib, 1981). In xanthelasma, lipid-
filled cells may be observed. The cytologic presentation of molluscum contagiosum is discussed in Chapters 14 and
36. Squamous papilloma may show evidence of human papillomavirus infection in the form of squamous cells with
abnormal nuclei and a large perinuclear clear zone, known as koilocytes (see Chap. 11 for extensive discussion of
this entity). Other tumors occurring on the skin or surface of the eyelids are described in Chapter 36.
The sebaceous meibomian glands and the small serous glands located within the eyelids may be the site of benign
tumors mimicking tumors of the salivary glands, notably pleomorphic adenomas (see Chap. 32). Leiomyomas of
the eyelids have been described (Henkeind and Friedman, 1976).
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Malignant Tumors
Squamous Carcinoma and Its Precursors

Malignant epithelial tumors of the conjunctiva and surface of the cornea are predominantly squamous carcinomas,
which in fortuitous situations, may be diagnosed as preinvasive neoplastic lesions, such as carcinomas in situ (Fig.
41-4B,D). The term ocular surface squamous neoplasia (OSSN) has been proposed to include intraepithelial and
invasive squamous lesions (Lee and Hirst, 1995; Nolan et al, 1997). The spectrum of abnormalities ranged from
“simple dysplasia” to carcinoma in situ to invasive carcinoma. Subsequently, Nolan et al used the term “high-
grade” lesions for carcinomas in situ and related lesions. The presence of human papillomavirus type 16,
determined by PCR, was reported in a substantial proportion of premalignant and malignant lesions of the
conjunctiva and cornea (McDonell et al, 1989). For further discussion of human papillomavirus, see Chapter 11. It has
been reported that conjunctival intraepithelial neoplasia commonly occurs in patients with AIDS and may be a
marker for this disease (Karp et al, 1996).
The clinical presentation of carcinoma in situ is often misleading. Slight thickening of the conjunctiva combined
with increased vascularity may be mistaken for an inflammatory or degenerative lesion and treated as such by
ophthalmologists. This was the experience of Dykstra and Dykstra (1969), who used cytologic techniques for the
diagnosis of squamous carcinoma of the conjunctiva. In three of their eight cases, the lesion was still in situ and
was not suspected clinically. Nolan et al (2001) used touch preparations (impression samples—see methods of
sampling) of the corneae in 267 patients and compared the cytologic samples with biopsies. In 231 of these patients,
the lesions were preinvasive, and in several of these patients, there was no evidence of clinical disease (Hirst et al,
1998; Nolan et al, 2001). These observations from Australia, where corneal carcinoma is common in elderly people as
a consequence of exposure to ultraviolet light, indicate yet another use of cytologic techniques in the detection of
an important form of cancer, particularly in patients with AIDS.
Cytology of squamous carcinoma in situ of the cornea and conjunctiva is identical to similar lesions of the uterine
cervix or oral cavity (see Chaps. 11 and 21) and consists of small to moderately sized atypical, or frankly malignant,
squamous cells with markedly enlarged, hyperchromatic nuclei of variable sizes (Fig. 41-4A). Nolan et al (1997)
stressed that in many of the preinvasive squamous lesions and in some invasive squamous carcinomas, there was
evidence of heavy keratinization and the cytologic presentation of these lesions was similar to the keratinizing
variant of carcinoma of the uterine cervix (Fig. 41-4C). In some of the invasive squamous carcinomas, the smear
patterns were those of poorly differentiated tumors with little or no keratin formation and large nuclei containing
large nucleoli.
There is limited knowledge on the cytologic presentation of low-grade lesions and it may be assumed they
resemble similar lesions of the uterine cervix (see below and Chap. 11).
Dysplasia after Exposure to Mustard Gas

