PAG. 27-42 03-MRW407 ingles - OFTALMO

CONJUNCTIVAL TUMORS

TUMORES DE LA CONJUNTIVA

SAORNIL MA1, BECERRA E2, MÉNDEZ MC3, BLANCO G4

Received: 26/6/07. Accepted: 7/1/09.CSUR Ocular Oncology Unit of the National Health System. University Clinical Hospital of Valladolid. Miguel N Burnier Ocular PathologyRegistry. Institute of Applied Ophthalmobiology. University of Valladolid. Spain.At the time of writing the article, all the authors were members of the Miguel N Burnier Ocular Pathology Registry.1 Ph.D. in Medicine. University Clinical Hospital of Valladolid. Spain.2 Graduate in Medicine. Scholar of the Carolina Foundation in IOBA2005. Valladolid. Spain.3 Ph.D. in Medicine. Pathological Anatomy Dept. of Valladolid University. Valladolid. Spain.4 Ph.D. in Medicine. Río Hortega University Hospital. Valladolid. Spain.

Correspondence:M. A. SaornilHospital Clínico UniversitarioRamón y Cajal, 347005 ValladolidSpainE-mail: [email protected]

RESUMEN

Los tumores de la conjuntiva son unos de los másfrecuentes del ojo y anejos. Abarcan un amplioespectro desde lesiones benignas como el papilomaa otras malignas que pueden poner en peligro lafunción visual y la vida del paciente, como el carci-noma epidermoide y el melanoma. Pueden surgir decualquiera de las células que componen la conjunti-va aunque los más frecuentes son los de origen epi-telial y melanocítico. El diagnóstico precoz es fun-damental para prevenir la extensión ocular y sisté-mica y para preservar la función visual. En este artí-culo se revisan las características clínicas de lostumores conjuntivales más frecuentes y se discutesu tratamiento.

Palabras clave: Tumores conjuntivales, neoplasiaintraepitelial, nevus, melanoma, linfoma.

ABSTRACT

Conjunctival tumors are one of the most frequent ofthe eye and adnexa. They comprise a large varietyof conditions, from benign lesions such as nevus orpapiloma, to malignant lesions such as epidermoidcarcinoma or melanoma which may threaten visualfunction and the life of the patient. They can arisefrom any cellular component, but the most frequentare of epithelial and melanocytic origin. Early diag-nosis is essential for preventing ocular and systemicspread and to preserve visual function. In this paperwe review the clinical characteristics of the mostfrequent conjunctival tumors, and we discuss tumormanagement (Arch Soc Esp Oftalmol 2009; 84: 7-22).

Key words: Conjunctival tumors, intraepithelialneoplasia, nevus, melanoma, lymphoma.

ARCH SOC ESP OFTALMOL 2009; 84: 7-22 REVISION

EPIDEMIOLOGY ANDCLASSIFICATION

Conjunctival tumors are one of the most frequentof the eye and adnexa. They comprise a large vari-ety of conditions, from benign lesions such as papil-loma to malignant lesions such as epidermoid carci-noma or melanoma which may threaten visual func-

tion and the life of the patient if not diagnosed ear-ly (table I) (1,2). Conjunctival tumors may arisefrom any of the cells comprising the conjunctiva,although the most frequent ones are of epithelialand melanocytic origin (Table I). Epithelial tumorsaccount for a third to half of all tumors, with preva-lence being higher in countries with larger actinicexposure. As regards melanocytic tumors, most are

benign with variations according to the ethnic pig-mentation and age of patients (1,2).

At the Ocular Oncology Unit of the ValladolidUniversity Hospital 314 conjunctival tumors havebeen diagnosed, of which 149 (48%) weremelanocytic (87% benign), 124 (39.6%) of epithe-lial origin (64.5% pre-cancerous), 30 (9.6%) origi-nated in soft tissue and 10 (3.2%) of the lymphoidtype (3,4). In the majority of cases, the clinical dif-ferentiation between pre-cancerous benign andmalign lesions is difficult, requiring a biopsy for adefinitive diagnostic. On many occasions the biop-sy is also therapeutic as it involves complete extrac-tion in the case of circumscribed lesions (excision-al biopsy).

ANATOMICAL-HISTOLOGICALUPDATE

The conjunctiva is a thin and flexible mucousmembrane that extends from the internal surface ofthe eyelids (palpebral) to the fornix and the anteriorsurface of the ocular globe (bulbar) up to the scle-rocorneal limbus (limbar). Its functions include

contributing to the pre-corneal lachrymal film bymeans of producing the mucosal layer, as well asbeing an important barrier for foreign bodies andinspections, and limbar zone for maintaining thecorneal epithelium. It received vascularization frombranches of the margin on arches of the eyelids(tarsal) and the anterior ciliary arteries (bulbar). Thelymphatic connections of the conjunctival run par-allel to those of the eyelids, draining the pre-auric-ular and sub-mandible lymphatic nodes, and thesensory enervation is derived from the V cranialpair (1,2,5,6).

