Tumors of Epithelial Origin Neoplastic Disorders of the Conjunctiva Vanee Virasch, M.D.

Neoplastic Disorders of the
Tumors of Epithelial Origin
• Epithelial inclusion cyst
• Benign epithelial tumors
– Conjunctival papilloma
– Pseudoepitheliomatous hyperplasia
• Preinvasive epithelial tumors
Vanee Virasch, M.D.
Department of Ophthalmology
November 2006
– Conjunctival intraepithelial neoplasia
• Malignant epithelial tumors
– Squamous cell carcinoma
– Mucoepidermoid carcinoma
– Spindle cell carcinoma and Basal cell carcinoma
Epithelial Inclusion Cyst
Epithelial Inclusion Cyst
• Pathogenesis
– Congenital or acquired
– Small cysts formed by apposition of conjunctival folds
– Large, single cysts – epithelium implanted into the substantia
propria by trauma, surgery, inflammation
– Lined by normal conjunctival epithelium
• Clinical findings
– Appear clear
• Management
– Complete excision or marsupialization necessary to prevent
– Simple incision will lead to recurrence d/t remaining inner
epithelial cells
Conjunctival Papilloma
• Pedunculated
– HPV, type 6 or 11
– Fleshy, exophytic growth with
fibrovascular core
– Emanates from a stalk with
multilobulated appearance with
smooth, clear epithelium and
small corkscrew vessels
– Inferior fornix, tarsal or bulbar
– May be multiple – more in HIV
Conjunctival Papilloma
• Sessile
– HPV, type 16 or 18
– More likely dysplastic or
– Limbus
– Flat base with glistening
surface and numerous red
– Signs of dysplasia
• Keratinization (leukoplakia)
• Inflammation
• Invasion
– Rare variant – Inverted
Conjunctival Intraepithelial Neoplasia
Conjunctival Intraepithelial Neoplasia
• Analogous to actinic keratosis of skin
• Does not invade underlying basement membrane
• Contributing factors: HPV, sunlight, host factors,
t l
d t
• Most common
– Exposed areas of bulbar conjunctiva, at or near limbus
– Light-complected, older male smokers
• More rapid growth in AIDS pts
• Potentiated by systemic immunosuppression
Conjunctival Intraepithelial Neoplasia
Conjunctival Intraepithelial Neoplasia
• Clinical findings
– 3 clinical variants:
• Papilliform – sessile papilloma harboring dysplastic cells
• Gelatinous
G l ti
– resultlt off acanthosis
th i andd ddysplasia
l i
• Leukoplakic – hyperkeratosis, parakeratosis, and dyskeratosis
Conjunctival Intraepithelial Neoplasia
• Management
– Excisional biopsy with adjunctive cryotherapy
• Recurrence rates at 10 yyears
– Negative surgical margins ~ 33%
– Positive surgical margins ~ 50%
Mild inflammation and abnormal vascularization
Classification: Mild, Moderate, Severe (Carcinoma in situ)
Slow growing tumors
Potential to spread to other ocular surfaces
Squamous Cell Carcinoma
• Pathogenesis
– Risk factors: UV radiation, viral, genetic
– More common and aggressive in:
• Xeroderma pigmentosa
– Topical chemotherapeutic agents
• Interferon, MM-C, 5-FU
• No long term recurrence studies
Squamous Cell Carcinoma
• Clinical findings
– Broad based lesion at or near limbus in
interpalpebral fussure
– Grow outward with sharp borders
– Can
C be leukoplakic
– Usually remains superficial rarely penetrating sclera
– Pigmentation in dark-skinned pts
– Engorged conjunctival vessels feeding tumor
– Inflammation
– Locally invasive and can metastasize
Squamous Cell Carcinoma
Squamous Cell Carcinoma
• Management
– Complete local excision
• 4 mm beyond clinically apparent margins
• Thin lamellar scleral flap beneath tumor
Absolute alcohol to remaining underlying sclera
Adjunctive cryotherapy to margins
Risk of recurrence related to surgical margins
Extensive external spread
• Orbital exenteration and possible radiation therapy
Mucoepidermoid Carcinoma
• Rare carcinoma of limbal conjunctiva, fornix, or caruncle
• Clinically resembles aggressive variant of squamous
cell carcinoma
• Neoplastic epithelial cells + Malignant goblet cells
– Demonstrated with mucin stains
• More likely to invade globe or orbit
• Treatment
– Wide surgical excision
– Adjuvant therapy: cryotherapy, radiation
Other Carcinomas
• Spindle Cell Carcinoma
– Rare tumor of bulbar or limbal conjunctiva
– Anaplastic cells appear spindle shaped
• Basal Cell Carcinoma
Glandular Tumors
• Oncocytoma
• Dacryoadenoma
• Sebaceous adenocarcinoma
– Rare to arise from conjunctiva