Safaci et al (2001) reported on several cases of conjunctival dysplasia in soldiers exposed to mustard gas during the
Iraq-Iran war. The cells illustrated in this paper were reminiscent of low-grade squamous precancerous lesions of the
uterine cervix (see Chap. 11). It is known that mustard gas has carcinogenic properties (Watson et al, 1989). Similar
conjunctival lesions were designated as “keratitis” (Atkinson, 1946) or as “keratopathy” (Pleyer et al, 1999). It is not
known whether these lesions are precursors of corneal carcinomas, therefore, follow-up information on Safaci's
patients would be of great interest, particularly in view of the bioterrorist threat. Nitrogen mustard, a
chemotherapeutic agent related to mustard gas, is a known lung carcinogen, as discussed in Chapter 20.
Malignant Melanomas
Malignant melanomas of the conjunctiva or the limbus may be related to benign nevi that occasionally occur in
these locations. The differential diagnosis between an atypical nevus and a melanoma may be very difficult in biopsy
material. To our knowledge, no attempts have been made to diagnose these lesions by scrape cytology. However,
there are several reports of melanomas of the eyelid, diagnosed by aspiration biopsy (Arora et al, 1990; Gonidi et
al, 1997). Cytology of uveal malignant melanoma is discussed below and in Chapter 34.
Carcinomas of Meibomian Glands

An adenocarcinoma of meibomian glands, thought clinically to represent a common inflammation of meibomian
glands (chalazion) of the lower eyelid, was diagnosed on a scrape smear, showing poorly differentiated cancer cells
of variable sizes (Fig. 41-5). Arora et al (1990) reported the results of aspiration biopsy cytology of several tumors
of the eyelid, including invasive squamous carcinoma and sebaceous carcinoma. Sebaceous carcinoma is the most
common variant of cancer of meibomian glands, fully capable of metastases to neck lymph nodes or the parotid
(Jakobiec and Chatlock, 1979; Sadeghi et al, 1999). The tumor is characterized by obvious cancer cells with the
cytoplasm studded with small vacuoles representing lipids.
THE ORBIT AND THE EYE
Sampling Techniques
During the 1970s and 1980s, the cytologic methods of diagnosis of diseases of the orbit and the eye made great
strides because of the developments of new targeting techniques, such as computed tomography (CT) and
ultrasonography, combined with the thin-needle aspiration biopsy (FNA) (Dubois et al, 1979). To be successful,
the method requires specialized equipment and skilled ophthalmologists, familiar with the intricate anatomy of this
region. The aspiration procedure of the orbit is relatively simple and requires only local anesthesia. Aspiration of the
eye is quite complex and requires an incision of the cornea or sclera. Special procedures have been used to aspirate
lesions of the iris. The technical details of the procedure were previously described in detail and the interested
reader is referred to the sources cited (Jakobiec et al, 1979; Engel et al, 1981, 1982; Char and Norman, 1982;
Augsburger and Shields, 1984; Czerniak et al, 1985; Koss et al, 1992; Glasgow and Foos, 1993; Zeppa et al, 1997; Sen
et al, 1999).
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Figure 41-4 High-grade ocular surface squamous neoplasia (carcinomas in situ of the cornea). A. Poorly
differentiated squamous cancer cells, corresponding to the histologic lesion shown in B. C. Keratin-forming
cancer cells, corresponding to the keratinized intraepithelial lesion shown in D. (Photographs courtesy of Dr.
G.R. Nolan and Prof. L.W. Hirst, Royal Brisbane Hospital, Brisbane, Australia.)
Figure 41-5 Carcinoma of meibomian glands, clinically mistaken for a chalazion. A. Scrape smear of the
lesion containing numerous cancer cells, singly and in clusters. B. Biopsy of the lesion showing a duct replaced
by cancer cells and areas of invasive carcinoma. (Case courtesy of Dr. Clifford Urban, Phoenixville, PA.)
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The rare complications of the procedure include intraorbital hemorrhage and scar formation that may result in optic
neuropathy and limitation of ocular mobility.
Lesions of the Orbit

Clinically, the space-occupying lesions of the orbit may cause dysfunction of ocular motility, ptosis of the eyelids,
proptosis (protrusion of the eye), and considerable visual difficulties. These symptoms may be caused by a variety
of disorders, ranging from orbital inflammation to tumors.
Benign Nonneoplastic Lesions Inflammatory Lesions

