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«PRINCESS MARGARET CANCER CENTRE CLINICAL PRACTICE GUIDELINES OCULAR ONCOLOGY CONJUNCTIVAL MALIGNANCY Site Group: Ocular – Conjunctival Malignancy ...»

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PRINCESS MARGARET CANCER CENTRE

CLINICAL PRACTICE GUIDELINES

OCULAR ONCOLOGY

CONJUNCTIVAL MALIGNANCY

Site Group: Ocular – Conjunctival Malignancy

Prepared by: Harmeet S. Gill MD, FRCSC and E. Rand Simpson MD, FRCSC

Latest Revision: N. Laperriere, H. Krema

1. INTRODUCTION 3

2. PREVENTION 4

3. SCREENING AND EARLY DETECTION 4

4. DIAGNOSIS 5

5. PATHOLOGY 10

6. MANAGEMENT 13

6.1 MANAGEMENT ALGORITHMS 13

6.2 SURGERY 15

6.3 CHEMOTHERAPY 16

6.4 RADIATION THERAPY 17

6.5 OTHER THERAPY 18

6.6 ONCOLOGY NURSING PRACTICE 18 6.7 18

CLINIC COORDINATION/MANAGEMENT

7. SUPPORTIVE CARE 18

7.1 PATIENT EDUCATION 18

7.2 PSYCHOSOCIAL CARE 18

7.3 SYMPTOM MANAGEMENT 19

7.4 CLINICAL NUTRITION 19

7.5 PALLIATIVE CARE 19

8. FOLLOW-UP CARE 19

9. REFERENCES 20 Last Revision Date – August 2015 2

1. INTRODUCTION Conjunctival malignancies may be divided into epithelial, melanocytic, lymphoproliferative, or secondary/metastatic lesions. When managed early, most will not invade other ocular structures or metastasize. However, left untreated they can become vision- and life-threatening.

A. Epithelial. Ocular surface squamous neoplasia (OSSN) comprises a spectrum of malignancy from dysplasia (mild, moderate, severe, carcinoma in situ) to invasive squamous cell carcinoma (SCC) arising from the non-melanocytic conjunctival epithelial cells. These tumors constitute the most common conjunctival malignancy in the United States. The incidence of OSSN has been reported between 0.02 and 3.5 persons per 100,000 each year, althoughthere is wide geographic variation on the basis of solar exposure and the incidence of untreated AIDS. The tumor may arise from epithelial cells in the cornea, limbus, or conjunctiva.

B. Melanocytic. Abnormal melanocytic proliferations account for 50% of all conjunctival neoplasms. Conjunctival melanocytic proliferation appears to have a distinct pathway different from its cutaneous or uveal counterparts. Normal conjunctival melanocytes have a dendritic configuration and reside in the basal epithelium amongst the more numerous basal squamous cells. Their function is to secrete melanin, which provides protection from ultraviolet radiation. Increased proliferation of melanocytes results in a lesion that may be totally pigmented, partially pigmented, or non-pigmented. Whether or not a lesion is pigmented does not depend on the number of melanocytes, but rather the overall amount of melanin.

Not all pigmented lesions are melanocytic tumors and not all melanocytic tumors are pigmented. 
 A melanocytic lesion may be benign (nevus), premalignant (primary acquired melanosis [PAM] with or without atypia) or malignant (melanoma). There are also some rare benign melanocytic tumors such as the Blue nevus and other variants. Pigmented lesions are also found on the caruncle or eyelid margin that are benign (i.e. nevus, oncocytoma) or malignant (melanoma). There is also subconjunctival melanocytic proliferation that may be associated with cutaneous, scleral and uveal pigmentation termed oculodermal or ocular melanocytosis.

Melanoma can also secondarily involve the conjunctiva from cutaneous or uveal melanoma metastasis or from a continuous cutaneous melanoma. Any pigmented lesion that exhibits growth, change in shape or color, or involves the palpebral or forniceal conjunctiva is biopsied.

C. Lymphoproliferative. Lymphoproliferative lesions of the conjunctiva represent a spectrum of disease from reactive lymphoid hyperplasia (RLH) to malignant lymphoma. Lymphoid tumors can involve the conjunctival stroma, the eyelids, or the orbital structures (including lacrimal gland and sac) as a primary lymphoma or secondarily as part of a systemic lymphoma condition that affects multiple organs including the ocular adnexa. Together these are termed ocular adnexal lymphoid neoplasms (OALNs) and represent less than 10% of all extranodal non-Hodgkin lymphomas. Lymphoid proliferations constitute about 2% of conjunctival neoplasms, however the incidence of OALNs is increasing. The conjunctiva is involved primarily Last Revision Date – August 2015 3 in about one third of cases, which tends to result in a relatively better prognosis compared with other OALNs. Although non-Hodgkin lymphoma (NHL) of B-cell origin is most commonly encountered, T-cell or natural killer (NK)-cell lymphomas can also involve the ocular adnexa.

