Conjunctival tumors include a broad array of neoplasms, some of which are benign and others that demonstrate premalignant or malignant features.1-5 The types and frequency of conjunctival tumors differ with demographic features such as age and race, systemic immune status, and chronic exposures, along with specific location within the conjunctiva.4-6 There have been few published series on conjunctival tumors with most emanating from pathology registries including, among others, the Armed Forces Institute of Pathology, Bethesda, Maryland (n = 1120 tumors),7 Singapore Cancer Registry (n = 125 patients),8 Uganda (n = 312 patients),9 and Wilmer Eye Institute, Baltimore, Maryland (n = 2455 lesions in adults).3 Subsequently, there have been large series with clinicopathologic correlation from Wills Eye Hospital, Philadelphia, Pennsylvania (n = 1643 patients)4 and a recently updated comprehensive series from the same institution (n = 5002 patients, all ages)5 with subanalysis of tumors in children (n = 806).10
Based on the series of 5002 conjunctival tumors referred to an ocular oncology tertiary care center, conjunctival tumors were found to be benign (52%), premalignant (18%), or malignant (30%).5 Of the 18 broad categories of tumor types and 80 specific diagnoses, the 5 most common lesions, inclusive of all patient ages, were nevus (23%), ocular surface squamous neoplasia (OSSN) [conjunctival intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC)] (14%), primary acquired melanosis (PAM) (12%), melanoma (12%), and lymphoid tumor [benign reactive lymphoid hyperplasia (BRLH) or lymphoma] (9%).5 In that series, the malignant tumors included melanoma (n = 601, 12%), squamous cell carcinoma (n = 440, 9%), lymphoma (n = 358, 7%), Kaposi sarcoma (n = 15, <1%), metastatic tumors (n = 6, <1%), plasmacytoma (n = 4, <1%), leukemia (n = 3, <1%), extrascleral extension of uveal melanoma (n = 30, 1%), and others.5 Comparatively, conjunctival tumors in children demonstrate malignancy in only 3% of cases.10 Herein, we review the frequency of conjunctival tumors and describe in detail the most serious conjunctival tumors, the premalignant/malignant tumors including OSSN, melanoma, and lymphoid tumors.
FREQUENCY OF CONJUNCTIVAL TUMORS
The list of conjunctival tumor categories from an ocular oncology tertiary referral center is shown in Table 1 with a comparison of cases in all ages groups (n = 5002) with those specifically found in the pediatric age group (<21 years old) (n = 806).5,10 The newly printed American Joint Committee on Cancer (AJCC) eighth edition classification of conjunctival malignancies, released in 2016, is listed for OSSN (Table 2), melanoma (Table 3), and lymphoid tumors (Table 4).11-13
OCULAR SURFACE SQUAMOUS NEOPLASIA
Conjunctival carcinoma is included in the general clinical term of OSSN, along with the more specific histopathologic terms of CIN and SCC.14-23 Overall, OSSN includes a spectrum of malignancy that ranges from mild epithelial dysplastic changes (CIN) to more severe invasive carcinoma, invading through the basement membrane into the substantia propria (SCC).
