Benign and malignant epibulbar tumors

1. CONJUNCTIVAL TUMORS
Presenter - Dr Poonam Rawat
Moderator - Dr Jyoti Batra Ohri

2. BENIGN EPIBULBAR TUMOURS
• Conjunctival naevus
• Conjunctival papilloma
• Limbal dermoid
• Dermolipoma
• Pyogenic granuloma
• Benign melanosis
• Miscellaneous benign epibulbar tumours
MALIGNANT AND PREMALIGNANT EPIBULBAR TUMOURS
• Primary acquired melanosis/conjunctival melanocytic intra-
epithelial neoplasia
• Conjunctival melanoma
• Ocular surface squamous neoplasia
• Lymphoproliferative lesions
• Kaposi sarcoma

3. BENIGN EPIBULBAR TUMORS
1.Conjunctival Naevus
• M/c melanocytic conjunctival tumour
• Risk of malignant transformation is <1%
• Histological appearance is similar to that of cutaneous naevi, but as
there is no conjunctival dermis, subepithelial and stromal replace
dermal in the nomenclature

4. Evolution of naevus
• Junctional naevi
- First or second decade
- Consist of nests of naevus cells at the epithelial–subepithelial
junction
• Compound naevi
-Second to third decade
-Naevus cells gradually migrate into underlying stroma
-At this stage pseudocysts form in lesion
• Subepithelial lesions
- Third to fourth decade
- Lesion migrates to reside
entirely in stroma
(subepithelial)
a.Compound naevus b.Junctional naevus

5. Clinical features
Symptoms- first or second decade (typical)
Signs
• Solitary
• Slightly or moderately elevated
• Pigmented or partially pigmented lesion
• Variable size
• Site – bulbar conj(72 %), caruncle (15%)
Most frequently juxtalimbal; over half
contain small cysts
• Naevi -mobile over the underlying sclera
• Clinically evident pigment in 84% and
amelanotic in 16% (relatively common)

6. Do not mistake it for malignant transformation
• Naevi becomes more pigmented with time
• May show true increase in size in young children
• May become inflamed especially in children and adolescents
Signs of potential malignancy (Indication of early excision)
• Unusual site such as the palpebral or forniceal conjunctiva
• Prominent feeder vessels
• Sudden growth or increase in pigmentation
• Development after the second decade
• Larger lesion with no cysts
• Positive family h/o of melanoma
• Distinct onset in middle age or later

7. CLINICAL VARIENTS
1.Speckled naevus
• Less well defined and patchy area of pigmentation
• Resembles PAM , differs as it contains subtle clear
cysts and occurs in younger individuals
2. Blue naevus
• Blue to black , circumscribed, slightly ill defined lesion
• Deep to conjunctival epithelium ,sometimes partially
attached to sclera
• Diffuse growth pattern and resemble PAM,
rarely undergo malignant transformation
3.Combined naevus
• Conjunctval naevus with features of both conventional naevus +
deeper dendritic cells (blue naevus)

8. • When not pigmented ,clear cystic spaces help to diff
from papilloma, lymphoma and amelanotic melanoma
Investigation
• Immunohistochemical technique – diff melanocytic lesions from
non melanocytic
• Melanoma specific Ag (HMB-45) –positive to both naevus and
melanoma (not reliable)
Treatment
• Small typical naevus- observation with photographs
• Growth documented –local excision
• Suspicious change or growth- excisional biopsy done same as in
melanoma

9. 2.Conjunctival Papilloma
• Viral induced lesion
• Histopathology -fibrovascular core
covered by an irregular proliferation of
non-keratinized stratified squamous
epithelium containing goblet cells
• Clinical features Lesions are
i. Sessile (wide base and flattish
profile)-
ii. Pedunculated (frond-like)

