4/9/2014

Conjunctival Melanoma

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Overview
Malignant melanoma of the conjunctiva presents as a raised, pigmented or nonpigmented lesion.[1] This lesion is uncommon but potentially lethal. It can arise in previously unblemished and unpigmented regions (approximately 10% of cases), from a preexisting nevus (approximately 20% of cases), or from the flat, spreading pigmentation of primary acquired melanosis with atypia (60-70% of cases). Examples of the disease are seen below.

Conjunctival melanomas may be associated w ith primary acquired melanosis (75%) or may arise from a preexisting nevus or de novo. Reprinted from University of Utah, Peter DeBry, Kw ok Li, and Nick Mamalis, MD, Ophthalmic Pathology: An Internet Ocular Pathology Archive, w ith permission from University of Utah Ophthalmic Pathology.

Conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

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Tarsal conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Invasive conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

In addition to spreading by lymphatics and the bloodstream, conjunctival melanoma can undergo direct extension to the eyeball and orbit.[2] The most frequent site of metastasis is the lung, followed by the liver, brain, and bone. In managing these patients, it is important to palpate the regional lymph nodes because spread to the ipsilateral preauricular, submandibular, and cervical nodes from the conjunctival sac is well recognized. Cohen et al reported an isolated gastric metastasis from a conjunctival melanoma.[3] Gastric metastases are frequently seen in cutaneous melanoma. Go to Ciliary Body Melanoma, Choroidal Melanoma, and Iris Melanoma for complete information on these topics.

Etiology
Together with mucus-secreting goblet cells within the stratified epithelium, melanocytic cells are found in the basal layer of the conjunctiva. These melanocytic cells are of neuroectodermal origin, and melanocytic tumors may arise from these cells. Theoretically, conjunctival melanoma may originate from primary acquired melanosis, from preexisting nevi, or as de novo lesions (that is, without any histologic or clinical evidence of a preexisting lesion). It may be difficult to determine the precursor lesion in many cases.[4]

Primary acquired melanosis

Approximately 50-75% of cases of conjunctival melanoma arise in a setting of primary acquired melanosis. Typically, primary acquired melanosis is found in middle-aged whites; along with malignant melanomas, it is extremely rare in the younger population. The natural history of primary acquired melanosis begins with the development of superficial epithelial pigmentation, with a typical peppered distribution of pigment. These lesions can slowly evolve over years, waxing and waning, extending in a radial manner over larger areas of conjunctiva and skin.

Nevus
Evidence indicates that approximately 20-25% of patients with conjunctival melanoma have a history or microscopic evidence of a benign conjunctival nevus. (See the image below.)

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Conjunctival nevus. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Malignant melanomas arising from nevi (they may arise from junctional and compound nevi) usually appear as a change (increasing nodularity, variegated pigmentation, bleeding, or inflammation) in known pigmented lesions of the conjunctiva, but it may be impossible to establish a clear clinical history of a preexisting history of nevus. Occasional reports of cases showing the presence of both acquired melanosis and a nevus have been documented. However, some uncertainty surrounds the role of nevi in the histogenesis of malignant melanoma. Previously, compressed cells at the melanoma base were considered to be nevi, but reports now suggest that these flattened cells are, in fact, compressed melanoma cells and not nevus cells.

De novo
Approximately 25% of cases of conjunctival melanoma come from de novo lesions. These lesions can be ulcerative, amelanotic, papillary, or fungating.

Epidemiology
Incidence in the United States
Primary malignant melanoma of the conjunctiva is much less common than are intraocular or skin melanomas. Malignant melanoma of the conjunctiva accounts for only 2% of all ocular malignancies.

