Secondary Logo

Journal Logo

Review Article

Conjunctival Tumors: Review of Clinical Features, Risks, Biomarkers, and Outcomes—The 2017 J. Donald M. Gass Lecture

Shields, Carol L. MD; Chien, Jason L. BS; Surakiatchanukul, Thamolwan BS; Sioufi, Kareem MD; Lally, Sara E. MD; Shields, Jerry A. MD

Author Information
Asia-Pacific Journal of Ophthalmology: March 2017 - Volume 6 - Issue 2 - p 109-120
doi: 10.22608/APO.201710
  • Free

Abstract

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

T1A-2
TABLE 1:
Types and Frequency of Conjunctival Tumors in a Survey of All Patient Ages (n = 5002) and Those Specifically Found in Children (n = 806)
T1B-2
TABLE 1:
(Continued)
T2-2
TABLE 2:
AJCC 8th Edition Classification of Conjunctival Carcinoma (OSNN)
T3-2
TABLE 3:
AJCC 8th Edition Classification of Conjunctival Melanoma
T4-2
TABLE 4:
AJCC 8th Edition Classification of Ocular Adnexal Lymphoma

OCULAR SURFACE SQUAMOUS NEOPLASIA

Introduction

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).

Clinical Features

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

F1-2
FIGURE 1.:
Ocular surface squamous neoplasia. A, Limbal OSSN extending as a flat sheet onto the cornea. B, Limbal OSSN with prominent intrinsic vascularity and feeder vessels. C, Limbal OSSN with prominent vascularity and extension onto the cornea. D, Forniceal OSSN overhanging the eyelid margin.
F2-2
FIGURE 2.:
Management of OSSN. A, Gelatinous vascular OSSN at the temporal limbus. B, After surgical resection, the limbus remains well healed and without recurrence. C, Gelatinous multinodular vascular OSSN at the temporal limbus. D, After interferon alpha 2-b, the mass has resolved, leaving intact limbus.
F3-2
FIGURE 3.:
Imaging of OSSN. A, Vascular OSSN at the limbus with corneal extension. B, Optical coherence tomography angiography (OCTA) demonstrating the intrinsic tumor vascularity.

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.

Classification

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.

Management

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 MELANOMA

Introduction

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

Clinical Features

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

F4-2
FIGURE 4.:
Conjunctival melanocytic tumors. A, Macrocystic pigmented conjunctival nevus at medial limbus. B, Microcystic nonpigmented conjunctival nevus at superior limbus. C, Darkly pigmented primary acquired melanosis. D, Nodular pigmented melanoma with prominent feeder vessels. E, Mixed pigmented/nonpigmented conjunctival melanoma arising in the fornix from primary acquired melanosis. F, Tarsal melanoma arising from primary acquired melanosis.
F5-2
FIGURE 5.:
PAM with microscopic melanoma. A, Comparison of unaffected right eye and affected left eye with extensive PAM. B, PAM involving inferior bulbar conjunctiva. C, Diffuse PAM with multifocal intensely dark areas, likely representing microscopic melanoma.

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.

Classification

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

Management

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

Introduction

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.

Clinical Features

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.

F6-2
FIGURE 6.:
Conjunctival lymphoid tumors. A, Benign reactive lymphoid hyperplasia of the conjunctiva in medial bulbar region. B, Conjunctival lymphoma, appearing as a “salmon patch,” involving superior, medial, and inferior forniceal regions.

Predisposing Factors

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

Classification

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

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

SUMMARY

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.