Conjunctival OSSN classically occurs in older white males, particularly those exposed to years of solar radiation in activities such as golfing, fishing, boating, construction, and farming. The incidence of SCC has been reported from 0.03-1.9 per 100,000 persons/year in patients in the United States and Australia.20-22 In the United States, the rate of SCC is 5-fold higher among males and whites.21 A recent analysis of 146 cases from Denmark found incidence rates of 0.1 (male) and 0.04 (female) per 100,000/year.19
The spectrum of OSSN is different in Africa, being nearly equally common in women and men and occurring at a younger age than in the United States.15 The incidence of OSSN is greatest in Africa and the highest age-standardized rate is found in Zimbabwe, with rates of 3.4 (males) and 3.0 (females) per 100,000/year.15 Gichuhi et al15 studied OSSN in Africa and documented that the risk increased with exposure to 2 to 4 hours of direct daylight [odds ratio (OR), 1.7] and outdoor occupations (OR, 1.7). Meta-analysis demonstrated strong association with human immunodeficiency virus (HIV) (OR, 6.2) and human papillomavirus (HPV) (OR, 2.6).15
Ocular surface squamous neoplasia usually presents as a unilateral vascularized gelatinous limbal mass, located in the sunexposed interpalpebral fissure medially or laterally (Figs. 1-3). Other occasional features include overlying leukoplakia, tortuous dilated feeder vessels, and foamy infiltration of the adjacent corneal epithelium. Rarely does conjunctival SCC invade into the globe or orbit.24 In the United States and Europe, this tumor is typically yellow-pink in color, whereas in Africa, it is fairly commonly pigmented with complexion-related melanocytes.17,18
Predisposing Factors, Pathophysiology, and Biomarkers
The most important environmental predisposing factors include chronic solar (ultraviolet B) radiation exposure and cigarette smoke exposure.14 In Australia, phenotypic factors such as pale skin, pale iris, propensity to sunburn, spending more than 50% of time outdoors in the first 6 years of life, and habitation within 30 degrees of the equator were related to the development of OSSN.22 Other important environmental factors include vitamin A deficiency, ocular surface injury, exposure to petroleum products, and chronic infection with HIV, HPV, and hepatitis B and C virus.6,23
The most important host predisposing factor is the status of the immune system. Patients with immune deficiency, particularly those infected with HIV, are at a relatively high risk for OSSN and have the worst outcomes.17,19,21,25 This is especially noted in Africa where HIV is more prevalent and OSSN occurs in both males and females at a younger age and with more aggressive tumors.15,17 Other immune dysregulation syndromes that can predispose to OSSN include medical immune suppression for organ transplantation, asthma/eczema/atopic diseases, ocular cicatricial pemphigoid, xeroderma pigmentosum, and other autoimmune diseases.6,25
The role of HPV in the development of OSSN has been debated.6,26-28 Gichuhi et al16 elaborated on the pathophysiology of OSSN, indicating that it arises in the basal epithelial cells, spreading upwards toward the conjunctival surface then later invading through the basement membrane. Ultraviolet radiation damages cellular DNA leading to pyrimidine dimers (CC>TT) that can transform cell regulation by affecting the tumor suppressor TP53. This, along with ultraviolet photoimmunosuppression and HPV (serotypes 16 and 18) activation, leads to cellular infection that triggers the neoplastic division.16
Promoter mutations in the telomerase reverse transcriptase (TERT) gene have been identified in several cancers including cutaneous melanoma and SCC, thyroid cancer, and gliomas, often signifying advanced disease with poor prognosis.29 Scholz et al29 identified TERT promoter mutations in 44% of 48 samples of conjunctival OSSN. They found that the TERT mutational profile supported ultraviolet light induction as the major source of the malignancy. There was no relationship with tumor recurrence comparing those with versus without TERT mutation.
In 2016, the eighth edition of the AJCC manual was released with updated classification on conjunctival carcinoma including SCC and CIN11 (Table 2). This classification groups cancer by the tumor, node, metastasis (TNM) staging system. For conjunctival carcinoma, the clinical classification is based on tumor size (≤5 mm versus >5 mm), tumor invasiveness [in situ, substantia propria, adjacent structures (fornix, plica semilunaris, caruncle, palpebrum), orbit, bone, sinuses, and brain]. The pathology classification is based on histopathologic grade of differentiation. Shields et al30 studied treatment outcomes using interferon alpha-2b for OSSN based on the AJCC seventh edition and noted excellent tumor control in all stages, indicating that the classification was not predictive of failure.
The management of OSSN involves surgical resection using the “no touch” technique versus nonsurgical therapies including topical chemotherapy (mitomycin C, 5-fluorouracil), topical/injection immunotherapy (interferon alpha-2b), topical antiviral medication (cidofovir), or photodynamic therapy (PDT)30-39 (Fig. 3). Galor et al39 studied OSSN after surgical resection and noted recurrence at 1 year of 10% and at 5 years of 21%. Ramberg et al19 observed postsurgical recurrence at 1 year in 10% and at 5 years in 17%. Nanji et al32 compared the cost of surgical versus medical treatment of OSSN in 98 patients and found equal efficacy of both treatments. However, medical treatment required more office visits, whereas surgical treatment was equal or more costly depending on the patient’s insurance. Siedlecki et al33 compared surgery versus interferon alpha-2b therapy for OSSN using a literaturebased decision analysis on publications between 1983 and 2015, revealing that surgical excision followed by interferon alpha-2b therapy for positive margins was the best strategy to minimize tumor persistence or recurrence.