International Incidence
The incidence of primary acquired melanosis with atypia or with malignant melanoma of the conjunctiva has been estimated to be 0.052 cases a year per 100,000 population in Denmark.[5] In Sweden, only 2 new cases of primary malignant melanoma of the conjunctiva were diagnosed in 1987; the agestandardized incidence of conjunctival melanoma is 0.74 cases per 1 million population in men, and 0.45 cases per 1 million population in women. The incidence of conjunctival melanoma increased in Sweden between 1960 and 2005.[6]

Race, sex, and age predilections

Conjunctival melanoma occurs predominantly in whites and is rarely seen in blacks. No clear sex predilection has been established. Typically, conjunctival melanoma occurs in patients in their early 50s. It is rarely seen in people younger than 20 years, although Strempel and Kroll reported 3 cases of conjunctival malignant melanoma in children.[7]

Prognosis
The overall tumor-related mortality rate for conjunctival melanoma is 25-26%. This rate increases to 40-44% if the tumor has arisen from primary acquired melanosis with an intraepithelial pagetoid growth pattern. This tumor tends to spread first to the parotid or submandibular nodes.[8] In several studies, the 5-year survival rate for patients with conjunctival melanoma after surgery and/or radiotherapy was 83-84%, and the 10-year survival rate was 69-80%. The 5-year recurrence rate was 39%.
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Paridaens et al listed the following prognostic factors in conjunctival melanoma (in increasing order of mortality risk): Two-fold risk - Tumors in unfavorable locations (eg, palpebral conjunctiva, fornices, plica, caruncle, lid margins) Three-fold risk - Mixed cell types, compared with pure spindle-cell types Four-fold risk - Histologic evidence of lymphatic invasion; initial thickness greater than 4 mm for tumors in unfavorable locations only Five-fold risk - Multifocal tumors in patients with lesions in favorable (epibulbar) locations only Other poor prognostic features, as outlined by Jakobiec and associates, include moderate-to-severe atypia, a paucity of small polyhedral cells in the tumor, invasion of deeper ocular tissues, greater than 5 mitotic figures per 10 high-power fields, and lack of a tumor-induced inflammatory response.

Patient History
Eliciting a good history of the growth characteristics of each lesion is important in patients with conjunctival melanomas. The well-informed patient often is aware of subtle changes that may be crucial in identifying these lesions. Melanomas that arise without a preexisting conjunctival nevus are usually at the limbus and are believed to initially have a short horizontal growth phase followed by a rapid vertical growth phase. Melanomas that arise in a preexisting nevus are often characterized by growth of the lesion or by increased vascularity. Any nevus that has increased in vascularity, size, or solidity or that has become fixed to the underlying sclera (nevi are always freely movable over the sclera, except at the fixation point at the limbus) should be suspected of being a malignant melanoma. In the case of primary acquired melanosis, the onset of malignant degeneration is often heralded by the development of nodular thickening in a previously flat area of pigmentation. Other noteworthy features of malignant degeneration include increased vascularity, fixation of the conjunctiva to the underlying sclera, and hemorrhage.

Physical Examination
The clinical presentation of conjunctival melanoma can vary and depends on the antecedent status of the conjunctiva. A melanoma can be distinguished from primary acquired melanosis by its tendency to become fixed to the underlying tissues, which is not a feature of primary acquired melanosis. In managing patients with conjunctival melanoma, it is important to palpate the regional lymph nodes, because spread to the ipsilateral preauricular, submandibular, and cervical nodes from the conjunctival sac is well recognized. Conjunctival melanomas may extend onto the peripheral limbus. Most melanomatous nodules at the limbus affect the peripheral cornea; some grow circumferentially around the limbus. Rarely, a melanomatous nodule may be located more centrally in the cornea. Pigmentation of the eyelid margins and skin occasionally accompanies primary conjunctival melanomas, particularly those located on the palpebral conjunctiva and fornix; this combined presentation discloses a poorer prognosis. Other uncommon manifestations include poliosis.

Monitoring
Documentation by photography and observation for growth of conjunctival melanomas over regular intervals of time is recommended for small lesions.