D. Secondary/Metastatic. Tumors that involve the eyelids, intraocular structures, or adjacent orbital tissues may spread by direct extension to the conjunctiva and are called “secondary” lesions. In contrast, tumors that involve the conjunctiva by distant spread are termed “metastatic” lesions.

2. PREVENTION

Extrinsic risk factors that predispose to conjunctival malignancy include smoking, ultraviolet (UV-B) radiation, and oncogenic infections such as human papillomavirus (HPV) and human immunodeficiency virus (HIV). Intrinsic risk factors include older age, immunosuppression, genetic predisposition, fair skin (for melanocytic tumors), and a personal history of cutaneous or other malignancy.





Solar damage and immunosuppression are the most important risk factors in nonsyndromic patients (ie. xeroderma pigmentosa). For those who suffer from xeroderma pigmentosa, prevention involves avoidance of UV-light with sunglasses, hats, and staying indoors. HPV is a DNA virus and types 16 and 18 are implicated in cervical and conjunctival malignancy, although the association is more robust for the former. HPV types 6 and 11 are associated with most benign conjunctival papillomas.

However, based on the available evidence, there is no role for routine testing of HPV DNA or mRNA in patients with conjunctival squamous neoplasia. There is an increasing incidence of conjunctival squamous neoplasia, about 10-fold, in HIVpositive patients. Overall, patients are counseled on strategies to address all modifiable risk factors including smoking cessation, use of sunglasses, and normalization of immune status. Early treatment of pre-cancerous lesions with close monitoring and follow-up is paramount.

3. SCREENING AND EARLY DETECTION

Early recognition and treatment decreases tumor spread and improves prognosis for tumor control and visual preservation. Many conjunctival malignant tumors are difficult to distinguish from benign lesions based on the clinical examination alone.

An excisional biopsy is recommended in such cases. Intraocular surgical procedures such as cataract extraction should not be performed simultaneously with biopsy until conjunctival malignancy is ruled out.

Conjunctival squamous neoplasia presents in younger patients who are HIV-positive.

In an African patient, or one that is younger than 50 years of age that presents with conjunctival squamous neoplasia, an HIV test is mandatory. Similarly, patients with known HIV-seropositivity who have a conjunctival lesion should have a biopsy.

4. DIAGNOSIS Patients with suspicious conjunctival lesions are typically referred to the Princess Last Revision Date – August 2015 4 Margaret Hospital (PMH) Ocular Oncology service by vision care specialists. Some patients are referred because an excised lesion was found to be malignant and there is a need for adjunctive therapy and ongoing follow-up. There is a wide spectrum of clinical features for conjunctival tumors but some common signs of malignancy include an abnormal appearance, size, shape, or location of pigmented or nonpigmented tissue with aberrant surrounding vasculature (e.g. feeder vessels).

Lesions may be focal, multi-focal, diffuse, or infiltrative. Specific features of the four subtypes are described below.

Clinical Exam. All new patients will undergo a detailed ophthalmological examination of both eyes including Snellen visual acuity, pupil reactivity, intraocular pressure, and slit-lamp biomicroscopy. Detailed drawings and measurements as well as high-quality photographic documentation are performed. The base diameter of a conjunctival tumor is measured with the slit-lamp and tumor depth and presence of scleral penetration by ultrasound biomicroscopy (UBM).

