Benign epithelial tumors of the ocular surface include papillomas, which are caused by HPV infection and can be either pedunculated or sessile. Sessile papillomas have a risk of malignant transformation. Malignant epithelial tumors include ocular surface squamous neoplasia (OSSN), which presents as dysplasia or carcinoma in situ and can invade the cornea or globe if not treated with surgical excision or topical chemotherapy. Neuroectodermal tumors of the ocular surface include freckles, benign acquired melanosis (BAM), and primary acquired melanosis (PAM), which has a risk of progressing to conjunctival melanoma. Close monitoring is important to detect malignant transformation

1. Ocular surface neoplasia
Dr Haitham Al Mahrouqi, BMedSc (Hons), MB ChB
Oman Medical Speciality Board

2. Ocular surface
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• Composed of:
• Tear film
• Conjunctiva
• Cornea

3. Ocular surface
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
➢ Conjunctiva

4. Ocular surface
https://entokey.com/conjunctiva-4/
➢ Conjunctiva

5. Ocular surface
https://entokey.com/conjunctiva-4/
➢ Conjunctiva

6. Ocular surface
BCSC 2015: Fundamentals
➢ Cornea

7. Ocular surface
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• Cells found in the ocular surface:
• Epithelium
• Melanocytes and nevus cells
• Vascular endothelium and mesenchymal cells
• Lymphocytes

8. Neoplasia
Arun D Singh Bertil E. Damato, Jacob Pe’er, A. Linn Murphree, and Julian Perry. Clinical Ophthalmic Oncology. Saunders 2014.
• Definition: Cancer is a pathologic accumulation of clonally expanded cells derived
from a common precursor.

9. Neoplasia
• Classification
• Benign
• Malignant

10. Neoplasia
Cause
• The fundamental cause of all cancers is genetic damage that is usually acquired but
is sometimes congenital.
• In general, the genetic dysregulation that gives rise to uncontrolled cell
proliferation results from either activation of growth-promoting oncogenes and/or
deletion/ inactivation of growth-inhibiting tumor suppressor genes.
• Additional contributions to carcinogenesis come from genes that regulate
programmed cell death (apoptosis) and genes involved in DNA repair.

11. Neoplasia
Cause
• Most accepted theory

12. Neoplasia
• Carcinogens

13. Neoplasia
• Carcinogens

14. Neoplasia
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
• “Hallmarks of cancer”

15. Ocular surface
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• Cells found in the ocular surface:
• Epithelium
• Melanocytes and nevus cells
• Vascular endothelium and mesenchymal cells
• Lymphocytes

16. Tumors of epithelial
origin

17. Epithelial tumors

18. Case 1
• 30 year old lady with right eye
localized red lesion. Noticed
since 1 year and has been semi-
stable in size.
• Unremarkable ocular and
medical hx

19. Papilloma
• Benign tumor of the conjunctival
epithelium.
• Two varients:
• Pedunculated
• Sessile
• Cause:
• Pedunculated: HPV 6 (in
children) and 16 (in adults)
• Sissile: HPV 16 or HPV 18

20. Papilloma : Pedunculated
• Children associated with HPV 6
• Multiple
• Clinical features: Exophytic fleshy growth
with fibrovascular core. Typically found in
the inferior fornix or caruncle.
• Histology: fronds of hyperplastic
epithelium with goblet cells and
fibrovascular core.
• Management: Self involutes in months to
years. May need excision if irritating or
diagnosis is in doubt.

21. Papilloma : Sessile
Eyelid, Conjunctival, and Orbital Tumors and Intraocular Tumors An Atlas and Text (Sheilds)
• Adults associated with HPV 16
• Clinical features: flat fleshy growth with
fibrovascular core. Typically found at
limbus.
• Histology: Hyperplastic epithelium with
goblet cells and fibrovascular core.
• Management:Difficult to distinguish from
a malignant form. Therefore needs
monitoring.

22. Papilloma : Sessile
Honavar SG, Manjandavida FP. Tumors of the ocular surface: A review. Indian Journal of Ophthalmology. 2015;63(3):187-203. doi:10.4103/0301-
4738.156912.
• Sessile papilloma may become malignant.
• Signs of malignancy include: leukoplakia, inflammation and symblepharon.

23. Papilloma : Sessile
Honavar SG, Manjandavida FP. Tumors of the ocular surface: A review. Indian Journal of Ophthalmology. 2015;63(3):187-203. doi:10.4103/0301-
4738.156912.
Management:
• Very close observation for any worrisome signs of malignant transformation.
• Medical treatment include:
• Topical mitomyocin C or interferon ⍺2b
• Oral cimitidine
• If excision warranted:
• Excision with minimal manipulation of the healthy conjunctiva.
• Adjunctive cryotherapy

24. .