Histologically (5,6) the conjunctiva is similar toother mucous membranes and comprises a non-ker-atinized stratified epithelium having two or morelayers over a stroma formed by fibrovascular con-nective tissue containing vessels, nervous and lym-phatic tissue (fig. 1). The basal layer of the epithe-lium comprises melanocytes which producedmelamine and inject it in the surrounding cells.Throughout the length of the epithelium we canobserve cup-shaped cells in charge of producing themucoid component of the lachrymal film. Thesecells are more numerous in the lower nasal portionof the bulbar conjunctiva. In the internal edge wefind the half-moon fold and the carbuncle where we

8 ARCH SOC ESP OFTALMOL 2009; 84: 7-22

SAORNIL MA, et al.

Table I. Classification of conjunctival tumors based on origin

Origin Benign Pre-cancerous Malign

Epithelial * Papillomas * Actinic keratosis * Squamous Ca.* Pseudoepitheliomatous hyperplasia * ICN: Intraepithelial neoplasia * Mucoepidermoid Ca.

* Ca. Basocellular

Melanocytic * Nevus without atypia * Nevus with atypia * Melanoma* Racial Pigmentation * Acquired Melanosis 1st with atypia* Ocular Melanocytosis* Secondary Melanosis* Acquired Melanosis 1st without atypia

Secondary glands * Oncocytoma * Sebaceous Adenocarcinoma* Pleomorphic Adenoma* Apocrine Adenoma* Sebaceous Adenoma

Soft tissue * Pyogenic Granuloma * Kaposi’s Sarcoma* Hemangioma * Fibrous Histiocytome* Lymphangioma * Rabdomyosarcoma* Fibroma* Mixoma* Osteoma

Lymphoid * Lymphoid Hyperplasia * Lymphoma* Leukemia* Plasmocitoma

can find thin pilous follicles and sebaceous glands,and even secondary lachrymal glands.

Throughout the bulbar conjunctiva and up to thesub-tarsal folds of the eyelids there is a lymphoidlayer which, in some areas, forms specialized aggre-gates known as Conjunctival-associated LymphoidTissue -CALT- corresponding to the Mucosa-associ-ated Lymphoid Tissue -MALT-) from other regionsof the body, formed by aggregates of T- and B- lym-phocytes related to the anti-genic informationprocess (5-7).

EPITHELIAL TUMORS

Benign

Squamous Papilloma. Expresses as exophyticlesions, pink color, soft to the touch and irregularsurface. It can be of viral origin (human papillo-mavirus) in which case it can recur. It tends to bepedunculate in children (more frequent in lowerfornix) and short in adults (more frequent in bulbarconjunctiva). It is generally non-symptomatic andfree of associated inflammation signs. At the clini-cal level, it can be difficult to differentiate from pre-cancerous and carcinomatous lesions. Histological-ly, it consists in connective-vascular axes coveredby acanthoic conjunctival epithelium without signsof atypia (fig. 2) (1,2,8).

Pseudo-epitheliomatous or pseudo-carcino-matous Hyperplasia. This is an epithelium hyper-plasia which is reactive to inflammation or chronicirritation processes. The source of the inflammation

is usually a pre-existing pterygium with chronicinflammation wherein the epithelium begins to pro-liferate and keratinize. Clinically it consists in araised, pinkish, rapidly growing mass similar to acarcinomatous lesion which may appear leukopla-kic. Histologically, the epithelium proliferatesforming lobules and exhibits an increased mitoticactivity secondary to the inflammation. It can bedifferentiated from the squamous carcinoma by theabsence of nuclear atypia and the marked underly-ing stromal inflammation. A variant of this lesionwith rounded morphology, abrupt and raised edgesis the keratoacanthoma (1,2).

Precancerous

Actinic keratosis. This a leukoplakic lesionwhich is well circumscribed, raised and limbic andgrows slowly on the epithelium of the inter-palpe-bral area, generally over a pre-existing pterygium. Itmay simulate a carcinoma. Histologically it is char-acterized by acanthotic and hyper-kerathotic epithe-lium with abrupt edges and different degrees of cel-lular atypia which rarely comprises the entireepithelium (slight or moderate displasia) andelasthotic degeneration in the stroma. It can evolveto become a conjunctiva squamous carcinoma,although this is highly infrequent (fig. 3) (1,9).

Intraepithelial neoplasia: In situdisplasia/carcinoma. This is one of the most fre-quent tumors of the ocular surface, with an approx-imate prevalence of 2 cases /100.000 per year.Clinically it appears in 60-70 year-old patients withpale skin. It can also appear in young people withimmune depression and can be bilateral. It is a gel-like lesion, short or papillomatous with a tendencyto superficial diffuse extension, generally in the

9ARCH SOC ESP OFTALMOL 2009; 84: 7-22

Conjunctiva tumors

Fig. 1: Normal conjunctival histology: non-keratinizedstratified epithelium with melanocytes in the basal layerand cup-shaped cells which have a positive dye with PASdye (40x).