10. CONJUNCTIVAL PAPILLOMA
CHILDHOOD ADULT
• Children and young adults
• Virus induced lesion HPV 6
and 11
• Solitary or multiple
Sessile or pedunculated
• Red fleshy appearance owing
to numerous fine vascular
channel
• Involves inferior fornix or
bulbar conjunctiva rarely
encroaches on cornea
• No malignant potential
• Young to elderly adults
• Probably assoc with HPV
• Unilateral and solitary (rarely
multifocal)
• Resemble squamous cell Ca
and amelanotic melanoma
• Involves Limbus and bulbar
conj encroaches cornea
• Lighter pink color

11. Childhood Adult
• Numerous vascularized
papillary fronds lined by
acanthotic epi with minimal or
no keratinization
• Incomplete excision induces
liberation of virus particles
into surrounding tissues
• Cryo to lesion, lifting and
freezing entire lesion &
immediately cutting normal
conjunctiva
• Surgical excision and
supplemental cryotherapy

12. • Treatment
 Small lesions may resolve spontaneously
 Large lesions
-Excision
-Cryotherapy to the base and the
surrounding area
 Recurrences
-Subconjunctival interferon alfa
-Carbon dioxide laser vaporization
-Topical mitomycin C and oral cimetidine

13. 3.Limbal Dermoid
• Choristoma
• Consists of mass of collagenous tissue containing dermal elements
• Covered by stratified squamous epithelium
• Presentation - early childhood, with a smooth, yellowish, soft
subconjunctival mass commonly located at the inferotemporal
limbus, often with protruding hair
• Lesions are occasionally very
large and may virtually
encircle the limbus

14. Grading of Limbal Dermoid
• Grade 1
-Superficial lesion measuring <5 mm and are localized to limbus
-With slow growth resulting in oblique astigmatism and
flattening of cornea adjacent to the lesion
• Grade 2
-Larger lesion covering most of the cornea and
-Extending deep to the stroma down to DM without involving it
• Grade 3
- Least common of all the presenting dermoids
- Larger lesion covering the whole cornea and extending through
histological structures between the anterior surface of the eye ball
and the pigmented epithelium of iris

15. NEWER CLASSIFICATION

16. Treatment indication
• Cosmesis
• Chronic irritation
• Dellen formation
• Amblyopia from astigmatism or involvement of the visual axis
• Small dermoids - simple excision
• large lesions - lamellar keratosclerectomy
Systemic associations
1) Treacher Collins syndrome (mandibulofacial dysostosis)
• Malformation of derivatives of the I and II branchial arches,
principally mandibular and ear anomalies
• Lower eyelid coloboma
• Ocular anomalies slanted palpebral apertures, cataract,
microphthalmos and lacrimal atresia

17. 2.) Goldenhar syndrome (oculoauriculovertebral
spectrum)
-Usually sporadic
• Systemic features
-Malar Hypoplasia
-Maxillary and mandibular regions
-Macrostomia and microtia
-Preauricular and facial skin tags
-Hemivertebrae (usually cervical)
-Mental handicap
-Cardiac, renal and CNS anomalies
• Ocular features
-Dermoids
-Upper lid notching or coloboma
-Microphthalmos
-Disc coloboma

18. 3.) Linear naevus sebaceus of Jadassohn
 Systemic features
-Warty or scaly cutaneous lesions
- Infantile spasms
-CNS anomalies and developmental delay
 Ocular features
-Dermoid
-Ptosis
-Cloudy cornea,
-Lid colobomas, fundus colobomas and
-Microphthalmos

19. 4.Dermolipoma
• Similar in composition to a solid dermoid but also contains fatty
tissue
• Presentation
-Congenital lesion that is often not detected until adulthood
-Soft yellowish subconjunctival mass near the outer canthus
-Surface is usually keratinized, and may exhibit hairs.
-Occasionally the lesion may extend into the orbit or anteriorly
towards the limbus

20. • Treatment is generally avoided due to the possibility of
complications such as scarring, ptosis, dry eye and ocular motility
problems
• In selected cases- debulking the anterior portion may improve
cosmesis with lower risk
• It is critical to distinguish a dermolipoma from a prominent lacrimal
gland lobe and from orbital fat prolapse lymphoma can also present
in a similar fashion