Inflammatory lesions may be caused by bacterial infections leading to an acute inflammation of orbital connective
tissue, or a cellulitis. The aspirates of the orbit in such cases yield predominantly polymorphonuclear leukocytes,
accompanied by necrotic tissue fragments. The lesions may also be caused by fungi, mainly Aspergillus species, but
occasionally by other organisms as well (Cangiarella et al, 1996). Granulomatous lesions, either tuberculosis or
sarcoidosis, may be observed (Hoover et al, 1986). Very rare cases of orbital involvements by Langerhans' cell
histiocytosis were also reported (Kramer et al, 1997; Nassar et al, 2000). For description of cytologic presentation of
these entities, see Chapters 19 and 31.
Benign Tumors and Tumor-Like Disorders
Among the benign orbital lesions of note are:
n Cysts
n Benign tumors of lacrimal glands
n Inflammatory pseudotumors
n Meningiomas and benign gliomas of optic nerve
Foreign body granulomas (Iyer et al, 1998) and displaced benign lacrimal tissue (Boccato et al, 1992) may mimic
tumors of orbit.
With the exception of meningiomas and benign mixed tumors (pleomorphic adenomas) of the lacrimal glands, the
aspirates of benign lesions are usually scanty and great care is required to preserve the material.
Orbital Cysts
These may be mucoceles, probably derived from lacrimal glands and lined by cuboidal or columnar mucus-producing
cells. The very rare enterogenous type cysts are lined by benign cuboidal glandular cells. The cyst content may
show high levels of carcinoembryonic epithelial antigen (CEA), as described by Ballesteros et al (1997). Dermoid
cysts, characterized by acellular keratin debris, have also been reported (Arora et al, 1992).
Benign Tumors of the Lacrimal Glands

These are commonly pleomorphic adenomas with a cytologic presentation identical to that of salivary gland tumors
(see Chap. 32). A pigmented pleomorphic adenoma of the ciliary body, mimicking a malignant melanoma, was
described in the cytologic sample by Laver et al (1996). Boccato et al (1992) pointed out that normal ectopic
lacrimal glands may be mistaken for a neoplasm.
Meningiomas
Meningiomas of the orbit may occur secondarily as an extension of intracranial meningiomas but may also be
primary, derived from meningothelial cells accompanying the optic nerve. The benign tumors can be recognized
cytologically by whorls of cells with abundant cytoplasm, known as meningothelial cells, often accompanied by
psammoma bodies. The small tumor cells may also form cohesive flat clusters (Fig. 41-6) (Cristallini et al, 1990;
Koss et al, 1992; Cangiarella et al, 1996). For further description and illustrations of cytology of this tumor, see
Chapter 42.
Gliomas of the Optic Nerve

These exceedingly rare tumors are usually observed during the first decade of life and are known as juvenile
pilocytic astrocytomas (Marquardt and Zimmerman, 1982). Cytology of these tumors was described by Kennerdell et
al (1979, 1980) and by Koss et al (1992). Elongated cells with bland nuclei against a fibrillary background were
observed. Gliomas may also occur in patients with neurofibromatosis.
Other Benign Tumors