Fig. 2: Squamous Papilloma: A: short lesion in bul-bar conjunctiva, pinkish and richly vascularized. B:Histopathologically we observe acanthosic epitheliumaround connective-vascular axes (Hematoxiline eosinHE4x).

inter-palpebral groove, affecting the limbus withpoorly defined edges. It usually extends over thecorneal epithelium. Pathogenically, it is akin to dis-plasia which appears in non-exposed mucous. Thehuman papillomavirus is involved in its develop-ment (even more so in immune-suppressed patientsor with bilateral disease). Also involved is theacquired immunodeficiency virus, solar exposureand environmental factors such as exposure topetroleum derivatives, industrial oil, tobacco, etc.(fig. 4) (2,10.11).

The clinical appearance is a consequence of thehistological changes consisting in the appearance ofa epithelial hyperplasia in varying degrees wherethe corneal epithelium (full or partial thickness) issubstituted by a proliferation of atypical cells (dis-plasia) which begins in the basal layers of theepithelium and may involve the epithelium partial-ly (slight, moderate and severe displasia) or fully(in situ carcinoma). The term ICN (conjunctivalintraepithelial neoplasia) includes the various

degrees of displasia (slight, moderate or severe)(fig. 5) and the in situ carcinoma (fig. 6), meaningthat these entities are different levels of the develop-ment range of an intraepithelial neoplasia, consid-ered as a pre-cancerous lesion, because if the atyp-ical cells break the basal membrane and invade thesub-conjunctival tissue, the result is the conjunctivainvasive squamous carcinoma (1,9,10). The risk ofdeveloping squamous carcinoma is low but proba-bly greater than the risk of developing actinic ker-atosis.


SAORNIL MA, et al.

Fig. 3: Actinic keratosis. A:, Raised and leukoplakiclimbic lesion. B: Acanthotic epithelium with slight dis-plasia and superficial keratinization conferring the leu-koplakic appearance (HE4x).

Fig. 4: Intra-epithelial conjunctival circumscribed neoplasia: limbic, exophytic, vascularized lesions with well-defi-ned limits which invade the cornea.

Fig. 5: Conjunctival intraepithelial neoplasia with seve-re displasia extending beyond 2/3 the epithelial thicknessbut respecting the superficial layers and basal membra-ne (HE40x).

Due to the lack of precise limits and the tenden-cy towards diffuse growth, incomplete resection iseasier than in actinic keratosis, giving rise to fre-quent relapses. Compared with similar lesions inother locations, its development is relativelybenign as it usually is restricted to the epitheliumand rarely becomes invasive. For the most part,these lesions do not follow the course of a trulymalign tumor which is invasive and metastasizing,with the surface extension and recurrences creatinga bigger problem than the risk of systemic exten-sion. Early diagnostic is important because theexcisional biopsy with resection margin, with orwithout supporting treatment, is usually definitive.However, advanced lesions can extend throughout

the cornea and a large part of the conjunctiva,obstructing complete removal and jeopardizing thevisual function and requiring complex surgery andcoadjuvating therapies such as topical chemothera-py (Mitomycin C, 5-Fluorouracyl, Interferon alfa-2b) (12-17) (fig. 7).

Malign

Squamous carcinoma. This growth originatesfrom actinic keratosis and intra-epithelial neopla-sia. It appears when an in situ carcinoma breaksthe basal membrane and invades the subconjunc-tival tissue, accessing lymphatic vessels and


Conjunctiva tumors

Fig. 6: Diffuse Intraepithelial Conjunctival Neoplasia. A: diffuse, elevated and vascularized conjunctival lesion cove-ring the entire corneal surface. B: Conjunctiva in situ carcinoma. Epithelial hyperplasia with displasia extending toall the epithelium layers (HE10x).

Fig. 7: Diffuse corneal-conjunctival intraepithelial neoplasia of >1 year of evolution (A) and post-treatment with par-tial excision-biopsy of 2/3 of the lesion and treatment of the residual matter with topical Mitomycin C (B).

becoming potentially metastasic. Clinically, itexpresses as an exophytic lesion, short or pedun-culated in the inter-palpebral exposure area, withvariable appearance, frequently close to the lim-bus, with slow growth. In its natural evolution itcan occupy the entire conjunctival bulbar area andfrom there extend through the orbitary septum,invading the orbit (fig. 8). Alternatively it caninvade the sclero-corneal lamella penetrating inthe ocular globe (18,19). However, in most casesit tends to be only superficially invasive and tohave a relatively benign course. Even though itaccesses lymphatic vessels metastatic disease israre: percentages found in literature are around1%. Immuno-suppressed patients (organ trans-plant, AIDS) are at greater risk of developing thiscarcinoma, and in these cases it is more aggres-sive and with higher potential for metastasis(1,2,20).