21. 5.Pyogenic granuloma
• ‘Misnomer’ as the lesion is neither pyogenic
nor granulomatous
• Fibrovascular proliferative response to a
conjunctival insult such as surgery or trauma
or in association with a chalazion or FB
incarceration
• Histology- granulation tissue with both acute
and chronic inflammatory cells and a
proliferation of small blood vessels

22. • Presentation
 Typically few weeks after surgery for chalazion, strabismus or
enucleation
 Rapidly growing dark pink fleshy conjunctival mass
• Treatment
 Topical steroids- often successful
 Resistant cases – excision
 Shaving excision at the small base, followed by
cautery and cryotherapy, is usually effective
• D/D
 Suture granuloma-which can often be large
and mistaken for a malignant lesion
 Tenon capsule granuloma or cyst

23. 6.Benign Melanosis
• Aka Benign conjunctival epithelial melanosis (conjunctival
hypermelanosis- normal variant)
• More common in darker-skinned individuals (over 90% of blacks,
5% of whites)
• Presence of excess melanin within basal layer conjunctival epithelial
melanocytes
• Melanocyte numbers are normal ie there is no melanocytic
hyperplasia
• May have a protective effect against neoplasia

24. • Appears during the first few years of life
• Static by early adulthood
• B/L but asymmetrical
• Areas of flat, patchy, brownish pigmentation
may be seen throughout the conjunctiva,
concentrated at
- Limbus and
- Around perforating branches of vessels
or nerves as they enter the sclera
• Pigmented epithelium moves freely over the
surface of the globe
• A variant is seen in which small cysts are
present

25. 7.Miscellaneous benign
epibulbar tumours
• Epibulbar telangiectasia may be
associated with Sturge–Weber syndrome
• Reactive pseudoepitheliomatous
hyperplasia
-Rapidly growing white juxtalimbal
hyperkeratotic nodule
-Develops secondary to irritation
• Melanocytoma
-Rare congenital lesion
-Manifests as a slowly enlarging black
lump
-Can’t be moved freely over the globe

26. MALIGNANT AND PREMALIGNANT
EPIBULBAR TUMORS

27. 1.Primary Acquired Melanosis(PAM)/
Conjunctival Melanocytic Intra-Epithelial
Neoplasia (C-MIN)
• Arise in areas of melanocytic hyperplasia- approx 75%
• Some classifications have historically used the term PAM to
encompass both benign epithelial melanosis and melanocytosis/
melanocytic hyperplasia (with and without atypia)
• Others have restricted its use to the latter category
• Now the term PAM -preferred for lesions exhibiting proliferation of
melanocytes
• Reserved for clinical description before a histological diagnosis has
been established

28. • Symptoms
-Median age of 56 years
-Pigmented area on the surface of one or
both (10%) eyes
• Signs
 Uni- or multifocal flat areas
 Noncystic irregular golden-brown to dark
chocolate-coloured epithelial pigmentation
 Typically involving the limbus and
interpalpebral region
 PAM sine pigmento has been reported
 Any part of the conjunctiva may be affected, it
is important to evert the eyelids

29.  C-MIN may also extend onto the cornea
 Transformation to melanoma may be suggested by
the appearance of nodular areas
• D/D includes
1. Conjunctival naevus
2. Benign melanosis
3. Congenital ocular melanocytosis
4. Secondary pigmentation in Addison disease
5. Pigmented squamous cell carcinoma
Investigation
• Careful documentation -drawing and/or photography
• Immunohistochemical analysis of biopsied lesions is performed

30. Histology
• PAM without cellular atypia or with mild atypia
- Melanin pigmentation of basal epithelium with or
without hyperplasia of cytologically benign melanocytes
-Little or no risk of malignant transformation
• PAM with severe atypia (melanoma in situ)
-Similar pigmentary changes, but with cytologically
atypical melanocytes
- Progression to invasive melanoma over several years
(21%)
- Risk higher the greater the extent of the lesion
- Measured in clock hours
- Severe atypia is present in only a small
minority of PAM