25. Case 2
• 60 year old caucasian man,
smoker, construction
worker with recurrent right
eye redness.

26. OSSN : Replacing conjunctival intraepithelial
neoplasia (CIN)
Lee GA, Hirst LW. Ocular surface squamous neoplasia. Survey of Ophthalmology 1995;39(6):429-50
AAO BCSC 2015: Ophthalmic Pathology and Intraouclar Tumours.
The term OSSN first used
by Lee at el. In 1995:
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.

27. OSSN
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• Typically arises adjacent to the limbus, over a preexisting pinguecula, that is, over
an area of solar elastosis, similar to actinic keratoses of the skin, Hence UV light as
a risk factor.
• Other risk factors are:
• HPV
• HIV
• Xeroderma pigmentosa

28. Conjunctival/corneal intraepithelial neoplasia (CIN)
variants:
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
There are 3 principal clinical variants of CIN :
• Papilliform, in which a sessile papilloma
harbors dysplastic cells.
• Gelatinous, as a result of acanthosis and
dysplasia.
• Leukoplakic, caused by hyperkeratosis,
parakeratosis, and dyskeratosis

29. Corneal intraepithelial neoplasia
(CIN)/SCC
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• A granular, translucent, gray epithelial sheet broadly
based at the limbus extends onto the cornea. The
edges of corneal lesions have characteristic
fimbriated margins and pseudopodia-like
extensions.
• Rose bengal and lissamine green staining help
define the edges of the lesion.
• Corneal neovascularization does not typically
occur, which helps differentiate CIN lesions from
limbal stem cell failure.
• CIN and squamous cell carcinoma have similar
clinical picture.

30. OSSN: Histology
AAO BCSC 2015: Ophthalmic Pathology and Intraouclar Tumours.
The epithelium exhibits hyperplasia, loss
of goblet cells, loss of normal
cell polarity, nuclear hyperchromasia
and pleomorphism, and mitotic
figures. There is
often surface keratinization, correlating
with the leukoplakia observed clinically.

31. OSSN
AAO BCSC 2015: Ophthalmic Pathology and Intraouclar Tumours.
• Rarely invades the globe
• If it does, commonly occurs are
previously violated sites: e.g. cataract
surgery, PPV.
• If non-violated structures, invasion
occurs in cases of immunosuppression
or neglected highly invasive lesions.

32. OSSN: Epidemiology
Radhakrishnan A. Ocular Surface Squamous Neoplasia [OSSN] - A Brief Review. KSOS 2011; XXIII(4)
➢ Third most common ocular tumor after melanoma,
lymphoma.
➢ Australia: OSSN accounts for 10% of all pterygia excised.

33. Assessment:
Examination
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumors.
• Site of pre-existing pterygium (nasally).
• Corckscrew and feeding vessels
• Leukoplaqia
• Pigmentation can occur in dark skinned patients
• Invasion to the cornea or globe
• Lymphadenopathy

34. Diagnosis
➢ Clinical suspicion followed by:
❑ impression cytology: 80% sensitive
❑ Incisional/Excisional biopsy
Mittal R, Rath S, Vemuganti GK. Ocular surface squamous neoplasia – Review of etio-pathogenesis and an update on clinico-pathological diagnosis.
Saudi Journal of Ophthalmology 2013;27(3):177-86.

35. Investigations
➢ Rarely metastasizes
➢If any suspicion: imaging including AS-OCT, UBM,
CT/PET.
AAO BCSC 2015:External diseases and Cornea.

36. Treatment
Ref:
AAO BCSC 2015:External
diseases and Cornea.
➢ Invasion of the globe or
eyelids: enucleation or
exenteration.

37. Treatment
Radhakrishnan A. Ocular Surface Squamous Neoplasia [OSSN] - A Brief Review. KSOS 2011; XXIII(4)
• If topical chemotherapeutic agents are used:
• Punctal occlusion
• Avoid in pregnancy
• Side-effects;
• Ocular surface toxicity
• Epithelial defects
• Cataract
• Punctal stenosis

38. Video

39. Prognosis
• Recurrence rate 30-50% if margins of specimen are
involved.
• Recurrence is only 12% if cryo used along with
excision.
• Recurrence is only 5% if free margins.
AAO BCSC 2015:External diseases and Cornea.