Histologically, most carcinomas are well differ-entiated, with exophytic growth of epithelial cells.In more advanced tumors the matter usuallyexhibits inflammation containing niches of atypicalcells with hyperplasic hyper-chromatic nuclei,diskeratosis, cornea pearls (collections of kera-tinized cells) and atypical mitosis (1,2,5).

Fusiform squamous carcinoma. This carcino-ma is rare and much more aggressive, expressing ashighly aggressive flat lesions with a tendencytowards intra-ocular penetration, sometimes simu-lating peripheral corneal ulcers. Histologically, thecells are fusiform and pleomorphic, with a hyper-chromatic nucleus, sometimes difficult to differen-tiate from fibroblasts leading to the possibility of anerroneous diagnostic as fibrous histiocytomes orfibrosarcoma. Positive immune-histochemical stud-ies for cytokeratines confirm the epithelial nature ofthis tumor (21).

Mucous-epidermoid carcinoma. This carci-noma is rare and generally appears in elderly peo-

ple, being more aggressive than squamous carci-noma and with a tendency to invade the ocularglobe and the orbit. It usually appears in the con-junctival sac fundus, exhibiting a yellowish glob-ular component due to the mucous-secreting cellscomponent. Its histological characteristics arethose of an epithelial neoplasia containing a vari-able proportion of mucus-secreting cells and onsome occasions areas of differentiation to adeno-carcinoma (1).

Treatment of epithelial tumors

The objectives in treating conjunctival tumorsare:

• To completely destroy or extirpate the tumorby means of surgery and adjuvating treatments ifprescribed and necessary (cryotherapy, topicalchemotherapy, radiotherapy).

• Carry out a precise histopathological diagnos-tic because at the clinical level it is very difficult todistinguish benign, pre-cancerous and malignlesions. Diagnostic confirmation will allow for theright therapeutic approach, as well as prognosis andfollow-up.

• Minimizing recurrencesTo achieve the above, a complete pre-op assess-

ment must be made, including a highly precise clin-ical approach to the diagnostic: whether the lesionis circumscribed or diffuse, bilateral or unilateral,suspected to be pre-cancerous or malign. The exten-sion of the tumor must also be assessed, determin-ing the existence of intra-ocular and/or orbitaryinvasion, carrying out a palpation of regional lym-phatics and, when considered appropriate, a sys-temic extension study for detecting metastasis(which are rare) (22).

In general, for tumors which are circumscribed,limbar or conjunctival bulbar, complete extirpation(excisional biopsy) with the smallest possibleamount of manipulation and a resection margin of3-5 mm could be sufficient treatment. Bowman’slayer should be respected because its removalwould facilitate the intraocular penetration of anyrecurrence. Cryotherapy and controlling the resec-tion edges by means of intra-op biopsies haveproved to diminish recurrences in pre-cancerousand malign lesion cases (20.22-24).

In diffuse and extended lesions where com-plete resection is difficult, the largest possible


SAORNIL MA, et al.

Fig. 8: Conjunctival squamous carcinoma with invasionof orbit in the nasal area (A). The neoplasic cells haveruptured the basal membrane and invaded the sub-con-junctival tissue (B) (HE4x).

extirpation must be made which must also allowfor a precise histopathological diagnostic. If theresection is too large, autologous conjunctival orbucal mucosa grafts can be implanted. For theresidual tumor adjuvating therapies can beemployed such as topical chemotherapy (Mito-mycin C, 5-Fluoruracyl, interferon) and alsoradiotherapy (25,15-17).

In the case of intra-ocular invasion, enucleation isprescribed. If there also is anterior orbitary inva-sion, anterior exenteration must be performed, pre-serving the eyelids provided the palpebral conjunc-tiva is not affected.

MELANOCYTIC TUMORS

Pigmented conjunctival tumors account forabout half of conjunctival tumor lesions (1,2) andmainly affect white patients. These tumors arederived from melanocytes which migrate from theneural crest during embryological development tothe epithelium and sub-conjunctival tissue.Epithelial melanocytes are located at the basallayer and account form most of pigmented con-junctival lesions, causing a range of alterationsfrom benign lesions such as conjunctiva nevus tomalign and potentially mortal conditions such asthe conjunctival melanoma. The clinical andhistopathological identification of these lesions isimportant for their correct treatment (26-27) asbenign lesions treated as malign will mean unnec-essary treatments, while undervalued melanomaeor melanosis which are not treated early lead to areduction in the patient’s vital prognosis as theyevolve towards melanomas having a mortality rateof 25% after 5 years (26).