A. Epithelial. Conjunctival squamous neoplasia usually involves the limbal conjunctiva with or without corneal involvement and rarely presents in the palpebral or forniceal areas. In most developed nations, conjunctival squamous neoplasia tends to present as a slow-growing mass of the interpalpebral conjunctiva in elderly, fairskinned, males in the 7th or 8th decade. In Africa and parts of Asia, the disease presents quite differently. Patients are much younger (around 35 years of age), female, and have specific risk factors including a combination of high sun exposure, HIV pandemic, and high exposure to HPV resulting in earlier and more rapid presentation and a higher rate of recurrence (40% or higher). The appearance of squamous neoplasia is variable and the clinical features may not allow delineation between benign versus malignant lesions. These neoplasms may be isolated or coexist with corneal degenerations such as pingueculae or pterygia. The macroscopic appearance is most commonly leukoplakic, gelatinous, or papilliform. The growth pattern is nodular or diffuse and there may be visible intrinsic tumor vessels or feeder vessels. The intratumor vascular pattern is often typical and its highly disordered appearance is quite distinct from the linear vessels noted in other conjunctival reparative or inflammatory processes. Early squamous cell carcinoma (SCC) presents similarly to dysplasia. Rarely, it can grow diffusely without tumefaction and masquerade as a sclerokeratitis, scleromalacia, or interstitial keratitis. Left untreated, SCC causes disfigurement, profound vision loss, loss of the eye, or rarely (in other areas of the world) fatal metastatic disease. Intraocular invasion is rare (0% to 7%). Clinical features of intraocular extension include an anterior chamber or ciliary body mass, broad anterior synechiae in the area of the tumor, neovascularization of the iris, scleritis, or scleral perforation. Invasion of orbital tissues is reported in 12% to 16% of invasive tumors. Local recurrence, mainly a function of incomplete tumor removal, is reported in up to 15% of cases.

Recurrent cases are more likely to progress and result in scleral invasion or intraocular penetration. The main predictors for recurrence are older age, large lesion size, scleral involvement, positive surgical margins, or a high Ki-67 score (elevated proliferation index), and atypical features. Metastasis occurs in less than 1% of cases and mostly involves regional lymph nodes. Sites of metastasis include the Last Revision Date – August 2015 5 parotid, submandibular and submaxillary glands, cervical lymph nodes, the lungs, and bone. Mortality from conjunctival SCC ranges from 0% to 8%, and mainly occurs in Middle Eastern and African countries. Variants of SCC (i.e. mucoepidermoid carcinoma, adenoid squamous cell carcinoma, spindle cell carcinoma, or clear cell carcinoma) tend to be more aggressive and the management involves wider local excision and closer follow-up. They are differentiated on the basis of their histopathological features.

B. Melanocytic. Conjunctival melanocytic nevus is the most common melanocytic tumor of the conjunctiva. It is a benign, well-circumscribed, flat proliferation of melanocytes often with inclusion cysts and is similar to its cutaneous counterpart.

Both cutaneous and conjunctival nevi are classified similarly--junctional, compound, and subepithelial. Conjunctival melanocytic nevi typically involve the bulbar conjunctiva, the caruncle, or the plica semilunaris, and do not extend onto the cornea.

Most bulbar conjunctival nevi are found at the nasal or temporal limbus but about 10% are seen in the superior or inferior quadrants. About 5% to 10% of nevi are junctional (intramucosal) and are found more commonly in younger patients. The vast majority are compound nevi, which account for 70% to 80% of all nevi and are deeper proliferations into the superficial substantia propria. The subepithelial nevi account for the remaining 5% to 10% and are found in older patients with proliferations completely within the substantia propria, without any intraepithelial component. Conjunctival melanocytic nevi may be congenital or acquired, but most will be evident within the first few decades of life. While typically non-pigmented earlier in life, about 70% of nevi become pigmented after puberty. This frequently results in a referral for biopsy of the lesion. About 50% to 60% of conjunctival nevi have intralesional cysts. It is very uncommon (less that 1%) for progression to malignant melanoma. Intralesional cysts are extremely rare in PAM and melanoma, and the clinical detection of an intralesional cyst suggests the tumor is a benign melanocytic proliferation.

Although there is congenital melanosis (i.e. racial melanosis) and secondary melanosis (related to certain systemic conditions like Addison’s disease), the most common type is primary acquired melanosis (PAM) of the conjunctiva, as described initially by Algernon Reese. PAM is an acquired lesion that develops during middle-age in fair-skinned persons and tends to be unilateral, flat, conjunctival or limbal pigmentation. The cornea is involved in over 20% of PAM cases. Conjunctival malignant melanoma (CMM) is relatively rare compared with PAM and makes up only 1% to 2% of all eye cancer cases. The incidence may be increasing but remains less than 1 case per million persons per year in the United States. The incidence is about 0.8 cases per million for Whites and 0.2 cases per million for Asians or Blacks.

Despite the rarity of the tumor, it remains important because the 10-year mortality rate is as high as 13% to 50%. CMM is more common in older, fair-skinned patients but may present in a person of any age or race. Clinically, CMM appears as a raised, pigmented lesion with increased vascularity or prominent feeder vessels and can be surrounded by a flat PAM lesion. Minimally pigmented CMM is seen in 19% of cases.



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