Leiomyomas of the orbit were described by Jakobiec et al (1975).
Pseudotumors
Inflammatory pseudotumors are acute and chronic inflammatory disorders affecting intraorbital tissues (Blodi and
Gass, 1967). Another type of pseudotumor (idiopathic pseudotumor) is a nonspecific inflammatory reaction with
occasional formation of granulomas and fibrosis. The acute inflammatory disorders are readily recognized clinically,
as discussed above.
The lesion that may cause significant diagnostic difficulties is the benign lymphoid pseudotumor, yielding cytologic
material composed of a spectrum of lymphoid cells, showing various stages of maturation, not unlike a
hyperplastic lymph node (Arora et al, 1992; Cangiarella et al, 1996). The aspirate usually does not permit a secure
differentiation between a benign, follicle-forming lymphoid lesion and a malignant lymphoma. In any event, even
the fate and the significance of the lymphoid pseudotumor are not secure and in at least some cases, a malignant
lymphoma develops with the passage of time (Jakobiec, 1978; Brady et al, 1982). Flow cytometry and
immunocytology, to determine
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the clonality of the disorder, may be applied to orbital aspirates, as described below (Nassar et al, 2000).
Figure 41-6 Meningioma of orbit. Aspirate. A. Typical field of a smear of meningioma showing medium-sized
cells forming concentric whorls. B. A flat sheet of cells with clear cytoplasm and small nuclei, some showing
small nucleoli. Some nuclei show intranuclear cytoplasmic inclusions. (Photographs courtesy of Dr. Joan
Cangiarella, New York University, New York.)
Malignant Tumors
The principal malignant tumors occurring in the orbit are:
Tumors of lacrimal glands
Adenoid cystic carcinoma
Adenocarcinoma
Malignant tumor ex pleomorphic adenoma or malignant mixed tumor
Rare tumors
Malignant lymphomas
Sarcomas (rare)
Children: embryonal rhabdomyosarcomas
Adults: sarcomas of muscle, connective tissue or vessels
Tumors invading the orbit from adjacent sites (i.e., nasal sinuses, parotid)
Metastatic tumors (see end of chapter)
Malignant Tumors of Lacrimal Glands

We and others (Sturgis et al, 2001) have observed reported cases of examples of adenoid cystic carcinoma. De Rosa
et al (1986) and Rosenbaum et al (1995) reported cases of acinic cell carcinoma. The histology and cytologic
presentation of these tumors is discussed at length in Chapter 32.
We have also observed two patients with malignant tumors ex pleomorphic adenomas (malignant mixed tumors),
which share the morphologic features with the corresponding tumors of salivary glands. These uncommon tumors are
best recognized by the presence of two cytologic patterns side by side, one with features of a benign pleomorphic
adenoma and the other a malignant tumor that can be a carcinoma or, very rarely, a sarcoma. In one of the cases
seen by us, the dominant cytologic pattern of the malignant component of the tumor was an adenocarcinoma. The
initial biopsies disclosed a benign mixed tumor. The documentation of the malignant nature of the tumor required
several additional biopsies (Fig. 41-7). Similar cases have been reported by Arora et al (1992), Das et al (1994),
Cangiarella et al (1996), and Dávila et al (1998).
A case of mucoepidermoid carcinoma of the lacrimal gland has been reported by Das et al (1994).
Malignant Lymphomas and Related Lesions

Malignant lymphomas of the orbit became more frequent with the onset of AIDS. These are non-Hodgkin's
lymphomas, usually of B-cell type, that have the same characteristics as primary malignant lymphomas, described in
Chapter 31 (Ling et al, 1988; Cangiarella et al, 1996; Laucirica and Font, 1996; Weber et al, 1996). Zeppa et al
(1997) and Nassar et al (2000) suggested that flow cytometry and immunocytochemistry may be used on orbital
aspirates to identify monoclonal (malignant) from polyclonal (benign) populations of lymphoid cells and thus
separate true lymphomas from inflammatory pseudotumors (see above). An example of large cell lymphoma of the
orbit in vitreous fluid is shown in Figure 41-11. Nassar et al (2000) reported three cases of primary orbital
plasmacytoma.
Sarcomas
Embryonal rhabdomyosarcomas are observed in children. Arora and Betharia (1994) described the smears as
composed of medium-size cancer cells without cytoplasmic striations. The cells were positive for neuron specific
enolase and desmin. We observed an aspirate of a sarcoma, not further classified, involving the orbit in an 82-year-
old woman with Paget's disease of bone. The aspirate contained a few malignant cells, insufficient to determine
tumor type. The cytology of these tumors is discussed in Chapter 35.
THE EYE
As discussed above, the aspiration biopsy of the eye is a technically difficult procedure best performed by qualified
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ophthalmologists. Sen et al (1999) proposed that the cell sample may be obtained by direct route across the eye
rather than via the orbit. Usually the preliminary diagnosis of the space-occupying lesion is suggested on clinical
grounds and the aspiration biopsy serves to confirm the clinical impression. The repertoire of primary eye space-
occupying lesions is fairly limited.
Figure 41-7 Malignant mixed tumor (malignant tumor ex pleomorphic adenoma) of a lacrimal gland in a
68-year-old male. A,B. Aspirate stained with Papanicolaou (A) and Diff-Quik (B), showing large malignant
cells, some in papillary configuration and some of cuboidal or columnar shape, suggestive of adenocarcinoma.
C. Original biopsy of the orbital mass showing a benign pleomorphic adenoma. D. Second large biopsy
disclosed the presence of duct-forming adenocarcinoma.
Benign Lesions
Case reports describing the cytology of benign processes within the eye are exceedingly rare. Stewart et al (1993)
described the findings of an uncommon congenital abnormality of the eye known as Coats' disease (Chang et al,
1984). The sediment contained numerous “pigmented bodies” of unknown derivation and cholesterol crystals.
Bilateral Diffuse Melanocytic Proliferation