Benign

Congenital/acquired Nevus. This is the mostcommon melanocytic lesion of the conjunctiva. Itis congenital and expresses clinically duringchildhood as a circumscribed, flat, scarcely pig-mented, slightly elevated lesion in the inter-palpe-bral bulbar conjunctiva (fig. 9). It usually increas-es in pigmentation and form cysts in the seconddecade of life, at which time the patient generallyvisits the ophthalmologists practice (fig. 9B). Asof this stage, the nevus remain stable during adultlife and any change in size, color, edges orappearance must lead us to suspect its maligntransformation into melanoma, but this occurs inunder 1% of cases (fig. 9C). Its characteristiclocation is the bulbar conjunctiva, but it also canappear in the juxta-limbar area and in the carun-cle. It moves freely over the sclera but does notextend over the cornea. Exceptionally it is foundin the sac fundus and tarsal conjunctiva, so anylesion in these locations must be considered as amelanoma or precursor thereof and biopsied. Asregards pigmentation, it varies broadly from lightbrown to dark chocolate, and 30% are not pig-mented (1,26-28).

Histologically, this nevus undergoes evolution-ary changes as those in the skin, evidenced in theclinical changes described above. In the initialstage, the niches of nevus cells are in the basal lay-er (epithelial nevus) to appear later on in the inter-face between the epithelium and the stroma (junc-tional nevus). In its evolution, the niche of nevuscells penetrate the stroma (composite nevus),dragging epithelial cells which can form pseudo-cysts to end up locating only in the sub-conjuncti-val tissue (subepithelial or stromal nevus)(1,22,24) (fig. 10).


Conjunctiva tumors

Fig. 9: conjunctiva nevus in the first decade of life (A), in the adult, with characteristic cysts (B) and with changes incolor and edges, suspected malignization (C).

Racial pigmentation. In African and dark-skinned subjects it is frequent to find more pigmen-tation in the conjunctival epithelium. This pigmentis more prominent in the inter-palpebral fissure, isusually bilateral, it moves over the ocular globe sur-face and it can be marked in the limbus and extendto the peripheral cornea. Microscopically, it is char-acterized by a uniform hyper-pigmentation of theconjunctiva epithelium basal layer.

Ocular melanocytosis . This condition is theresult of the incomplete migration of melanocytesfrom the neural crest, which do not reach the con-junctiva and may appear in the uvea, sclera, episcle-ra, optic nerve, meninges and the eyelid skin. Ifonly the ocular globe is involved, it is called Con-genital ocular melanosis or Melanosis Oculi.When the pigmentation reaches the skin of the eye-lid, it is called Oculodermic melanocytosis orNevus of Ota.

Clinically, it is unilateral and appears as a dif-fuse episcleral bluish-gray pigmentation. Theedges of the pigmentation do not move with the

conjunctiva (fig. 11), it is spiculated and themelanocytes surround and limit the lymphaticsand blood vessels. The ipsilateral uvea and irisusually have a darker color, producing heterochro-mia of the iris and the eye fundus (fig. 11B). His-tologically, the melanocytes are uniformly but notintensely pigmented and are located in the scleraand episclera more than in the conjunctiva.Although this entity exhibits greater risk for thedevelopment of orbit and uvea glaucoma andmelanoma (1/400), it does not pose a risk for con-junctival melanoma as there is not a single casedescribed in the literature (29,30).

Secondary acquired melanosis. This is theincrease of conjunctival pigmentation due to differ-ent causes such as metabolic diseases (for ex.,Addison’s disease), deposits due to topicallyinstilled drugs, irradiation, inflammation, hormonalchanges or chronic conjunctival disorders. Thismelanosis does not predispose to the developmentof melanoma. Histologically, the normal epitheliummelanocytes become excited, proliferate and pro-duce melanine.

Pre-cancerous

Nevus with atypia. As described above, nevusare benign lesions with cells which may undergo amalignant transformation, generally in adult lifeover 40. associated to changes in clinical morphol-ogy that, without treatment, usually evolves tomelanoma (fig. 9C) (28).

Primary acquired melanosis (PAM). This is amulticentric, acquired, unilateral, epithelialmelanocytic proliferation which appears in adultsand affects predominantly white and light-skinned people. In literature it is referred to in anumber of ways, including Reese precancerous


SAORNIL MA, et al.

Fig. 10: Optical microscopy of conjunctival nevus withniches of junction and stromal cells, and inclusion cysts(HE40x).

Fig. 11: Melanosis oculi with blue spots on the sclera (A) and iris heterochromia (B).

melanosis, benign or idiopathic acquiredmelanosis and atypical intraepithelial melanocitichyperplasia.

Clinically, it begins insidiously in the middleage as a subtle, multicentric and unilateral pig-mentation extended throughout the conjunctiva,including sac fundus and tarsal conjunctiva (fig.12). When the conjunctiva of the palpebral edge isinvolved, it frequently extends to the adjacentskin. In contrast to nevus, it usually is flat, withincreased volume being a sign of malignization.Its color is irregular, ranging from no pigmenta-tion at all to dark brown. Its evolution is unpre-dictable: pigmentation can disappear in one areaand appear or increase in another. The rate ofdevelopment is variable, but generally it is meas-ured in years (26,31).