REFERENCES

1. Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors. An Atlas and Textbook. 3rd ed. Philadelphia: Lippincott Wolters Kluwers; 2016:251-244.
2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49:3-24.
3. Grossniklaus HE, Green WR, Luckenbach M, et al. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea. 1987;6:78-116.
4. Shields CL, Demirci H, Karatza E, et al. Clinical survey of 1643 melanocytic and nonmelanocytic tumors of the conjunctiva. Ophthalmology. 2004;111:1747-1754.
5. Shields CL, Alset AE, Boal NS, et al. Conjunctival tumors in 5002 cases. Comparative analysis of benign versus malignant counterparts. The 2016 James D. Allen Lecture. Am J Ophthalmol. 2017;173:106-133.
6. Verma V, Shen D, Sieving PC, et al. The role of infectious agents in the etiology of ocular adnexal neoplasia. Surv Ophthalmol. 2008;53:312-331.
7. Ash JE. Epibulbar tumors. Am J Ophthalmol. 1950;33:1203-1219.
8. Lee SB, Au Eong KG, Saw SM, et al. Eye cancer incidence in Singapore. Br J Ophthalmol. 2000;84:767-770.
9. Templeton AC. Tumors of the eye and adnexa in Africans of Uganda. Cancer. 1967;20:1689-1698.
10. Shields CL, Sioufi K, Alset AE, et al. Conjunctival tumors in children. Features differentiating benign from malignant tumors. JAMA Ophthalmol. In press.
11. Conway RM, Graue GF, Pelayes DE, et al. Conjunctival carcinoma. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Switzerland: Springer; 2017:787-793.
12. Coupland SE, Barnhill R, Conway RM, et al. Conjunctival melanoma. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Switzerland: Springer; 2017:795-803.
13. Heegaard S, Chevez-Barrios P, White VA, et al. Ocular adnexal lymphoma. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Switzerland: Springer; 2017:849-854.
14. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol. 1995;39:429-450.
15. Gichuhi S, Sagoo MS, Weiss HA, et al. Epidemiology of ocular surface squamous neoplasia in Africa. Trop Med Int Health. 2013;18:1424-1443.
16. Gichuhi S, Ohnuma S, Sagoo MS, et al. Pathophysiology of ocular surface squamous neoplasia. Exp Eye Res. 2014;129:172-182.
17. Newton R, Ziegler J, Ateenyi-Agaba C, et al. The epidemiology of conjunctival squamous cell carcinoma in Uganda. Br J Cancer. 2002;87: 301-308.
18. Shields CL, Manchandia A, Subbiah R, et al. Pigmented squamous cell carcinoma in situ of the conjunctiva in 5 cases. Ophthalmology. 2008;115: 1673-1678.
19. Ramberg I, Heegaard S, Prause JU, et al. Squamous cell dysplasia and carcinoma of the conjunctiva. A nationwide, retrospective, epidemiological study of Danish patients. Acta Ophthalmol. 2015;93:663-666.
20. Emmanuel B, Ruder E, Lin SW, et al. Incidence of squamous-cell carcinoma of the conjunctiva and other eye cancers in the NIH-Diet AARP and Study Health. Ecancermedicalscience. 2012;6:254.
21. Sun EC, Fears TR, Goedert JJ. Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:73-77.
22. Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol. 1992;110: 525-527.
23. Basti S, Macsai MS. Ocular surface squamous neoplasia: a review. Cornea. 2003;22:687-704.
24. Arepalli S, Kaliki S, Shields CL, et al. Plaque radiotherapy for scleralinvasive conjunctival squamous cell carcinoma: analysis of 15 eyes. JAMA Ophthalmol. 2014;132:691-696.
25. Shields CL, Ramasubramanian A, Mellen P, et al. Conjunctival squamous cell carcinoma arising in immunosuppressed patients (organ transplant, human immunodeficiency virus infection). Ophthalmology. 2011;118:2133-2137.
26. Scott IU, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia. Ophthalmology. 2002;109:542-547.
27. Chauhan S, Sen S, Sharma A, et al. Human papillomavirus: a predictor of better survival in ocular surface squamous neoplasia patients. Br J Ophthalmol. 2012;96:1517-1521.
28. Eng HL, Lin TM, Chen SY, et al. Failure to detect human papillomavirus DNA in malignant epithelial neoplasms of conjunctiva by polymerase chain reaction. Am J Clin Path. 2002;117:429-436.
29. Scholz SL, Thomasen H, Reis H, et al. Frequent TERT promoter mutations in ocular surface squamous neoplasia. Invest Ophthalmol Vis Sci. 2015;56: 5854-5861.