31. • C-MIN
-Graded from 0 to 10 according to degree of atypia and spread:
0- absence of any melanocyte proliferation or atypia (i.e.
melanosis only)
5 - conjunctival melanoma in situ
 PAM with atypia can appear almost as junctional naevus –
clinician must provide history to pathologist
-patients’ age ,clinical description or photograph of lesion

32. Treatment
• Small (<one clock hour) lesions-Observation
• Excision biopsy is generally preferred to incisional biopsy
Indications of biopsy and active t/t
• Lesion dia >=5mm
• Documented progression of lesion
• Thickness of lesion
• Distinct nodule arising within lesion (pigm or nonpigm)
• Nutrient vessels to lesion
• Corneal or palpebral conj involvement
• Dysplastic nevus syndrome (in affected pt or close relative)
• Personal h/o cutaneous or uveal melanoma

33. • Double freeze–thaw cryotherapy to residual involved conjunctiva
to devitalize melanocytes that could spawn melanoma
• Following histological confirmation of C-MIN postoperative topical
MMC e.g. four cycles of 0.04% four times daily for 7 days separated
by 3-week intervals, with punctum plugs in situ
-To reduce the risk of punctal stenosis and
-Increase drug–surface contact time
• Amniotic membrane grafting- for large excision sites

34.  Larger lesions
• Mapping incisional biopsies accompanied by cryotherapy to all
pigmented areas or topical MMC as above
• Long-term follow-up mandatory in all cases
• Corneal involvement- alcohol mediated epitheliectomy followed by
topical mitomycin C
• Corneal component of pigmentation scraped taking care not to
penetrate deep to BM (prevent intraocular invasion)

35. 2.Conjunctival Melanoma
 Rare-2% of all ocular malignancies
 Around 75% arise from an area of PAM
 About 20% - pre-existing junctional or compound naevus and
rarely de novo 5%
 Presentation - Sixth decade
 Patients with the rare dysplastic naevus syndrome develop
multiple melanomas at a considerably younger age
 D/D
 Naevus
 Ciliary body melanoma with extraocular extension
 Melanocytoma
 Pigmented conjunctival squamous carcinoma

36.  Appearance
• Elevated Black or grey vascularized nodule
• May be fixed to the episclera
• Common site- Limbus and bulbar
conj
But a melanoma may arise anywhere
in the conjunctiva
• Association with PAM/C-MIN is very common
-diffuse or multiple, ill defined margins
• Amelanotic tumours may give rise to diagnostic
difficulty (25%)

37.  Overall mortality
• Up to 19% at 5 years
• 30% at 10 years
 Metastasis
• Occurs in 20–30%
• Main sites are regional lymph nodes, lung, brain and liver
 Worse prognosis factors
• Caruncular
• Forniceal or lid margin location
• Pagetoid or full –thickness intraepithelial spread
• Tumour thickness >= 2 mm

38. • B-scan ultrasonography- helpful in characterization of the lesion
• Systemic screening
-Regular general examination
-LFT and ultrasound
-Chest X-ray
-Whole body (PET/CT) imaging
• Histology -Melanomatous cellular atypia with invasion of the
subepithelial stroma
• Sentinel lymph node biopsy-helpful in staging
(place has not yet been fully defined)

39. Treatment
1.) Classic limbal lesions
Best removed primarily by alcohol corneal epitheliectomy, wide
partial lamellar scleroconjunctivectomy, double freeze thaw
cryotherapy, and primary conjunctival closure
2.) Larger lesions that extend into the forniceal region
May require wider excision with primary closure or a graft from the
opposite conjunctiva, buccal mucosa, or amniotic membrane
3.) Lesions that extend into the globe
May require a modified enucleation and those that extend into the
orbit may require orbital exenteration
• To prevent tumour seeding during excision
-Contact with the tumour itself should be avoided
-Fresh instruments used to close the conjunctival defect

40. • Exenteration may not improve survival, therefore reserved for
patients with extensive and aggressive disease when the eye cannot
be preserved
• Adjunctive radiotherapy-Routinely administered
by some authorities, even if histology s/o complete
excision
• Cryotherapy to the bed and surrounding tissue is an alternative
• Proton beam RT- if the caruncle or fornix is involved
• Diffuse melanoma assoc with extensive PAM/C-MIN-treated by
excision of localized nodules with MMC or cryotherapy to diffuse
component