Histopathologically, primary acquiredmelanosis is classified as PAM with or withoutatypia (26). The Latter group involves melanocyt-ic hyper-pigmentation or hyperplasia limited tothe epithelial basal layer. Any type of atypical cell

growth different to a basilar hyperplasia is consid-ered a PAM with atypia. This differentiation isrelevant for prognosis because atypical PAM hasa 70-90% risk of evolving to melanoma, whereasPAM without atypia has a low risk of maligniza-tion (20%).

Melanoma

Conjunctival melanoma is an extremely rareand potentially deadly neoplasia, with an estimat-ed prevalence of 0.2 to 0.5 cases per millioninhabitants/year in Caucasian populations. Itaccounts for 1-2% of ocular malign tumors. Eventhough ultraviolet radiation has been signaled ascausal agent, its etiology remains unknown. Inabout 75% of cases, it originates at the clinicallevel in a PAM with atypia (fig. 5), but it also canoriginate in a previous nevus (20-30%) or appearde novo (5-10%) without pre-existing lesions (fig.5B) (32-34).


Conjunctiva tumors

Fig. 12: Primary acquired melanosis. A: Juxta-limbic localization. B y C: Multicentric localization with involvementof sac fundus, tarsal conjunctiva, caruncle and palpebral edge.

Fig. 13: Primary acquired melanosis without atypia. A: Melanocytic hyperplasia restricted to the basal layer (10x).B: basal layer hyperpigmentation (HE10x).

It affects adult or elderly Caucasian popula-tions and has no gender preference. The mostcommon clinical presentation is an elevated masswith variable pigmentation and associated signsof PAM or history of nevus, localized in the lim-bus, bulbar conjunctiva, fornix or palpebral con-junctiva. It can extend locally to the orbit andocular globe, and systemically through thelymphs. Accordingly, prior to treatment it isimportant to determine the degree of tumorextension, with a complete ocular and orbitaryassessment, palpation of neck ganglions and sys-temic extension study.

At the histopathological level, the conjunctivamelanoma comprises atypical melanocytic cellswith diverse morphology which invade the con-junctival substance (fig. 16). Morphology is highlyvariable, ranging from large pleomorphic cells withprominent nucleoles to small polyhedral or

fusiform cells without identifiable pigmentation.Immune histochemistry for protein S-100 andHMB-45 can assist in the diagnostic of non-differ-entiated and amelanocytic cases (1,29-34).

Even with adequate treatment, about half ofpatients exhibit local recurrences, and one thirdmetastases within 10 years (32,33). Accordingly,ongoing follow-up is important for these patients.The most frequent localization of initial metas-tases are regional lymphatic nodes (preauricular,under the jaw and cervical), although there also isremote dissemination through the hematogenousroute. When the disease appears disseminatedthere is no efficient treatment and patients have arelatively short survival time. The most importantprognostic factors are the tumor thickness, thepalpebral or caruncle localization, lymphaticinvasion, elevated proliferation rate and the page-toid histological pattern and recurrences (1,26,32-34). At present, different aspects are underresearch such as the importance of the sentinellymphatic ganglion biopsy in early detection of


SAORNIL MA, et al.

Fig. 14: Primary acquired melanosis with atypia. A:Atypical melanocytic cell niches occupying virtuallythe entire epithelium with sub-epithelial inflammatoryinfiltration (HE10x). B: Melanocytic cells leave a posi-tive mark with HMB45 demonstrating that the basalmembrane is respected (HMB4510x).

Fig. 15: Multicentric conjunctiva melanoma originated in a PAM (A), and advanced de novo melanoma (B).

Fig. 16: Conjunctival melanoma. A: Cell proliferationin sub-conjunctival tissue with irregular pigmentation(HE4x). B: with a larger zoom (HE40x) atypical pleo-morphic cells can be observed, of epithelioid nature andvariable pigmentation with multiple mitosis.

regional metastases (35,37), the identification ofrisk factors for tumoral development and theassessment of prognostic markers for morbidityand mortality (5,34,37,38).

Treatment of melanocytic tumors

The general objectives in melanocytic tumortreatment are similar to those described for epithe-lial tumors: excision or complete destruction of thetumor, precise histopathological diagnostic andminimization of recurrences. This is a particularly9important objective in pigmented tumors as theyworsen the patient prognosis.

Generally, benign lesions do not require muchmore than a correct clinical diagnostic and regularobservations. Most nevus occurring in patientsunder 40 do not require treatment except for esthet-ic purposes. The same occurs with repetitioninflammatory processes because melanoma isextremely rare in young people, even in elderly peo-ple. Only in the case of growth or color or morphol-ogy changes should the lesion be removed to dis-card malign transformation.