40. Aggressive variants of OSSN
• Mucoepidermoid carcinoma
• Spindle cell carcinoma
Kapur R, Sugar J, Edward DP. Conjunctival Mucoepidermoid Carcinoma: Clear Cell Variant. Arch Ophthalmol.2005;123(9):1265–
1268. doi:10.1001/archopht.123.9.1265

41. Summary epithelial tumors
• Benign:
• Papillomas
• Pedunculated: Children, HPV 6, benign
• Sessile: Adults, HPV 16, can be pre-invasive
• Malignant:
• OSSN (CIN to SCC) : Treated with surgical excision or topical
chemotherapy. Rarely metastasizes.
• Other aggressive variants: Mucoepidermoid and spindle cell
carcinomas.

42. Tumors of neuroectodermal
origin

43. Neuroectodermal tumors

44. Epithelial neuroectodermal tumors:
Freckles
• A conjunctival freckle, or ephelis,
is a flat brown patch, usually of
the bulbar conjunctiva near the
limbus.
• It is more common in darkly
pigmented individuals and is
present at an early age.

45. Epithelial neuroectodermal tumors: Benign acquired
melanosis (BAM or racial melanosis)
• Seen in dark complexion people.
• Bilateral
• Flat lesions
• Involves bulbar conjunctiva

46. Epithelial neuroectodermal tumors: Primary
acquired melanosis (PAM)
• Seen in light complexion people.
• Unilateral
• Flat lesions
• Involves bulbar conjunctiva, but higher risk of malignancy if involves the caruncle, fornix or
palpebral conjunctiva.
• PAM with atypia progresses to conjunctival melanoma in 36%-75% of cases

47. Epithelial neuroectodermal tumors: Primary
acquired melanosis (PAM)
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumors.

48. Epithelial neuroectodermal tumors: Primary
acquired melanosis (PAM)
1. Lesion diameter 5 mm; or > 3 clock hours
2. Documented progression of the lesion;
3. Thickness of the lesion;
4. Distinct nodule arising within the lesion
(pigmented or
nonpigmented);
5. Nutrient vessels to the lesion;
6. Involvement of the cornea;
7. Involvement of palpebral conjunctiva;
8. Dysplasic nevus syndrome in the affected
patient or close
relatives
9. Personal history of cutaneous or uveal
melanoma; and
10. Patient cancerophobia.
Eyelid, Conjunctival, and Orbital Tumors and Intraocular Tumors An Atlas and Text (Sheilds)
When to biopsy?

49. Sub-epithelial neuroectodermal tumors: ocular
melanocytosis
• Congenital
• Unilateral
• Melanocytes deep in the episclera/sclera
• Can involve the skin where it is called
oculodermal melanocytosis (naevus of ota)
• Both ocular and oculardermal melanocytosis
are risk factors for secondary glaucoma.
• Increased risk of uveal melanoma (1/400) in
ocular melanocytosis and orbital and CNS
melanomas in oculodermal melanocytosis.
• The increased risk of melanomas seems to
occur in fair complexion people.
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumors.

50. Naevi
• Some consider them as hamartomas.
• Most common conjunctival hamartoma/neoplasm
• Congenital, although may acquire pigmentation and enlarge after puberty.
• Three stages of evolution histologically (some consider them as types):
• Junctional
• Complex
• Sub-epithelial
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumors.

51. Naevi
• Three stages of evolution histologically (some consider them as types):
• Junctional
• Complex
• Sub-epithelial

52. Naevi

53. Naevi
• Naevi are usually benign. Malignant transformation in < 1%
• Management:
• F/U in 6 - 12 months with serial photographs
• Biopsy/excision is warranted if:
• Location: Palpebral, fornicial or caruncular mass
• Growth
• Feeder vessel
• Recurrence after excision

54. Conjunctival melanoma
• Rare: 1 in 2 million people
• 1% of ocular malignancies
• Rare in dark complexion people
• Conjunctival melanomas may arise from PAM with atypia (70%) or nevi (20%) or may arise de novo
(10%)
• 25% are amelanotic. Recurrent melanomas are usually amelanotic.
• Associated with dysplastic nevus syndrome, xeroderma pigmentosa.
• Although malignant melanoma ofthe conjunctiva has a better prognosis than cutaneous melanoma,
the overall mortality rate is 25%
• Regional metastasis to pre-auricular and submandibular lymph nodes, distant metastasis to brain,
liver, bone.
Eyelid, Conjunctival, and Orbital Tumors and Intraocular Tumors An Atlas and Text (Sheilds)

55. Conjunctival melanoma
Eyelid, Conjunctival, and Orbital Tumors and Intraocular Tumors An Atlas and Text (Sheilds)

56. What imaging modality does this patient need?

57. Conjunctival melanoma:
Management
Surgical steps: (similar in OSSN):
• Classic limbal lesions are best removed primarily by alcohol corneal
epitheliectomy
• Wide partial lamellar sclero- conjunctivectomy with 4mm clear margin.
• Double freeze thaw cryotherapy to the margins and cautery + absolute alcohol to
the base