Conjunctival melanocytic tumors are fairly common, representing approximately 53% of cases in one large series of 1643 tumors and 52% in a second major review of 5002 conjunctival tumors.4,5 Conjunctival melanocytic tumors include nevus, complexion-related melanosis, PAM, and melanoma.1-5 Although conjunctival melanoma is rare, Yu et al40 and Tuomaala and Kivela41 noted an increase in the age-adjusted incidence of conjunctival melanoma with doubling between 1973 and 1999 in the United States from 0.27 to 0.54 per million and in Finland from 0.40 to 0.80 per million. The incidence increased 295% in white men from the United States over the 27-year period, especially among men aged 60 years or older.40 They speculated that the increasing rate, similar to cutaneous melanoma, was likely related to ultraviolet light exposure.40,41
Conjunctival melanoma is a pigmented or nonpigmented epibulbar malignancy that can arise from PAM, nevus, or de novo.1,42-46 Melanoma can be found on the limbal, bulbar, forniceal, or palpebral conjunctiva and demonstrates dilated tortuous feeder and intrinsic vessels typically surrounded by flat PAM (Figs. 4, 5). In general, tumors measuring 2 mm or less in thickness show less risk for metastatic disease compared with those greater than 2 mm. Tumor invasion into the orbit is particularly serious with substantial metastatic risk. Conjunctival melanoma can show both local tumor recurrence (50%) and distant metastasis (25%).43,44 Multiple recurrences, especially those involving the orbit, necessitate orbital exenteration. Metastases can occur in the regional lymph nodes, including ipsilateral preauricular or submandibular nodes. There is debate about the importance of obtaining a sentinel lymph node biopsy.47,48
Predisposing Factors and Biomarkers
The most important predisposing factors for conjunctival melanoma include conjunctival nevus and PAM. Histopathologic evaluation of conjunctival melanoma has revealed origin from PAM in 74%, de novo in 19%, and nevus in 7%.44 Clinical studies have estimated that 1 in 300 nevi develop into melanoma.49,50 Regarding PAM, a large-cohort clinical study found that the 10-year estimate of PAM transformation into melanoma was 11% and, specifically, progression to melanoma occurred in 0% of PAM without atypia, 0% of PAM with mild atypia, and 13% of PAM with severe atypia.51 A small-cohort histopathologic study revealed a similar 0% transformation rate for PAM without atypia and a 46% rate for PAM with atypia.52
The differentiation of conjunctival nevus from melanoma can be challenging.49,50 In a recent analysis of 510 cases of conjunctival nevus versus melanoma in children, comparison revealed that melanoma was significantly more common in older children [relative risk (RR), 4.80], with greater tumor thickness (RR, 1.14), greater base (RR, 4.92), tumor hemorrhage (RR, 25.30), and lacking intrinsic cysts (RR, 5.06).10 These features, predictive of conjunctival melanoma in children, were assigned to the mnemonic CATCH Melanoma, representing Children Age older, Thickness/base greater, Cyst lacking, Hemorrhage for Melanoma.10
Similarly, differentiation of PAM from melanoma can be difficult.51 In an analysis of 1224 cases of PAM versus melanoma in all ages, comparison revealed melanoma with significantly greater median patient age (54 vs 61 years, P < 0.0001), male sex (35% vs 49%, P < 0.0001), location in fornix (2% vs 6%, P = 0.0016) and tarsus (1% vs 4%, P = 0.0018), larger median basal diameter (6 vs 8 mm, P < 0.0001) and thickness (<1 vs 1 mm, P < 0.0001), intralesional cysts (0% vs 7%, P < 0.0001), feeder vessels (10% vs 48%, P < 0.0001), intrinsic vessels (4% vs 33%, P < 0.0001), and hemorrhage (<1% vs 3%, P = 0.0001).5
Tissue biomarkers in malignancy have become important for assessment of conjunctival melanoma. Larsen et al53 evaluated 110 melanomas and identified 39 (35%) that were BRAF mutated, a feature predictive of metastasis (univariate analysis). Koopmans et al54 studied TERT promoter mutations in conjunctival tumors and found mutations in 16 (41%) of 39 melanomas, 2 (8%) of 25 PAM with atypia, and 0 (0%) of 56 nevi and 14 PAM without atypia. Westekemper et al,55 in a study of 70 samples of conjunctival melanoma and 12 nevi, found higher expression of heat shock protein-90 (P < 0.0001) and higher loss of nuclear tumor suppressor phosphatase and tensin homologue (PTEN) expression (P = 0.001) in melanoma than in nevus. Identification of melanoma biomarkers is critical in planning systemic therapy for treatment or prevention of metastasis, as targeted therapies against biomarkers are currently available, such as vemurafenib for BRAF-mutated malignancy.