The management of PAM depends on the exten-sion of the lesion. If small, occupying under onefourth of the conjunctiva, its full removal should beconsidered. If the lesion is large, the thickened areasshould be removed (due to suspected melanoma)and perform map biopsies of the non-removed PAMareas to determine the risk of evolving to conjuncti-val melanoma. In addition, biopsies should be tak-en in apparently uninvolved areas due to the pres-

ence of PAM without pigmentation. If the completeremoval of atypia areas cannot be done or recur-rences emerge, supporting therapies should be uti-lized such as intra-op cryotherapy or post-surgerytopical chemotherapy, of which Mitomycin C is themost tested and tried (fig. 17) (32,39-41).

In the de novo melanoma or one arising from anevus, the primary treatment for the tumor is com-plete surgical removal with 3-5 mm of free margins,with or without intra-op supporting cryotherapy.Regardless of the origin of the melanoma, theobjective is its removal combining necessary thera-pies in the first approach to prevent recurrencesbecause these deteriorate the vital prognosis of thepatient.

In follow-up, patients must carefully checked,exploring the full conjunctiva surface with palpa-tion of pre-auricular and cervical ganglions. If pre-auricular ipsilateral, sub-mandibular and/or cervicalinvasion is detected, a non-radical regional gan-glionary cleaning is recommended.

If orbitary and/or intraocular invasion is detected,the usual primary treatment consists in exentera-tion. Enucleation is not usually performed becauseit leaves the conjunctiva (the origin of the tumor,which can give rise to new recurrences).

TUMORS IN SOFT TISSUE, GLANDSAND THEIR APPENDICES

Non-epithelial conjunctival tissue comprisesvascular and lymphatic structures, peripheral


Conjunctiva tumors

Fig. 17: Multi-centric Melanoma in PAM (A). Post-treatment with removal of thickened nodules, map biopsy and tre-atment with topical Mitomycin for the residual pigmentation (B).

nerves, connective elements, glands and theirskin appendices in the caruncle, which may giverise to any soft tissue tumor with the samehistopathological characteristics, although mostof them are rare. Sarcomas, fibromas, neurofibro-mas, schwanomas, neurotekiomas and other softtissue tumors may appear in the conjunctiva butmore frequently the conjunctiva is a secondaryarea of involvement in the orbit (1,2,42,43). Themost frequent and/or relevant tumors aredescribed below.

Benign tumors

Caruncle: Oncocytoma or eosinophilic cys-tadenoma. Most tumors originating in secondaryeyelid structures, eyebrows and orbit, can start inthe caruncle (e.g., pleomorphic adenoma, oncocy-toma, sweat glands carcinoma, sebaceous carcino-ma). This is not surprising because the carunclecontains accessory lachrymal teas, sebaceousglands and hair follicles. The most frequent maligntumor in the caruncle is the sebaceous carcinoma,while the most frequent benign tumor is oncotyomawhich also appears in the lachrymal sac and gland.It appears as a slow-growing raised pink-coloredmass in elderly patients (1,42).

Microscopically, oncotyomas have a variable pat-tern and the cells can arrange themselves in flatplanes, strings or nests and can form cystic or glan-dular structures. Their cells typically have the broadeosinophyllic cytoplasm full of substance which, inelectronic microscopy, are mytochondriae. Thisoncocytic transformation is not specific and takes

place in other glands and mucous of the body andcan represent a change of ageing.

Pyogenic granuloma. Clinically, this expressesas a pedunculated lesion, of papillomatous appear-ance which develops after a surgical or accidentaltrauma or a local inflammatory process (reactionagainst a foreign body). The differential diagnosticmust be made mainly with a pediculated papilloma,as the main differentiating factor is the progressionrate and the history of traumatism. Histopathologi-cally, it consists in granulated tissue comprised by alax stroma containing numerous capillaries extend-ing radially outward and a combination of acute andchronic inflammatory cells (fig. 18) (1). Its treat-ment consists in excisional biopsy (4).

Hemangioma. These are tumors which consist ina benign vascular proliferation which can be locat-ed in the conjunctiva itself or as part of heman-giomas affecting other structures. The conjunctivais an unusual place for hemangiomas but it isinvolved in capillary orbit and eyelid hemangiomaswhich appear early but regress spontaneously in thefirst years of life, and also in the Sturge-Weber syn-dromes which frequently exhibit ipsilateral con-junctival diffuse hemangiomas (1).

Lymphagiectasia/Lymphangioma. This tumorconsists in the dilatation of conjunctival lymphat-ic vessels, which can appear in the bulbar or tarsalconjunctiva. They appear as an irregular reddishmass made up of numerous dilated lymphatic ves-sels which can contain blood. Their developmentis slow and becomes exacerbated with catarrh.These are lymphangiomas which are frequentlypart of a lesion involving the orbit and eyelids (fig.19) (1).