This unusual paraneoplastic syndrome occurs mainly in patients with gynecologic cancer and consists of a benign
proliferation of uveal melanocytes forming nodules in the iris and choroid. The patients also develop cataracts and
retinal detachment (Barr, 1982; recent summary in Chahud et al, 2001). Although there is no record of cytologic
evaluation of these uncommon lesions, they may well enter into the differential diagnosis of primary ocular
melanoma.
Malignant Tumors
The most common malignant tumors are retinoblastomas in children and malignant melanomas in adults.
Retinoblastoma
Retinoblastoma originates in the retina. This highly malignant tumor can be unilateral or bilateral and affects mainly
children in the first 2 years of life. The tumor has very interesting implications in genetics and molecular biology of
cancer. For a discussion of the retinoblastoma gene ( Rb gene), see Chapter 7.
Aspiration biopsy of a retinoblastoma yields cells and cell rosettes that cannot be distinguished on morphologic
grounds from cells of related tumors, neuroblastomas (see Chap. 40) or medulloblastoma (see Chap. 27). An
example of metastatic neuroblastoma to the orbit is shown in Figure 41-12. Several such cases were reported by Das
et al (1989), O'Hara et al (1993), Arora and Betharia (1994), Sen et al (1999), and a case in an older child by
Decaussin et al (1998).
Malignant Melanoma
Histology
Melanomas are the most common primary intraocular malignant tumors, occurring mainly in adults. These tumors
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may originate in the uvea, choroid, iris, or ciliary body and are thus sometimes collectively referred to as uveal
melanomas (Czerniak et al, 1983; Char et al, 1989; Koss et al, 1992; Shields et al, 1993). The tumors are
subclassified into spindle-cell types A and B and epithelial type (McLean et al, 1982). The prognosis is distinctly
more favorable with spindle-cell type melanoma type A, composed of slender tumor cells, often with nuclear folds
(creases) along the long axis of the nucleus, and small nucleoli. The type B spindle cell melanoma is composed of
bundles of clearly malignant spindly cells, some containing deposits of melanin. The epithelial type melanomas are
composed of obvious malignant cells, usually with abundant pigment formation.
Cytology
The most difficult to recognize are cells of the type A spindly melanoma. The aspirates contain a fairly monotonous
population of small, spindly cells with slender cytoplasmic extensions, resembling smooth muscle cells. The oval
nuclei of such cells are granular, contain small but clearly visible nucleoli, and show prominent nuclear creases.
Pigmented cells are relatively few (Fig. 41-8A,B). In type B spindly ocular melanoma, the aspirates contain
abundant cancer cells forming bundles. The cells are larger than in type A and have long fragile bipolar cytoplasmic
processes. The nuclei are hyperchromatic, coarsely granular and provided with large nucleoli. Intranuclear
cytoplasmic inclusions have been observed (Koss et al, 1992).
Figure 41-8 Melanomas of the eye. Aspiration smears and corresponding histology. A,B. Spindle-cell
melanoma, type A. The aspirate (A) shows sparse spindly cells with finely granular nuclei, tiny nucleoli, and
nuclear creases. The corresponding tumor of the choroid is composed of bundles of spindly cells. C,D.
Carcinomatous melanoma. The smear (C) is composed of obviously malignant mononucleated and
multinucleated cells, some containing cytoplasmic pigment. The corresponding tumor (D) was a carcinomatous
melanoma. (Both cases courtesy of Dr. Jacek Sygut, Oncology Institute, Kielce, Poland.)
Melanoma of the epithelial type is the easiest to recognize. Large polygonal or approximately spherical tumor
cells, usually containing abundant melanin pigment, are easily identified. Many of these tumors shed oddly-shaped,
heavily pigmented tumor cells in which the nucleus cannot be visualized (Fig. 41-8C,D). Other cells, however,
display morphologic features characteristic of malignant melanoma: cells with marked nuclear abnormalities,
multinucleated cells, and intranuclear cytoplasmic inclusions. Bipolar pigmented cells and cells resembling
dendrites with multiple cytoplasmic extensions also occur in ocular aspirates (Koss et al, 1992). The very rare
paraneoplastic syndrome of diffuse melanocytic proliferation (see above) must be considered in the differential
diagnosis of malignant melanoma.
An interesting feature of ocular malignant melanoma is the propensity of these tumors to form delayed liver
metastases,
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sometimes 20 or more years after the removal of the primary tumor. This writer (LGK) called this the “syndrome of
a glass eye and protuberant abdomen” (see Chap. 38).
THE VITREOUS BODY