Differential Diagnosis
Not all conjunctival melanomas are pigmented; melanomas with little or no pigment can look like squamous and
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sebaceous gland carcinomas, papillomas, lymphoid hyperplasia, and even pterygia. Amelanotic melanomas can puzzle even the pathologist; staining with the S-100 protein stain and the more specific homatropine methylbromide (HMB-45) antibody stain can assist in diagnosis. Differentials to consider include the following: Choroidal Melanoma Ciliary Body Melanoma Iris Melanoma Conjunctival squamous cell carcinoma Conjunctival melanosis Conjunctival mycosis Conjunctival seborrheic keratosis Acquired melanosis (primary or secondary) Foreign body (eg, graphite) Drug toxicity (eg, epinephrine) Conjunctival pseudomelanoma - Iatrogenic secondary to scleral tunnel

Ultrasonographic Biomicroscopy
Extrascleral extension of a ciliary body melanoma can simulate a conjunctival melanoma in some cases. Ultrasonographic biomicroscopy (UBM) of such eyes confirms the presence, character, and extent of the underlying ciliary body tumor and often reveals the route of access of the tumor to the surface by way of a scleral emissary canal. UBM may serve as an additional diagnostic tool to estimate the tumor thickness before surgical resection of a conjunctival melanoma.[9]

Conjunctival Excision Biopsy

Because acquired melanosis, nevi, melanomas, and other pigmented lesions (eg, papillomas, adrenochrome deposits, foreign bodies, blood-filled cysts) may have comparable clinical features, biopsies of such lesions usually should be taken before more extensive therapy is considered. A biopsy of a malignant melanoma does not seem to augment its lethality and may prevent needless, mutilating surgery. Conjunctiva is an easily accessible tissue source for diagnostic biopsy.[10, 11, 12, 13]

Histopathology
Invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned. (See the images below.)

Histologic findings of invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

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Histologic findings of invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Dysplastic melanocytes may invade beyond the epithelium into the substantia propria or into the globe or lids. Reprinted from University of Utah, Peter DeBry, Kw ok Li, and Nick Mamalis, MD, Ophthalmic Pathology: An Internet Ocular Pathology Archive, w ith permission from University of Utah Ophthalmic Pathology.

Melanoma cells are larger than nevus cells and grow as irregular nests or as individual cells in nodules that extend through all the layers of the epidermis and dermis. Typically, these cells have large nuclei with chromatin clumping at the periphery of the nuclear membrane and distinct eosinophilic nucleoli. The ascent of atypical melanocytes to the surface of the conjunctival epithelium is indicative of malignancy.[14] As previously mentioned, not all conjunctival melanomas are pigmented; melanomas with little or no pigment can look like squamous and sebaceous gland carcinomas, papillomas, lymphoid hyperplasia, and even pterygia. Staining with the S-100 protein stain and the more specific homatropine methylbromide (HMB-45) antibody stain can assist in diagnosis.[15] The Callender classification for melanoma does not apply to conjunctival melanomas.

Staging
This classification applies only to melanoma. Histologic verification of the melanocytic lesion should occur. The assessment of the cancer is based on inspection, slit lamp examination, palpation of the regional lymph nodes, and when indicated, radiologic (including computed tomography) and ultrasonographic examination of the orbit, paranasal sinuses, and chest. Complete resection of the primary site is indicated. Histologic study of the margins and the deep aspect of resected tissues is necessary. Resection or needle biopsy of enlarged regional lymph nodes or orbital masses is desirable.[16, 17, 18]

Clinical classification (cTNM)

A primary tumor (T) is classified as follows: TX - Primary tumor cannot be assessed TO - No evidence of primary tumor T1 - Tumor(s) of bulbar conjunctiva occupying 1 quadrant or less T2 - Tumor(s) of bulbar conjunctiva occupying more than 1 quadrant T3 - Tumor(s) of conjunctival fornix and/or palpebral conjunctiva and/or caruncle T4 - Tumor invades eyelid, cornea, and/or orbit (see the images below)

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An aggressive conjunctival melanoma w ith lid involvement. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Large conjunctival melanoma that has invaded the orbit. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.