30. Shields CL, Kaliki S, Kim HJ, et al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer classification. Cornea. 2013;32:248-256.
31. Shields JA, Shields CL, De Potter PV. Surgical approach to conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol. 1997;115: 808-815.
32. Nanji AA, Moon CS, Galor A, et al. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications. Ophthalmology. 2014;121:994-1000.
33. Siedlecki AN, Tapp S, Tosteson ANA, et al. Surgical versus interferon alpha-2b treatment strategies for ocular surface squamous neoplasia: a literature-based decision analysis. Cornea. 2016;35:613-618.
34. Shields CL, Naseripour M, Shields JA. Topical mitomycin C for extensive, recurrent conjunctival squamous cell carcinoma. Am J Ophthalmol. 2002; 133:601-606.
35. Yeatts RP, Engelbrecht NE, Curry CD, et al. 5-Fluorouracil for the treatment of intraepithelial neoplasia of the conjunctiva and cornea. Ophthalmology. 2000;107:2190-2195.
36. Karp CL, Galor A, Chhabra S, et al. Subconjunctival/perilesional recombinant interferon α2b for ocular surface squamous neoplasia: a 10-year review. Ophthalmology. 2010;117:2241-2246.
37. Shah S, Kaliki S, Kim HJ, et al. Topical interferon alpha 2b for management of ocular surface squamous neoplasia in 23 cases: outcomes based on American Joint Committee on Cancer (AJCC) classification. Arch Ophthalmol. 2012;130:159-164.
38. Kim HJ, Shields CL, Shah SU, et al. Giant ocular surface squamous neoplasia managed with interferon alpha-2b as immunotherapy or immunoreduction. Ophthalmology. 2012;119:938-944.
39. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology. 2012;119: 1974-1981.
40. Yu GP, Hu DN, McCormick S, et al. Conjunctival melanoma: is it increasing in the United States? Am J Ophthalmol. 2003;135:800-806.
41. Tuomaala S, Kivela T. Correspondence regarding Conjunctival melanoma: is it increasing in the United States? Am J Ophthalmol. 2003;136:1189-1190.
42. Seregard S. Conjunctival melanoma. Surv Ophthalmol. 1998;42:321-350.
43. Shields CL, Shields JA, Gunduz K, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol. 2000;118:1497-1507.
44. Shields CL, Markowitz JS, Belinsky I, et al. Conjunctival melanoma. Outcomes based on tumor origin in 382 consecutive cases. Ophthalmology. 2011;118:389-395.
45. Shields CL, Kaliki S, Al-Dahmash S, et al. American Joint Committee on Cancer (AJCC) clinical classification predicts conjunctival melanoma outcomes. Ophthalm Plast Reconstr Surg. 2012;5:313-323.
46. Shields CL, Kels JG, Shields JA. Melanoma of the eye: revealing hidden secrets, one at a time. Clin Dermatol. 2015;33:183-196.
47. Ling J, Tauscher R, Mehta V, et al. The role for sentinel lymph node biopsy in the management of conjunctival melanoma. Int Ophthalmol Clin. 2017; 57:87-101.
48. Campbell AA, Grob SR, Freitag SK. Controversies in sentinel lymph node biopsy for ocular neoplasms. Int Ophthalmol Clin. 2015;55:73-79.
49. Shields CL, Fasiuddin AF, Mashayekhi A, et al. Conjunctival nevi: clinical features and natural course in 410 consecutive patients. Arch Ophthalmol. 2004;122:167-175.
50. Gerner N, Norregaard JC, Jensen OA, et al. Conjunctival naevi in Denmark 1960-1980. A 21-year follow-up study. Acta Ophthalmol Scand. 1996;74: 334-337.
51. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz E. Zimmerman Lecture. Ophthalmology. 2008;115:511-519.
52. Folberg R, McLean IW. Primary acquired melanosis and melanoma of the conjunctiva: terminology, classification, and biologic behavior. Hum Pathol. 1986;17:652-654.
53. Larsen AC, Dahl C, Dahmcke CM, et al. BRAF mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions. Acta Ophthalmol. 2016;94:463-470.
54. Koopmans AE, Ober K, Dubbink HJ, et al. Prevalence and implications of TERT promoter mutation in uveal and conjunctival melanoma and in benign and premalignant conjunctival melanocytic lesions. Invest Ophthalmol Vis Sci. 2014;55:6024-6030.
55. Westekemper H, Kanmi S, Susskind D, et al. Expression of HSP 90, PTEN, and Bcl-2 in conjunctival melanoma. Br J Ophthalmol. 2011;95:853-858.
56. Damato B, Coupland SE. An audit of conjunctival melanoma treatment in Liverpool. Eye. 2009;23:801-809.