• Slow-growing cystadenoma
• Arises from ductal and acinar cells of main and
accessory lacrimal glands
• Reddish-brown nodule on surface of caruncle in
elderly individuals
Sebaceous Cell Adenocarcinoma
1% of all lid tumors
5% of lid malignancies
Elderly individuals
g ppts on radiation tx
Masquerade as chalazia or chronic unilateral
• Pathogenesis
• Extremely rare
• Children or young adults
• Benign proliferation of accessory lacrimal gland
• Round, pink elevation on palpebral or bulbar
Sebaceous Cell Adenocarcinoma
• Clinical findings
Tend to involve lid margin
More common on upper lid (greater # of Meibomian glands)
Mayy see inflammation
Can be multicentric
Painless, slow-growing, firm, nonmobile, yellowish nodule
Chronic papillary conjunctivitis
– Most arise from meibomian gland
– Some arise from glands of Zeis, sebaceous glands of the
caruncle, or pilosebaceous glands of lids and brows
– Enlarged preauricular lymph node may indicate metastasis
Sebaceous Cell Carcinoma
Sebaceous Adenocarcinoma
• Intraepithelial pagetoid spread into the conjunctiva with
• Management
Full-thickness biopsy
Mapping biopsies may be needed because of skip lesions
Wide excision with tumor-free
tumor free margins necessary
Exenteration – multifocial or spreading tumores
Adjunctive radiotherapy
Local recurrence ~ 10 – 20%
Distant metastasis ~ 15 – 25%
Tumor-related mortality ~ 10%
Tumors of Neuroectodermal Origin
Pigmented Lesions
• Benign pigmented lesions
Congenital epithelial melanosis (freckle or ephelis)
Benign acquired melanosis
Ocular melanocytosis
• Preinvasive pigmented lesions
– Primary acquired melanosis
• Malignant pigmented lesions
– Melanoma
• Neurogenic and smooth muscle tumors
– Neurofibromas, schwannomas, neuromas
– Neurilemoma
– Leiomyosarcoma
• Pigment spot of the sclera
– Collection of melanocytes associated with an intrascleral
nerve loop or perforating anterior ciliary vessel
• Melanosis
– Excessive pigmentation without an elevated mass
• Epinephrine
• Silver
• Mascara
Congenital Epithelial Melanosis
Benign Acquired Melanosis
Freckle or ephelis
Flat, brown patch
Usually bulbar conjunctiva near limbus
More common in darkly pigmented individuals
Present at an early age
• Increasing pigmentation of the conjunctiva of both eyes
in middle aged individuals with dark skin
• Light brown pigmentation of the perilimbal and
interpalpebral bulbar conjunctiva
• Striate melanokeratosis – streaks and whorls that
extend into peripheral corneal epithelium
• Stimulus to melanocytic hyperplasia may be related to
sunlight exposure
Ocular Melanocytosis
Ocular Melanocytosis
• Congenital melanosis of the episclera
– Occurs in ~ 1 in every 2500 individuals
– More common in blacks, Hispanics, Asians
• Focal proliferation of subepithelial melanocytes
(blue nevus)
• Clinical findings
– Patches of nonmobile slate gray pigmentation
– May have diffuse nevus of the uvea
• Increased pigmentation of iris and choroid
– Oculodermal melanocytosis – in 50% of pts
• Nevus of Ota
– Ipsilateral dermal mealocytosis – proliferation of dermal
melanocytes in periocular skin of CN V1 and V2
• 5% are bilateral
Ocular Melanocytosis
Ocular Melanocytosis
• Management
– Secondary glaucoma occurs in affected eye in ~
– Malignant transformation possible but rare
• Occurs more often in fair-skinned pts
• Lifetime risk ~ 1 in 400
• Can occur in skin, conjunctiva, uvea or orbit
• Nevocellular nevi of conjunctiva – hamartia arising during
childhood and adolescence
• Junctional, Compound, Subepithelial
• Flat near limbus, Elevated elsewhere
• Pigmentation variable
• Small
S ll epithelial
ith li l iinclusion
l i cysts
t ~ 50%
• Secretion of mucin in inclusion cysts – enlargement
• Rapid enlargement at puberty
• High prevalence of junctional activity but rarely become
• Excision of suspicious lesions
• Excise nevi on palpebral conjunctiva
Primary Acquired Melanosis
• Preinvasive intraepidermal lesion of sun-exposed skin
• Flat, brown noncystic lesions of conjunctival epithelium
• PAM associated with cellular atypia – progress to
iin ~ 46%
• Pathogenesis
– Abnormal melanocytes proliferate in basal conjunctival
epithelium of middle-aged, light-skinned individuals
• Malignant transformation – nodularity, enlargement or
increased vascularity