Regional lymph nodes (N) are classified as follows: NX - Regional lymph nodes cannot be assessed N0 - No regional lymph node metastasis N1 - Regional lymph node metastasis Distant metastasis (M) is classified as follows: MX - Distant metastasis cannot be assessed M0 - No distant metastasis M1 - Distant metastasis

Pathologic classification (pTNM)

Pathologic tumor (T) staging (extent of disease through completion of definitive surgery) for conjunctival melanoma is summarized as follows, where pT is primary tumor[19, 20] : pTX Primary tumor cannot be assessed pT0 - No evidence of primary tumor pTis - Melanoma confined to the conjunctival epithelium; less than or equal to 1 quadrant*; melanoma confined to the conjunctival epithelium; melanoma in situ (includes the term primary acquired melanosis): Atypia replacing greater than 75% of normal epithelial thickness Epithelioid cytology including, (1) abundant cytoplasm, (2) vesicular nuclei or prominent nucleoli, and/or (3) the presence of intraepithelial nests of atypical cells ( 1 quadrant) T1 - Conjunctival melanoma of the bulbar conjunctiva pT1a - Thickness of 0.5 mm or less with invasion of the substantia propria; more than 1 but less than or equal to 2 quadrants* pT1b - Thickness greater than 0.5 mm but at least 1.5 mm with invasion of the substantia propria; more than 2 but less than or equal to 3 quadrants* pT1c Thickness greater than 1.5 mm with invasion of the substantia propria; more than 3 quadrants* T2 - Conjunctival melanoma of the nonbulbar conjunctiva (palpebral, forniceal, caruncular) region pT2a - Thickness 0.5 mm or less with invasion of the substantia propria pT2b - Thickness greater than 0.5 but at least 1.5 mm with invasion of the substantia propria pT2c - Thickness greater than 1.5 mm with invasion of the substantia propria pT3 - Melanoma invades the eye, eyelid, nasolacrimal system, sinuses, or orbit pT4 - Melanoma invades the central nervous system *Quadrants are defined by clock hour, starting at the limbus (eg, 3, 6, 9, 12) and extending from central cornea to
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and beyond the eyelid margins; this bisects the caruncle.

Stage group
No stage grouping is recommended at this time.

Histopathologic type
This categorization applies only to melanoma of the conjunctiva.

Histopathologic grade
The histopathologic grade, as follows, represents the origin of the primary tumor: GX - Origin cannot be assessed G0 - Primary acquired melanosis G1 - Malignant melanoma arises from a nevus G2 - Malignant melanoma arises from a primary acquired melanosis G3 - Malignant melanoma arises de novo

Medical and Radiologic Care

Mitomycin is an off-label drug that is used in ophthalmology. It is a potent chemotherapeutic agent that inhibits fibroblasts and, therefore, diminishes scarring after glaucoma filtering surgery. It has been used as an adjunct in pterygium surgery, photorefractive keratoplasty haze management, and conjunctival melanoma management. (Applied topically, however, mitomycin-C has reportedly resulted in an intumescent lens, requiring surgical intervention.)[21, 22] Outpatient radiotherapy is indicated as needed in patients with conjunctival melanoma.