From time to time, the semi-solid vitreous body may be removed by vitrectomy or aspirated to clarify the cause of
an intraocular opacity (Green, 1984). The semisolid material is centrifuged and the sediment prepared as cytospins
and cell blocks (Engel et al, 1982; Mandell et al, 1987).
Lin et al (1999) divided the lesions in three groups: inflammation and infections, hemorrhage, and malignant
tumors, mainly malignant lymphomas. In a summary of results of 74 vitreous fluid specimens from 60 patients, these
authors concluded that inflammatory or infectious processes, observed in 41 patients, are most common. A broad
array of microorganisms, including bacteria, fungi, and viral infections, were observed. The second group of
diagnoses was hemorrhage, observed in 12 patients, and the third, smallest group was caused by malignant
lymphomas (7 patients). Fibrovascular membranes, observed in diabetic retinopathy, and retinal fragments were
reported by Mandell et al (1987).
In the absence of inflammation or tumor, Koss et al (1992) observed that benign pigmented, melanin-containing
cells, probably derived from the uvea, and macrophages, may be observed in the vitreous. Small, slender
columnar cells with eosinophilic cytoplasm, known as hyalocytes, may also be observed (Fig. 41-9). The origin or
role of the hyalocytes is unknown (Spencer, 1996).
Asteroid hyalosis is a condition in which minute spherical structures, composed of calcium soap, may cause an
opacification of the vitreous body (Spencer, 1996). A cytologic diagnosis of this condition was reported by Loughman
and Lin (1995). Spherical bodies measuring from 30 to 80 µm in diameter and showing central birefringent
crystalline particles were observed.
In retinal detachment, fragments of the retina may be observed (Fig. 41-10) (Koss et al, 1992). Also, fragments of
the lens in the form of crystalline material may occur (Mandell et al, 1987).
Figure 41-9 Vitreous hyalocytes. Cell content of vitreous fluid aspirated because of intraocular opacity.
Elongated small epithelial cells with eosinophilic cytoplasm (hyalocytes) in company of a few lymphocytes and
pigmented cells.
Figure 41-10 Fragment of retina in vitreous fluid in retinal detachment.
Cells derived from uveal tumors may desquamate into the vitreous. We observed several cases of malignant
melanoma and malignant lymphoma, the latter either in the elderly or in patients with AIDS, easily recognizable by
the morphology of the dispersed cells, and confirmed by immunostaining with common lymphocyte antigen (Fig. 41-
11). Farkas et al (2004) recognized malignant lymphoma in the vitrous fluid in 9 of 13 samples. It is of note that only
3 of these patients had generalized lymphoma. Hence, it must be assumed that several of these ocular lesions
represent primary occular lymphomas. The cytologic presentation of these tumors was discussed above and in
Chapter 31.
METASTATIC TUMORS TO THE EYE AND ORBIT