Primary Acquired Melanosis
• Management
– Excisional biopsy
– All palpebral pigmented lesions should be excised
– Lesions that show atypia
• Adjunctive cryotherapy
• Mitomycin-C
– Check regional lymph nodes
• Less than 1% of ocular malignancies
• Prevalence: ~ 1 per 2 million in population of
European ancestry
– Rare in blacks and Asians
• Better prognosis than cutaneous melanoma
• Pathogenesis
– Arise from acquired nevi, PAM, or normal
– Malignant transformation of congenital conjunctival
nevus very rare
– Intralymphatic spread increases risk of metastasis
– Underlying ciliary body melanoma can extend
through sclera
– Cutaneous melanoma can rarely metastasize to conj
• Clinical findings
Most common on bulbar conj or at limbus
Variable pigmentation
Highly vascularized – bleed easily
Grow in nodular fashion
Can invade globe or orbit
• Bulbar melanomas have better prognosis than those on palpebral
conj, fornix, or caruncle
• Metastasis in ~ 26%, Mortality ~ 13% 10 yrs after surgical excision
– Cytologic risk factors for metastasis: large size, multicentricity,
epithelioid cell type, lymphatic invasion
– Can metastasize to LN’s brain, and other sites
• Management
Excisional biopsy
Excision of conjunctiva 4mm beyond clinically apparent margins
Excision of thin lamellar scleral flap beneath tumor
Treat remaining sclera with absolute alcohol
Cryotherapy to conjunctival margins
Primary closure or conj/amniotic membrane graft
Topical mitomycin-C – can be used for residual disease
Orbital exenteration – advanced disease or palliative tx
• Poor prognostic factors
– Melanomas arising de novo
– Tumors not involving limbus
– Residual involvement at surgical margins
Other neuroectodermal tumors
• Multiple endocrine neoplasia (MEN)
– Subconjunctival peripheral nerve sheath tumors
• Neurofibromas, shwannomas, neuromas
• Neurilemoma
– Very rare conj tumor originating form Schwann cell of a
peripheral nerve sheath
• Leiomyosarcoma
– Very rare limbal lesion with potential for orbital invasion
Vascular and Mesenchymal Tumors
• Benign tumors
– Hemangiomas
– Inflammatory vascular tumors
• Pyogenic granulomas, juvenile xanthogranuloma, fibrous
histiocytoma, nodular fasciitis
• Malignant tumors
– Kaposi sarcoma
– Other malignant tumors
• Isolated capillary and cavernous hemangiomas
of bulbar conjunctiva rare – likely extension from
adjacent structures
• Palpebral conjunctiva – Eyelid capillary
• Diffuse hemangiomatosis of palpebral or
foniceal conjunctiva – Orbital capillary
• Cavernous hemangioma of orbit
• Sturge-Weber syndrome
– Nevus flammeus (port-wine stain), vascular
hamartomas, secondary glaucoma, leptomeningeal
t i
• Ataxia-telangectasia
– Epibulbar telangectasis, cerebellar abnormalities,
immune disorders
Pyogenic Granuloma
• Common reactive hemangioma
• Misnamed – not suppurative, no
giant cells
• May occur
– Over chalazion
– Minor trauma
– Post op granulation tissue
• Rapidly growing red,
pedunculated, smooth lesion
• Bleeds easily and stains with
fluorescein dye
Pyogenic Granuloma
• Management
– Topical or intralesional corticosteroids may be
– Excision with cauterization to the base, primary
closure and post-op steroids to minimize recurrence
Other inflammatory vascular tumors
• Juvenile xanthogranuloma
– A histiocytic disorder that can present with conjunctival mass
• Subconjunctival granulomas – around parasitic and
mycotic infectious foci
• Connective tissue diseases
– RA nodules, sarcoid nodules (tan-yellow resemble follicles)
• Fibrous histiocytoma
– Fibroblasts and histiocytes with lipid vacuoles
• Nodular fasciitis
– Very rare benign tumor of fibrobascular tissue in lid or under
– May originate at insertion of rectus muscle
Kaposi Sarcoma
• Malignant neoplasm of vascular endothelium involves
skin, mucous membrans and internal organs
• Pathogenesis
– Infection with HHV-8
– Occurs
iin setting
tti off AIDS
• Clinical findings
– Reddish, highly vascular subconjunctival lesion
• Can be mistaken for subconjunctival hemorrhage
– Orbital involvement – lid and conjunctival edema
– Inferior fornix most common
– Nodular or diffuse
Kaposi Sarcoma
• Management
Treatment may not be curative
Nodular lesions less responsive to therapy
Surgical debulking
Local or systemic chemotherapy