Surgical Care
In an adult, all elevated or enlarged pigmented lesions with a history of change should be excised as suspected malignant melanoma. Note that metastatic melanomas from anywhere in the body and extensions from ciliary body melanomas may first become apparent in the conjunctiva. The treatment of conjunctival melanoma is surgical, with complete removal of the tumor, if possible. Damato and Coupland reported that high rates of local tumor control, with little ocular morbidity, resulted from excision of invasive melanoma with adjunctive brachytherapy and topical chemotherapy.[23] This audit also noted that when no caruncular involvement had occurred, disease-specific mortality was rare, except in patients who were referred after a surgical procedure. The investigators results suggested that risks of local recurrence and metastatic death are increased by inadequate surgical intervention. The suggestions of Shields in the surgical management of circumscribed conjunctival melanomas are advocated. The "no touch" technique is essential throughout the procedure. No surgical instrument is used more than once in any area (addressing the concern of microscopically seeding tumor cells). Treatment of primary conjunctival melanomas in the limbal region of the bulbar conjunctiva can usually be accomplished with initial, localized absolute alcohol epitheliectomy. This treatment is followed by wide (2- to 3-mm clear zone), local excision by a partial lamellar scleroconjunctivectomy. The bed of excision, as well as the adjacent conjunctiva or cornea away from the nodule, is treated with supplemental double freeze-thaw cryotherapy, using a specific technique (lifting the conjunctiva). Treat the entire area of the lesion, because untreated areas may lead to spread through local lymphatic channels. Laser therapy after excision has also been used.
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Nodal involvement indicates extensive metastatic disease, but occasionally, cases in which lesions were limited to regional nodes and cured by node resection have occurred. If the tumors are located in the fornical or palpebral conjunctiva, wide surgical resection with alcohol treatment to the scleral base and cryotherapy to the surrounding conjunctiva is performed.

Exenteration of the orbit

Exenteration of the orbit sometimes is necessary for large melanomas that have invaded the orbit, but this procedure does not improve the prognosis. It may be performed for patients in whom the objective is to do local debulking of a tumor, because this procedure is not linked to increased patient survival. The use of radical neck dissection at the period of exenteration is not without controversy.[24] The poor survival rate, despite orbital exenteration, suggests that metastasis has already occurred at the time of treatment and confirms that the extent of the disease at diagnosis is the most important factor in determining the outcome. Considerable orbital invasion indicates the necessity for exenteration; however, subtotal exenteration can be carried out if no evidence of radial extension of the lesion to the skin of the anterior lid exists.

Consultations
Consultation with a radiation oncologist is appropriate.[25] As previously stated, Damato and Coupland reported that high rates of local tumor control, with little ocular morbidity, resulted from excision of invasive melanoma with adjunctive brachytherapy and topical chemotherapy.[23]

Contributor Information and Disclosures

Author Manolette R Roque, MD, MBA, FPAO Section Chief, Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center; Section Chief, Ocular Immunology and Uveitis, International Eye Institute, St Luke's Medical Center Global City; Senior Eye Surgeon, The LASIK Surgery Clinic; Director, AMC Eye Center, Alabang Medical Center Manolette R Roque, MD, MBA, FPAO is a member of the following medical societies: American Academy of Ophthalmic Executives, American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, American Society of Ophthalmic Administrators, American Uveitis Society, International Ocular Inflammation Society, Philippine Medical Association, Philippine Ocular Inflammation Society, and Philippine Society of Cataract and Refractive Surgery Disclosure: Nothing to disclose. Coauthor(s) Barbara L Roque, MD, DPBO, FPAO Senior Partner, Roque Eye Clinic; Chief of Service, Pediatric Ophthalmology and Strabismus Section, Department of Ophthalmology, Asian Hospital and Medical Center; Active Consultant Staff, International Eye Institute, St Luke's Medical Center Global City Barbara L Roque, MD, DPBO, FPAO is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Society of Author: Manolette R Roque, MD, MBA, FPAO; Chief Editor: Hampton Roy Sr, MD Cataract and Refractive Surgery, Philippine Academy of Ophthalmology, Philippine Society of Cataract and more... Refractive Surgery, and Philippine Society of Pediatric Ophthalmolo