The AJCC eighth edition provides a clinical classification for conjunctival melanoma based on tumor extent by quadrants, tumor location, and invasive features12 (Table 3). The pathology classification is based on tumor location, thickness within the substantia propria, and invasive features. Shields et al45 studied treatment outcomes of conjunctival melanoma based on the AJCC seventh edition and noted that this staging was predictive of prognosis. Melanoma classified as T2 and T3 (compared with T1) showed significantly higher rates of local recurrence, regional lymph node metastasis, distant metastasis, and death.45
The management of conjunctival melanoma basically involves complete surgical resection using the “no touch” technique to avoid tumor seeding.31,43,44,56,57 Several studies have emphasized that the first surgery is the most important surgery, as delicate removal of the tumor without tumor seeding is key to the prevention of future recurrence and metastasis.43,44,56,57 Melanoma at the corneoscleral limbus is removed with precision under the operating microscope, with dry surgical field to avoid washing tumor seeds on the surface of the eye, and with a philosophy to avoid direct manipulation of the malignancy (“no touch” technique). The flat corneal component is removed with absolute alcohol application to corneal portion of the tumor followed by epitheliectomy without disruption of the Bowman membrane. The conjunctival portion is removed with 2-3 mm margins and the tightly adherent limbal region is released using partial lamellar scleroconjunctivectomy, followed by double freeze-thaw cryotherapy. Larger lesions that extend into the forniceal region or orbit require more extensive surgery, with a goal of tumor-free margins. Reconstruction of lost tissue involves primary closure techniques, rotational flap, or amniotic membrane transplantation. Often, symblepharon ring with amniotic membrane is required to re-form the fornix and protect the cornea. Melanoma that extends into the orbit requires orbital exenteration.
Patients with conjunctival melanoma should be monitored for local recurrence by an ocular oncologist and for metastatic disease, particularly with regional lymph node palpation and sentinel lymph node biopsy, by a systemic oncologist. Metastases initially appear in the preauricular or submandibular lymph nodes, then later in the lung and brain. Local recurrence of conjunctival melanoma and metastatic disease is most often found in patients with tumors in the conjunctival fornix, caruncle, or tarsal region and those with positive margins on histopathology.43,44,56 New evidence suggests that melanoma metastasis could be sensitive to BRAF inhibitors or immune checkpoint inhibitors.53,57-61
CONJUNCTIVAL LYMPHOID TUMORS
Lymphoid neoplasms are diverse, ranging from low-grade to high-grade tumors, but they share a common thread of derivation from monoclonal proliferation of lymphocytes. These tumors can arise in the lymph node (nodal) or from tissue other than lymph nodes (extranodal). The lymphomas that occur in the periocular region often involve several tissues such as the conjunctiva, orbit, and eyelid and are termed “ocular adnexal” lymphoid tumors, including benign reactive lymphoid hyperplasia (BRLH) and lymphoma.
Despite the numerous types of lymphoma involving B cells, T cells, plasma cells, and others, ocular adnexal lymphomas are typically of B-cell origin. Kirkegaard et al62 provided a multicenter study on 268 patients with conjunctival lymphoma and the 4 most common types included extranodal marginal zone lymphoma [ENMZL, previously termed mucosal associated lymphoid tissue (MALT)] (68%), follicular lymphoma (FL) (16%), mantle cell lymphoma (MCL) (7%), and diffuse large B-cell lymphoma (DLBCL) (5%).62 Other types in that series from Europe, the United States, India, and Australia included lymphoplasmacytic lymphoma and plasmacytoma. There were no cases of Burkitt lymphoma.