Intralesional interferon alpha-2a may be effective
Other Malignant Tumors
Malignant fibrous histiocytomas
Lymphatic and Lymphocytic Tumors
Lymphoid hyperplasia
• Proliferations of lymphatic
channel elements
• Usually present at birth and
enlarge slowly
• Patch of vesicles with
• Intralesional hemorrhage –
“chocolate cyst”
• Appears as irregularly dilated lymphatic
channels in bulbar conjunctiva
• Mayy be developmental
• Can follow trauma or inflammation
• Anomalous communication with venule can lead
to spontaneous filling of lymphatic vessels with
Lymphoid Hyperplasia
• Formerly called Reactive hyperplasia
• Benign-appearing accumulation of lymphocytes and
other leukocytes
• May represent low-grade B-cell lymphoma
• Pts > 40 y/o
• Clinical findings
– Minimally elevated salmon-colored subepithelial tumor with
pebbly appearance
– Often moderately to highly vascularized
– Clinically indistinguishable from conj lymphoma
– May appear similar to primary localized amyloidosis
Lymphoid Hyperplasia
• Management
May resolve spontaneously
Local excision
Topical corticosteroids
Biopsy specimen may require special handling for
special histo and immuno stains
– General medical consultation
• Neoplastic lymphoid lesion of conjunctiva
• Pathogenesis
• Clinical findings
– Salmon pink, mobile mass on
– Diffuse lesion – masquerade as
chronic conjunctivitis
– Epibulbar mass – may be
extension from uveal lymphoid
– Age > 50 yrs or
– AIDS increases risk
Can arise from conj lymphoid follicles
Some localized,
localized some linked to systemic lymphoma
Monoclonal B-cell lymphomas most common
Less common
• Conjunctival plasmacytoma
• Hodgkin lymphoma
• T-cell lymphomas
• Management
– Referral to oncologist for systemic
– Excisional biopsy
p y if small enough
– Incisional biopsy if too large
– Local external beam radiation therapy
Metastatic Tumors
Cutaneous melanoma
• Usually curative for lesions confined to conj
– Systemic chemotherapy for systemic
Epibulbar Choristomas
Epidermoid and dermoid cyst
Epibulbar dermoid tumor
Ectopic lacrimal gland
Other choristomas
Complex choristoma
Osseous choiristoma
Neuroglial choristoma
Phakomatous choristoma
Epidermoid and Dermoid Cyst
• Rare choristomatous anomaly
• Epidermoid cyst – no accessory skin structures
• Dermoid cyst – includes accessory skin
• Most common at Frontozygomatic suture
• Less common at Nasofrontal suture
• Excision recommended when cyst threatens to
cause amblyopia or cosmetic deformity
Epibulbar Dermoid Tumor
• 1 in 10,000 individuals
• Pathogenesis
– Displaced embryonic skin tissue
– Composed of fibrous tissue, hair with sebaceous glands
– Covered by conjunctival epithelium
• Clinical findings
– Well-circumscribed, solid, smooth, porcelain white, round to
oval elevated lesion embedded in superficial sclera or cornea
– Most common in infertemporal limbus
– Arcus-like deposit of lipid along anterior corneal border
– Corneal astigmatism – anisometropic amblyopia
Epibulbar Dermoid Tumor
• Goldenhar syndrome
– Oculoauriculovertebral
– Sporadic or AD syndrome
off first
fi t bbranchial
hi l archh
– Epibulbar dermoid
– Coloboma of upper lid
– Preauricular skin tags
– Aural fistulae
– Vertebral anomalies
• Pale yellow dermoid containing
adipose tissue
• Distinguish from herniation of
orbital fat
• Occurs superotemporally and
may extend posteriorly
• May be associated with
Epibulbar Dermoid Tumor
• Management
No malignant potential
Lesion often extends deep into underlying tissues
El t d portion
ti may bbe excised
i d
Relaxing incision or other corrective measure may
be considered
– Lamellar keratoplasty for cosmetic appearance
– Amblyopia treatment
Ectopic Lacrimal Gland
• Lacrimal gland tissue occurring outside of the
lacrimal fossa
• Round,
Round pink,
pink vascularized mass at the limbus
– Goldenhar syndrome
– Linear nevus sebaceous
Other Choristomas
• Complex choristoma
– Superotemporal globe
– Multiple tissues: cartilage, bone, lacrimal galnd lobules, hair
follicles, hair, sebaceous glands, and adipose tissue
• Osseous choristoma
– Solitary nodule of bone surrounded by fibrous tissue
– Superotemporal
• Neuroglial choristoma – more diffuse
• Phakomatous choristoma
– Subcutaneous nodule in the inferomedial lid composed of
disorganized lens cells