58. Conjunctival
Melanoma: Plaque
Radiotherapy for
Advanced,
Recurrent Tumor

59. Conjunctival melanoma:
Prognosis
Poor prognostic indicators include :
• location in the palpebral conjunctiva, caruncle, or fornix
• invasion into deeper tissues
• thickness >1.8 mm
• involvement of the eyelid margin
• pagetoid or full-thickness intraepithelial spread
• lymphatic invasion
• mixed cell type

60. Summary: Conjunctival pigmentary
lesions

61. Do you still remember!
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• Cells found in the ocular surface:
• Epithelium
• Melanocytes and nevus cells
• Vascular endothelium and mesenchymal cells
• Lymphocytes

62. Tumors of vascular
endothelium and mesechymal
cells

63. Tumors of vascular endothelium and mesechymal
cells

64. Tumors of vascular endothelium and mesechymal
cells: Capillary hemangioma
• Considered the most common hamartoma/vascular
malformation
• Most commonly occurs in the eyelid with a conjunctival
extension
• Grows in the first year and regresses by 4-5 years
• Treatment:
• Observation for spontaneous resolution
• Amblyopia therapy
• Intra-lesional steroid
• Systemic propranolol
• Surgical excision

65. Tumors of vascular endothelium and mesechymal
cells: Pyogenic granuloma
• Not pyogenic and not granuloma
• It is an exuberant granulation tissue
• Result from an insult: e.g. trauma, surgery, suture
• Rapid onset
• Fleshy vascular mass.
• Treatment: Topical steroids or surgery

66. Do you still remember!
AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumours.
• Cells found in the ocular surface:
• Epithelium
• Melanocytes and nevus cells
• Vascular endothelium and mesenchymal cells
• Lymphocytes

67. Tumors of the lymphatic
tissue

68. Tumors of vascular endothelium and mesechymal
cells: Lymphangioma/lymphangiectasia
• Dilated lymphatic channels, can be:
• flat (lymphangiectasia) or lobular (lymphangioma)
• Cystic or hemorrhagic (anomolous connection with
venules)

69. Tumors of vascular endothelium and mesechymal
cells: Lymphoma
• Basics
• Mucosal associated lymphoid tissue / follicles

70. Tumors of vascular endothelium and mesechymal
cells: Lymphoma
• Lymphoproliferative conjunctival tissue can be
benign or malignant.
• Clinically difficult to distinguish. Both have salmon
patch appearance and unilateral or bilateral.
• Incisional biopsy is advised.

71. Tumors of vascular endothelium and mesechymal
cells: Lymphoma
• Conjunctival lymphoma is mostly extranodal marginal zone lymphoma (formerly known as
MALToma)
• Low grade B-cell lymphoma
• 2/3 are not associated with systemic lymphoma
• Treatment:
• No systemic involvement: Radiotherapy
• Systemic involvement: Chemotherapy
• Some cases are associated with chlamydial infection similar to H.pylori in gastic
lymphoma, therefore treatment using doxycycline.

72. References
➢ Donaldson MJ, Sullivan TJ, Whitehead KJ, Williamson RM. Squamous cell carcinoma
of the eyelids. British Journal of Ophthalmology 2002;86(10):1161-65
➢ Cook BE, Bartley GB. Epidemiologic characteristics and clinical course of patients
with malignant eyelid tumours in an incidence cohort in Olmsted County,
Minnesota. Ophthalmology 1999;106:746–5
➢ Loeffler M, Hornblass A. Characteristics and behavior of eyelid
carcinoma. Ophthalmic Surg 1990;21:513–18
➢ AAO BCSC 2015: Ophthalmic Pathology and Intraocular Tumors (Volume 4) and
Orbit, Eyelids and Lacrimal System (Volume 7).
➢ Honavar SG, Manjandavida FP. Tumors of the ocular surface: A review. Indian
Journal of Ophthalmology. 2015;63(3):187-203. doi:10.4103/0301-4738.156912.
➢ Eyelid, Conjunctival, and Orbital Tumors and Intraocular Tumors An Atlas and Text
(Sheilds)

73. QUIZ

74. Which ocular/orbital lymphoma has the highest chance
of systemic involvement?
• Eyelid
• Orbit
• Conjunctiva

75. What is this tumor?

76. What is the name of this?

77. Diagnosis?

78. Diagnosis?
• Dark skinned with bilateral eye involvement

79. Diagnosis?

80. Is this malignant?

81. How will you treat this lesion?

82. Thanks

83. Topical chemotherapeutic agents