41.  Drug Vemurafenib -improves survival in patients with metastatic
disease with BRAF V600E mutation (50% of primary and metastatic
conjunctival melanomas)
 Orbital recurrences are treated by local resection and radiotherapy
 Recurrence
• Multifocal disease
• Non-limbal tumour location
• Tumour margin involvement
• Lack of adjunctive treatment

42. 3.Ocular Surface Squamous Neoplasia (OSSN)
 Incidence 0.02 to 3.5% per 1 lac
 Spectrum of benign, pre-malignant and malignant slowly
progressive epithelial lesions of the conjunctiva and cornea
 Older adults are usually affected unless a predisposing systemic
condition is present
 A rough summary of reported cases suggests that about 75% occur
in men, 75% are diagnosed in older patients ( 60 years old), and
more than 75% occur at the limbus
Shields JA, Shields CL, Luminais S, et al. Differentiation of pigmented conjunctival squamous cell
carcinoma from melanoma. Ophtha lmic Su r g La ser s Ima gin g 2003;34:406–408

43.  Risk factors include
 UV light exposure
 Pale complexion, cyclosporin, smoking, petroleum product
exposure, AIDS, atopic eczema and xeroderma pigmentosum
 HPV infection (esp type 16) has been implicated in some cases
Symptoms
-Visible mass in one eye
-Sometimes with conjunctivitis-type symptoms
Site
-Interpalpebral fissure, particularly at the limbus
-Any part of the conjunctiva or cornea may be involved

44. Signs
Wide clinical array
 Circumscribed, gelatinous, sessile,
papillomatous mass with variable
leukoplakia
• Large, dilated conj vessels frequently feed
and drain mass
• Locally invasive but metastasizes in 1-2%
• Extend locally to cover cornea and invade
orbit and globe(uncontrollable glaucoma)
 Diffuse, flat, poorly delineated neoplasm
without distinct tumefaction
• Confused clinically with conjunctivitis,
keratoconj, scleritis or pagetoid invasion of
sebacious Ca

45. • Two less common form( accounts for 5% of all conjunctival SCC)
a) Mucoepidermoid form
b) Spindle cell form
• Display a greater capacity for aggressive local behavior
• Elderly individual >70years
• Poor prognosis
• Site –caruncle (invade orbit and paranasal sinuses)
• Appearance – more yellow, globular, cystic app than typical SCC
• Introcular invasion-large mucinous cyst in suprauveal space
• Spindle cell Ca- locally invasive and greater tendency
to metastasize (lung and bone)

46. Diagnosis
• Small and localized –primary complete excision
• Large and diffuse- incisional biopsy or map
biopsy
• Impression cytology –establish diagnosis
• Histology shows the following spectrum
1. Conjunctival epithelial dysplasia- dysplastic
cells are confined to the basal epithelial layers
2. Carcinoma in situ- dysplastic cells involve the
full thickness of the epithelium
3. Squamous cell carcinoma-Invasion of
underlying stroma
• First two are sometimes termed conjunctival–
corneal intraepithelial neoplasia (CCIN)

47. IMPRESSION CYTOLOGY
• In IC, superficial epithelial cells collected by applying collecting
devices (either cellulose acetate filter papers or Biopore membrane
device
• Cells adhere to the surface and removed from the eye to be fixed,
stained, and then mounted on a slide for analysis
• Nolan et al.
55% of intraepithelial OSSN cases diagnosed by IC had keratinized
dysplastic cells often accompanied by hyperkeratosis
35% -had large syncytial-like groups
10% -had nonkeratinized dysplastic cells as a predominant feature

48. • Importantly, however, it was not possible to differentiate
intraepithelial lesions from invasive squamous cell carcinoma given
the superficial sampling of cells, thus limiting the utility of IC in
diagnosing invasive disease
• Inability of IC to reach deep atypical cells even with repeated
imprints of the same area of the lesion has also been noted in other
studies