Conjunctival lymphoma classically presents in older patients from the ages of 60 to 70 years with a predilection for females (58%) in those with ENMZL and for males (78%) in MCL.62-65 This tumor can manifest as a primary lymphoma, limited to the periocular region, or as a secondary lymphoma with remote lymphoid infiltrates elsewhere in the body. Generally, primary involvement is found with ENMZL and FL, whereas secondary involvement with DLBCL and MCL. In an analysis of 117 patients with conjunctival lymphoma, systemic lymphoma was found in 31%.63 Those with unilateral tumor demonstrated remote tumor in only 17%, whereas those with bilateral tumor showed remote lymphoma in 47%.63 Of the 101 patients who presented with conjunctival lymphoma and no systemic lymphoma, systemic involvement was eventually detected in 15% by 5 years and 28% by 10 years.63
Conjunctival lymphoma classically presents as a pink, salmon-colored subconjunctival mass in the substantia propria sometimes with feeder vessels (Fig. 6). This smooth, multilobulated mass can resemble follicular or papillary conjunctivitis. Locations of the tumor include the conjunctival fornix (44%) or midbulbar (42%) region and rarely in the caruncle (7%) or limbus (7%).63 The main symptoms include a mass (30%), irritation (29%), ptosis (8%), epiphora (7%), blurred vision (5%), proptosis (3%), diplopia (3%), or no symptoms (15%).63 In addition to the conjunctival infiltration, lymphoma can be found infiltrating the orbit (15%), eyelid (3%), or uvea (4%).63 Based on the current literature, there are no features that differentiate conjunctival lymphoma into histopathologic subtypes.
Factors that predispose to conjunctival lymphoma include immune deficiency, autoimmune conditions, immune dysfunction, infective etiologies (Helicobacter pylori, Chlamydia psittaci), genetic mutations, and immune regulation medications.6,66,67 Benign reactive lymphoid hyperplasia is believed to be a potential precursor to lymphoma and is occasionally found in children10,68,69 (Fig. 6). A comparison (BRLH vs lymphoma) in children revealed that lymphoma demonstrated significantly larger basal dimension (RR, 5.16) and location as diffuse, inferior, or superior verus nasal (RR, 16.5, 12.38, 8.25, respectively), whereas BRLH was typically smaller and located in nasal conjunctival fornix.10
There are several classifications for conjunctival lymphoma including the Ann Arbor staging, World Health Organization staging, and AJCC eighth edition staging70-72 (Table 4). The AJCC eighth edition clinical staging is based on tumor location, regional lymph node, and distant involvement, whereas the pathologic staging is based on the number of centroblasts per 10 high-power fields. According to the AJCC seventh edition staging, the histologic subtypes showed varied staging (ENMZL/FL/DLBCL/MCL) with T1 (77%/68%/50%/33%), T2 (22%/18%/50%/67%), T3 (<1%/14%/0%/0%), and T4 (0%/0%/0%/0%) and with limited prognostic capability.62
Management of conjunctival lymphoma primarily depends on the extent of periocular involvement, systemic involvement, and general health of the patient. Outcomes should be considered with regard to both ocular and systemic control. In patients with only conjunctival lymphoma and no systemic involvement, treatment is focused on complete surgical resection if possible versus treatment with external beam radiotherapy (EBRT) or rituximab, particularly if the tumor is large, infiltrative, and nonresectable.73-75 For those with periocular and systemic lymphoma, treatment with systemic rituximab, chemotherapy, or immunotherapy is typically considered.75-79 Systemic prognosis with conjunctival lymphoma is directly related to lymphoma subtype. Despite systemic therapies, 5-year survival was 97% for ENMZL, 82% for FL, 55% for DLBCL, and only 9% for MCL.62
Conjunctival tumors encompass a broad spectrum of tumors. In children, malignancy is found in only 3%, whereas in all age groups malignancy is found in 30%.5,10 The most common malignancies include OSSN, melanoma, and lymphoma. Recognition of the classic clinical features of these tumors, understanding of predisposing conditions and tissue biomarkers, and proper management are important for best patient outcomes.
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