Conjunctival tumors

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 N aevus M/c melanocytic conjunctival tumour R isk 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 - N aevus 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 P igmented or partially pigmented lesion V ariable 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 M ay show true increase in size in young children May become inflamed especially in children and adolescents Signs of potential malignancy (Indication of early excision) U nusual 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 L ess well defined and patchy area of pigmentation Resembles PAM , differs as it contains subtle clear cysts and occurs in younger individuals 2. Blue naevus B lue 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 P apilloma Viral induced lesion Histopathology - fibrovascular core covered by an irregular proliferation of non-keratinized stratified squamous epithelium containing goblet cells Clinical features Lesions are S essile (wide base and flattish profile)- P edunculated ( 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 - C ryotherapy to the base and the surrounding area Recurrences - S ubconjunctival 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 - E xtending deep to the stroma down to DM without involving it Grade 3 - Least common of all the presenting dermoids - L arger 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 D ellen formation A mblyopia from astigmatism or involvement of the visual axis Small dermoids - simple excision large lesions - lamellar keratosclerectomy Systemic associations Treacher Collins syndrome ( mandibulofacial dysostosis ) M alformation 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 - M acrostomia and microtia - P reauricular and facial skin tags - H emivertebrae (usually cervical) -Mental handicap -Cardiac , renal and CNS anomalies Ocular features - D ermoids - U pper 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 - D ermoid -Ptosis -Cloudy cornea, - L id colobomas , fundus colobomas and - M icrophthalmos

19. 4.Dermolipoma S imilar 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 ‘ M isnomer’ as the lesion is neither pyogenic nor granulomatous F ibrovascular 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 R apidly growing dark pink fleshy conjunctival mass Treatment T opical steroids- often successful R esistant cases – excision Shaving excision at the small base, followed by cautery and cryotherapy , is usually effective D/D S uture granuloma-which can often be large and mistaken for a malignant lesion Tenon capsule granuloma or cyst

23. 6.Benign M elanosis Aka Benign conjunctival epithelial melanosis ( conjunctival hypermelanosis - normal variant) M ore 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 S tatic by early adulthood B/L but asymmetrical Areas of flat, patchy, brownish pigmentation may be seen throughout the conjunctiva, concentrated at - L imbus and - A round perforating branches of vessels or nerves as they enter the sclera P igmented 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 - R apidly 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 I ntra-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 R eserved 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 i rregular golden-brown to dark chocolate- coloured epithelial pigmentation T ypically involving the limbus and interpalpebral region PAM sine pigmento has been reported A ny 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 Conjunctival naevus Benign melanosis Congenital ocular melanocytosis Secondary pigmentation in Addison disease 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 - P rogression 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 M apping 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 M elanoma Rare-2 % of all ocular malignancies Around 75% arise from an area of PAM A bout 20% - pre-existing junctional or compound naevus and rarely de novo 5% Presentation - S ixth decade P atients with the rare dysplastic naevus syndrome develop multiple melanomas at a considerably younger age D/D Naevus Ciliary body melanoma with extraocular extension Melanocytoma P igmented conjunctival squamous carcinoma

36. Appearance Elevated Black or grey vascularized nodule May be fixed to the episclera Common site- Limbus and bulbar conj B ut 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 O ccurs in 20–30% M ain sites are regional lymph nodes, lung, brain and liver Worse prognosis factors Caruncular F orniceal or lid margin location Pagetoid or full –thickness intraepithelial spread T umour 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 - M elanomatous 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 M ay require a modified enucleation and those that extend into the orbit may require orbital exenteration To prevent tumour seeding during excision - C ontact 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 T umour margin involvement L ack of adjunctive treatment

42. 3.Ocular S urface S quamous N eoplasia (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) Mucoepidermoid form Spindle cell form D isplay 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 Conjunctival epithelial dysplasia - dysplastic cells are confined to the basal epithelial layers Carcinoma in situ - dysplastic cells involve the full thickness of the epithelium S quamous cell carcinoma - Invasion of underlying stroma F irst 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 C ells 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 T ransformed the way OSSN is diagnosed and monitored Although there are limitations to each of these imaging modalities C an 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 M ost 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 

53. Treatment C onventional 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

54. Topical chemotherapy Primary modality -Avoid the scarring and stem cell damage associated with extensive excision - T o reduce tumour size prior to excision - T o 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 S tored in refrigeration Eyedrops administered 4 times daily until at least 1 month beyond complete clinical resolution of the tumor

55. 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

56. 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 - A ssociated 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

57. Symptoms Painless swelling, redness or irritation Often B/L, when systemic disease is more likely Other symptoms include ptosis and diplopia Signs S lowly growing salmon-pink or flesh- coloured M obile 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 U ninvolved eye should also be biopsied (inferior fornix )

58. 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 - C ryotherapy and intralesional injections of interferon alfa-2b or rituximab

59. 5. Kaposi sarcoma S lowly growing tumour that is typically found in patients with AIDS O ccasionally 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

60. 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

61. T reatment 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

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