49. Recent advances
• Transformed the way OSSN is diagnosed and monitored
• Although there are limitations to each of these imaging modalities
• Can be useful adjunctive tools in the diagnosis of OSSN and could
greatly assist the clinician in the management of OSSN patients
• Nevertheless, anterior segment imaging has not replaced
histopathology's role as the gold standard in confirming diagnosis

50. UBM
• Most useful in assessing intraocular tumor extension and metastasis

51. ASOCT
• Thickened hyperreflective epithelium, abrupt transition from
normal to abnormal epithelium, and a sharp plane of cleavage
between the lesion and underlying tissue

52. IN VIVO CONFOCAL MICROSCOPY
• Allows the sectioning of the ocular surface at the cellular level

54. Treatment
 Conventional standard approach
• Excision with 2–4 mm margins
• Assessment for completeness of clearance, with intraop frozen
section
• Complete histological excision is associated with recurrence of 5–
33%
 Adjunctive measures
• Like cryotherapy, brachytherapy or topical chemotherapy- reduce
recurrence

55. Topical chemotherapy
• Primary modality
-Avoid the scarring and stem cell damage associated with
extensive excision
- To reduce tumour size prior to excision
- To treat recurrence
• Agents include mitomycin C, 5-FU and interferon alfa-2b eye drop
regimens (5-FU and INF alpha-2b - better tolerated)
• Reconstitution of 1 mL of INF alfa-2b (10 million IU/Ml)
9 mL of distilled sterile water
• Stored in refrigeration
• Eyedrops administered 4 times daily until at least 1 month beyond
complete clinical resolution of the tumor

56. PROGNOSIS
• Prognosis quite good
• Local recurrence rate is 5%
• Regional LN metastasis is only about 2%
• Prognosis worse in mucoepidermoid or spindle cell variants and
immunosuppressed eg AIDS

57. 4.Lymphoproliferative lesions
• M/c -reactive lymphoid hyperplasia, a proliferation of both B
and T cells with germinal follicle formation
• Conjunctival lymphoma may arise
-De novo
-Extension from orbital lymphoma
-Associated with systemic lymphoma at
diagnosis (up to 30%)
• Most conjunctival lymphomas- B cell origin
• Arising from mucosa associated lymphoid tissue (MALT) and
tending to be indolent

58.  Symptoms
• Painless swelling, redness or irritation
• Often B/L, when systemic disease is more
likely
• Other symptoms include ptosis and diplopia
 Signs
• Slowly growing salmon-pink or flesh-
coloured
• Mobile infiltrate is seen on the epibulbar
surface or in the fornices
• Rarely, a diffuse lesion may mimic chronic
conjunctivitis
 Biopsy is taken to confirm diagnosis
 Uninvolved eye should also be biopsied
(inferior fornix)

59.  Investigation for systemic involvement
 Treatment
• Systemic disease is treated as indicated, when local conjunctival
measures may not be required
• External beam radiotherapy
• Other options include
-Chemotherapy
-Excision of small lesions with adjuvant treatment
-Cryotherapy and intralesional injections of interferon alfa-2b or
rituximab

60. 5. Kaposi sarcoma
• Slowly growing tumour that is typically
found in patients with AIDS
• Occasionally in elderly and in
immunosuppressed individual
• Infection with kaposi sarcoma associated
herpesvirus/human herpesvirus 8 (KSHV)
Clinical features
• A vascular bright red or purplish plaque or
nodule is seen
• Orbital involvement may produce eyelid and
conjunctival edema

61. • In the conjunctiva, presents as a reddish, highly vascular
subconjunctival lesion that simulate a subconjunctival hemorrhage
• Lesions are most often found in the inferior fornix
• Nodular lesions may be relatively less responsive to therapy
Histology
• Reveals a proliferation of spindle-shaped cells,
vascular channels and inflammatory cells

62. Treatment
• Systemic AIDS therapy should be optimized
• Options for controlling symptoms include surgical debulking,
cryotherapy, and radiotherapy
• Local or systemic chemotherapy
• Intralesional interferon-a2a has been reported to be effective

63. THANK YOU