Ferry and Font (1974, 1976) and Font and Ferry (1976) described their observations with nearly 300 malignant tumors
metastatic to the eye and adnexa. Surprisingly, these authors reported that most metastases are found in the
posterior portion of the eye and relatively few in the anterior part of the eye or the orbit.
In our experience, the malignant tumors to the orbit or the eye that are most commonly aspirated are metasta
ses from other organs. Usually, the primary site of the tumor is known, but occasionally, it may be occult and the
orbital lesion is the first manifestation of disease.
In infants and children, metastatic neuroblastoma is the most common orbital tumor (Koss et al, 1992; Arora and
Betharia, 1994). Protrusions of the eye and sometimes radiologic abnormalities of the skull (“sun ray” appearance of
bony spicules) occur fairly often. Metastatic neuroblastoma is probably the most common source of clinical
diagnostic errors in eye lesions in childhood, as they may be mistaken for lymphoblastic leukemia or even
thalassemia major. In a case reported from our laboratories, the orbital
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lesion in a 3.5-year-old girl was initially thought to represent acute lymphoblastic leukemia (Slamovits et al, 1991).
Morphologically, neuroblastomas are identical to primary retinoblastomas of the eye globe, which can be
recognized by ophthalmologic (or funduscopic) examination (Arora and Betharia, 1994). Cytologically, the small
tumor cells in both tumors form the characteristic rosettes filled with delicate neurofibrils (Fig. 41-12). Other
small cell tumors of childhood, such as Ewing's sarcoma and embryonal rhabdosarcoma, may occasionally involve
the orbit.
Figure 41-11 Malignant lymphoma in vitreous fluid. The aspirate shows a monotonous population of
dispersed atypical lymphocytes. Nuclear abnormalities are better appreciated in B under high magnification.
In adults, the origins of metastatic tumors to the orbit are diverse and include every conceivable primary site. In our
experience, mammary carcinoma is the most common metastatic tumor in women. The primary site can be
recognized if the small “signet ring” cancer cells show the cytoplasmic vacuoles with a central condensation of
mucus (magenta or target cells, see Chap. 29), characteristic of lobular carcinoma (Fig. 41-13A). In men, we have
seen examples of metastatic lung cancer and prostatic carcinoma (Fig. 41-13B). In the latter case, the precise
diagnosis could be established by a positive stain for prostate specific antigen. In Ferry and Font's experience (1974),
tumors of the gastrointestinal tract origin are also commonly observed in the eye. A case of occult primary
esophageal adenocarcinoma with orbital metastasis as the first manifestation of disease in a 61-year-old female
patient, was reported from this laboratory by Cangiarella et al (1996). The tumor was diagnosed in washings of the
vitreous (Fig. 41-13C,D). We also observed metastatic squamous carcinoma from the skin of the forehead and an
orbital extension of a chondrosarcoma of the nasal cavity. Heerema and Sudilovsky (2001) reported a case of
mucinous ovarian adenocarcinoma metastatic to the orbit. Logrono et al (1997) described a case of metastatic
leiomyosarcoma. In our experience, orbital and eye involvement in leukemias and generalized malignant
lymphomas is not uncommon, as confirmed by others (Weber et al, 1996; Nassar et al, 2000). Yakulis et al (1995)
described a case of multiple myeloma
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metastatic to the orbit in a young man with formation of amyloid that could be recognized in the aspirate.
Figure 41-12 Metastatic neuroblastoma. Aspirate of orbit in a 3 1/2-year-old girl with referral diagnosis of
acute lymphoblastic leukemia. A. Small, monotonous malignant cells surrounding spherical empty spaces,
corresponding to tumor rosettes. In B, the fibrillar core of a rosette stains pink. Special stains disclosed the
presence of neurofibrils in the center of the rosettes (not shown). (A: Pap stain, B: Diff-Quik.)
Figure 41-13 Metastatic carcinomas to orbit. A. Mammary lobular carcinoma in a 64-year-old woman. The
tumor derivation and type can be easily established because of small cells of “signetring” configuration and
condensations of mucus in the center of the large cytoplasmic vacuole (see Fig 29-37). B. Metastatic
pulmonary adenocarcinoma in a 60-year-old man. The origin of the tumor could not be determined on
morphology alone. C. Metastasis from occult adenocarcinoma of esophagus in washings of the vitreous. D.
Esophageal tumor corresponding to C. (C,D: Courtesy of Dr. Joan E. Cangiarella, New York University, New
York.)
Acknowledgment
I thank Dr. Pearl Rosenbaum, Professor of Pathology and Ophthalmology, Albert Einstein College of Medicine, and
Head of the Ophthalmic Pathology Laboratory at Montefiore Medical Center for her insightful comments and many
suggestions pertaining to this chapter.
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Eye Cytology