57. Shields JA, Shields CL, De Potter P. Surgical management of circumscribed conjunctival melanomas. Ophthal Plast Reconstr Surg. 1998;14:208-215.
58. Dagi Glass LR, Lawrence DP, Jakobiec FA, et al. Conjunctival melanoma responsive to combined systemic BRAF/MEK inhibitors. Ophthal Plast Reconstr Surg. November 23, 2016. [Epub ahead of print.]
59. Ford J, Thuro BA, Thakar S, et al. Immune checkpoint inhibitors for treatment of metastatic melanoma of the orbit and ocular adnexa. Ophthal Plast Reconstr Surg. September 21, 2016. [Epub ahead of print.]
60. Vora GK, Demirci H, Marr B, et al. Advances in the management of conjunctival melanoma. Surv Ophthalmol. 2017;62:26-42.
61. Larsen AC. Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile. Acta Ophthalmol. 2016;94:1-27.
62. Kirkegaard MM, Rasmussen PK, Coupland SE, et al. Conjunctival lymphoma - an international multicenter retrospective study. JAMA Ophthalmol. 2016;134:406-414.
63. Shields CL, Shields JA, Carvalho C, et al. Conjunctival lymphoid tumors: clinical analysis of 117 cases and relationship to systemic lymphoma. Ophthalmology. 2001;108:979-984.
64. Coupland SE, Krause L, Delecluse HJ, et al. Lymphoproliferative lesions of the ocular adnexa. Analysis of 112 cases. Ophthalmology. 1998;105: 1430-1441.
65. Stacy RC, Jakobiec FA, Schoenfield L, et al. Unifocal and multifocal reactive lymphoid hyperplasia vs follicular lymphoma of the ocular adnexa. Am J Ophthalmol. 2010;150:412-426.
66. Foster LH, Portell CA. The role of infectious agents, antibiotics, and antiviral therapy in the treatment of extranodal marginal zone lymphoma and other low-grade lymphomas. Curr Treat Options Oncol. 2015;16:28.
67. Sjö NC, Foegh P, Juhl BR, et al. Role of Helicobacter pylori in conjunctival mucosa-associated lymphoid tissue lymphoma. Ophthalmology. 2007;114: 182-186.
68. AlAkeely AG, Alkatan HM, Alsuhaibani AH, et al. Benign reactive lymphoid hyperplasia of the conjunctiva in childhood. Br J Ophthalmol. November 29, 2016. [Epub ahead of print.]
69. Beykin G, Pe’er J, Amir G, et al. Paediatric and adolescent elevated conjunctival lesions in the plical area: lymphoma or reactive lymphoid hyperplasia? Br J Ophthalmol. 2014;98:645-650.
70. Sniegowski MC, Roberts D, Bakhoum M, et al. Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines. Br J Ophthalmol. 2014;98:1255-1260.
71. Rath S, Connors JM, Dolman PJ, et al. Comparison of American Joint Committee on Cancer TNM-based staging system (7th edition) and Ann Arbor classification for predicting outcome in ocular adnexal lymphoma. Orbit. 2014;33:23-28.
72. Aronow ME, Portell CA, Rybicki LA, et al. Ocular adnexal lymphoma: assessment of a tumor-node-metastasis staging system. Ophthalmology. 2013;120:1915-1919.
73. Matsuo T, Yoshino T. Long-term follow-up results of observation of radiation for conjunctival malignant lymphoma. Ophthalmology. 2004;111: 1233-1237.
74. Bianciotto C, Shields CL, Lally SE, et al. CyberKnife radiosurgery for the treatment of intraocular and periocular lymphoma. Arch Ophthalmol. 2010; 128:1561-1567.
75. Zinzani PL, Alinari L, Stefoni V, et al. Rituximab in primary conjunctiva lymphoma. Leuk Res. 2005;29:107-108.
76. Abramson DH, Rollins I, Coleman M. Periocular mucosa-associated lymphoid/low grade lymphomas: treatment with antibiotics. Am J Ophthalmol. 2005;140:729-730.
77. Shome D, Esmaeli B. Targeted monoclonal antibody therapy and radioimmunotherapy for lymphoproliferative disorders of the ocular adnexa. Curr Opin Ophthalmol. 2008;19:414-421.
78. Aronow ME. Ocular adnexal lymphoma: evidence-based treatment approach. Int Ophthalmol Clin. 2015;55:97-109.
79. Tran KH, Campbell BA, Fua T, et al. Efficacy of low dose radiotherapy for primary orbital marginal zone lymphoma. Leuk Lymphoma. 2013;54: 491-496.
Keywords:

eye; conjunctiva; tumor; conjunctival intraepithelial neoplasia; squamous cell carcinoma; ocular surface squamous neoplasia; OSSN; nevus; primary acquired melanosis; melanoma; benign reactive lymphoid hyperplasia; lymphoma biomarkers

© 2017 by Asia Pacific Academy of Ophthalmology