SAORNIL MA, et al.

Fig. 18: Pyogenic granuloma after surgical trauma. A: Exophytic pinkish formation, richly vascularized. B: granula-tion tissue with numerous capillaries extending radially (HE4x).

Malign tumors

Caruncle: Sebaceous cell carcinoma. A raretumor but, according to the Washington ArmedForces Institute, it is the most frequent carunclemalign tumor (1). It originates in the sebaceousglands and its pagetoid dissemination substitutingthe conjunctival epithelium can simulate a unilater-al conjunctivitis. The conjunctiva is also frequentlyinvaded by this superficial dissemination of a seba-ceous gland originated in the eyelids.

Kaposi sarcoma. Until a few years ago, this wasa rare disease affecting elderly patients, associatedto Jewish-Mediterranean types. At present isappears in young individuals affected by AIDS andcould be taken as one of the early expressions ofsaid disease. Clinically it consists in the appearanceof nodules or reddish-bluish spots on the skin of thelegs in patients with the typical expression of thedisease, but in AIDS patients the lesions appear inthe upper part of the body (face, eyelids) and theconjunctival involvement can be the first clinicalsign of AIDS. It also appears as sub-epithelial nod-ules in the fornix or palpebral conjunctiva. Histo-logically it comprises fusiform cells with ovalnucleus and numerous capillaries (fig. 20) (1).

LYMPHOID TUMORS

The eye and surrounding area lymphomasaccount for 2-10% of extra-nodal lymphomas.These are rare and comprise a range from lymphoid

reactive hyperplasia to malign lymphoma, alwaysbased on microscopic characteristics. Conjunctivalymphomas account for 20-30% of lymphoidtumors of the eye and surrounding areas, and only20-30% of cases are associated to systemic disease(which may appear years later), and are bilateral innearly 40% of cases (44,45).

The majority of eye area lymphomas are of lowdegree non-Hodking type B cells and the greaterpart of the MALT type conjunctiva (low degree Blymphoma of the lymphoid tissue associated tomucosa) and are located at the most favorable endof malign lymphomas and on many occasions ondifficult ground for differential diagnostic in whichthere is no clear dividing line between the lowdegree malign lymphoma and lymphoid reactivehyperplasia.

Clinically, both benign and malign lesions tendto have a salmon-like color and are generally sub-


Conjunctiva tumors

Fig. 19: Conjunctiva lymphangioma. A: Broad dilatationof lymphatic vessels which infiltrates the bulbar conjunc-tiva, sac fundus and caruncle, grouping and becomingprominent. B: Twisted and dilated lymphatic vessels, par-tially filled with proteinaceous material (HE10x).

Fig. 20: Kaposi sarcoma. A: Reddish sub-epithelial conjunctival nodule with ill-defined limits. B: Fusiform cellula-rity with numerous capillary slits (HE40x).

conjunctival lesions with flat surface and soft tothe touch, located close to the fornixes. Clinicallyit is impossible to differentiate between benignlesions (lymphoid reactive hyperplasia) andmalign ones. Therefore it is essential to carry outa biopsy and, if the malign lesion diagnostic isconfirmed, a systemic exploration of the patientmust be performed to exclude the presence of asystemic disease (fig. 21).

In systemic lymphoma cases, the adequatetreatment is systemic chemotherapy. The conjunc-tival involvement will respond to chemotherapy inthe same way as the other affected cells of thebody. If there is no systemic involvement and thelesion is localized in the conjunctiva, surgicalremoval may be made followed by external radio-therapy if the lesion is extended or orbitaryinvolvement is suspected (20-40Gy). Alternative-ly, local interferon injections may be made andalso observation (44-47).

SUMMARY

A large variety of tumors may appear in the bul-bar or tarsal conjunctiva, sac fundus, semicircularfold or caruncle, affecting the epithelium or sub-epithelial tissue. Most are easy to detect in a routineophthalmological assessment and their benignnature allows for a conservative or hardly invasivetreatment. However, more aggressive, pre-malign oropenly malign tumors such as carcinoma,melanoma or lymphoma, which jeopardize thevisual function and/or the patient’s life are not anexception. Therefore a vigilant attitude must bemaintained to detect their presence at an early stage.In these cases, their existence must be confirmed

with a biopsy and surgery combined with differentsupporting therapies (chemotherapy, cryotherapy orothers) for achieving local control of the disease,preserving as much as possible the anatomical andfunctional integrity of the ocular surface. Newimaging techniques and methods such as the studyof the sentinel ganglion are important for identify-ing the local or remote extension of the disease. Inspite of all the diagnostic and therapeutic develop-ments, the core of a good approach for treating con-junctival tumors continues to hinge on a goodhistopathological study and diagnostic. For this, theclinical-pathological correlation is crucial, requir-ing good communication between the ophthalmolo-gist and pathologist.

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