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Ovid: Koss' Diagnostic Cytology and Its Histopathologic Bases Page 1 of 29

Editors: Koss, Leopold G.; Melamed, Myron R.

ANATOMIC AND HISTOLOGIC RECALL

THE EYELIDS AND EXTERNAL SURFACE OF THE EYE

Normal Cells in Conjunctival and Corneal Scrape Smears

have no diagnostic significance.

Trachoma Cornea and Cytoplasmic in Multiple small Clusters of

Inclusion Cytoplasmic in Same as above Clusters of

Adenovirus Conjunctiva Intranuclear in Multiple, small Few cells involved

Vaccinia Conjunctiva Cytoplasmic Single, large,

Herpes, Conjunctiva Intranuclear, Enlarged In herpes zoster

molding inclusions inclusions are rare

Measles Conjunctiva Multinucleated Multiple

Other Inflammatory Processes

Bacterial infections result in acute conjunctivitis characterized by a dominance of neutrophils in smears.

Onchocerciasis (River Blindness)

Squamous Carcinoma and Its Precursors

Dysplasia after Exposure to Mustard Gas

Carcinomas of Meibomian Glands

THE ORBIT AND THE EYE

Lesions of the Orbit

Benign Nonneoplastic Lesions Inflammatory Lesions

Benign Tumors and Tumor-Like Disorders

Among the benign orbital lesions of note are:

n Benign tumors of lacrimal glands

n Meningiomas and benign gliomas of optic nerve

Benign Tumors of the Lacrimal Glands

Gliomas of the Optic Nerve

Other Benign Tumors

Tumors of lacrimal glands

Adenoid cystic carcinoma

Malignant tumor ex pleomorphic adenoma or malignant mixed tumor

Children: embryonal rhabdomyosarcomas

Adults: sarcomas of muscle, connective tissue or vessels

Metastatic tumors (see end of chapter)

Malignant Tumors of Lacrimal Glands

Malignant Lymphomas and Related Lesions

Bilateral Diffuse Melanocytic Proliferation

cancer. For a discussion of the retinoblastoma gene ( Rb gene), see Chapter 7.

THE VITREOUS BODY

Figure 41-10 Fragment of retina in vitreous fluid in retinal detachment.

METASTATIC TUMORS TO THE EYE AND ORBIT

Bruckner R, Ludin H. Zur zytologischen Tumordiagnostik in der Opthalmologie. Opthalmologica 133:169-175,

Coutifari N, Nocolaou D. Le cyto-diagnostic en opthalmologie. Arch Opthamol 19:360, 1959.

Stevens A, Lowe J. Histology. London, Grower Medical Publishing, 1992.

Thygeson P. The cytology of conjunctival exudates. Am J Ophthalmol 29:1499-1513, 1946.

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