Conjunctival Melanoma

Updated: Oct 9, 2013 Disclosure: Nothing to disclose. C Stephen Foster, MD, FACS, FACR, FAAO Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution C Stephen Foster, MD, FACS, FACR, FAAO is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Association of Immunologists, American College of Rheumatology, American College of Surgeons, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, Massachusetts Medical Society, Royal Society of Medicine, and Sigma Xi
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Disclosure: Nothing to disclose. Specialty Editor Board Brian A Phillpotts, MD Former Vitreo-Retinal Service Director, Former Program Director, Clinical Assistant Professor, Department of Ophthalmology, Howard University College of Medicine Brian A Phillpotts, MD is a member of the following medical societies: American Academy of Ophthalmology, American Diabetes Association, American Medical Association, and National Medical Association Disclosure: Nothing to disclose. Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology Disclosure: Nothing to disclose. Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Institute Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, and International Society of Refractive Surgery Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; RPS Ownership interest Other; Bausch & Lomb Honoraria Speaking and teaching; Merck Consulting fee Consulting; Bausch & Lomb Consulting; Merck Honoraria Speaking and teaching Lance L Brown, OD, MD Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri Disclosure: Nothing to disclose. Chief Editor Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology Disclosure: Nothing to disclose.

References
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6. Triay E, Bergman L, Nilsson B, All-Ericsson C, Seregard S. Time trends in the incidence of conjunctival melanoma in Sweden. Br J Ophthalmol. Nov 2009;93(11):1524-8. [Medline]. 7. Strempel I, Kroll P. Conjunctival malignant melanoma in children. Ophthalmologica. 1999;213(2):129-32. [Medline]. 8. Kujala E, Tuomaala S, Eskelin S, Kivel T. Mortality after uveal and conjunctival melanoma: which tumour is more deadly?. Acta Ophthalmol. Mar 2009;87(2):149-53. [Medline]. 9. Ho VH, Prager TC, Diwan H, Prieto V, Esmaeli B. Ultrasound biomicroscopy for estimation of tumor thickness for conjunctival melanoma. J Clin Ultrasound. Nov-Dec 2007;35(9):533-7. [Medline]. 10. Esmaeli B, Eicher S, Popp J, Delpassand E, Prieto VG, Gershenwald JE. Sentinel lymph node biopsy for conjunctival melanoma. Ophthal Plast Reconstr Surg. Nov 2001;17(6):436-42. [Medline]. 11. Nijhawan N, Ross MI, Diba R, Ahmadi MA, Esmaeli B. Experience with sentinel lymph node biopsy for eyelid and conjunctival malignancies at a cancer center. Ophthal Plast Reconstr Surg. Jul 2004;20(4):291-5. [Medline]. 12. Tuomaala S, Kivel T. Metastatic pattern and survival in disseminated conjunctival melanoma: implications for sentinel lymph node biopsy. Ophthalmology. Apr 2004;111(4):816-21. [Medline]. 13. Cohen VM, Tsimpida M, Hungerford JL, Jan H, Cerio R, Moir G. Prospective study of sentinel lymph node biopsy for conjunctival melanoma. Br J Ophthalmol. Sep 24 2013;[Medline]. 14. Esmaeli B, Roberts D, Ross M, Fellman M, Cruz H, Kim SK, et al. Histologic features of conjunctival melanoma predictive of metastasis and death (an American Ophthalmological thesis). Trans Am Ophthalmol Soc . Dec 2012;110:64-73. [Medline]. [Full Text]. 15. Heegaard S, Jensen OA, Prause JU. Immunohistochemical diagnosis of malignant melanoma of the conjunctiva and uvea: comparison of the novel antibody against melan-A with S100 protein and HMB-45. Melanoma Res . Aug 2000;10(4):350-4. [Medline]. 16. Damato B, Coupland SE. Clinical mapping of conjunctival melanomas. Br J Ophthalmol. Nov 2008;92(11):1545-9. [Medline]. 17. Damato B, Coupland SE. Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Experiment Ophthalmol. Nov 2008;36(8):786-95. [Medline]. 18. Maly A, Epstein D, Meir K, Pe'er J. Histological criteria for grading of atypia in melanocytic conjunctival lesions. Pathology. Dec 2008;40(7):676-81. [Medline]. 19. Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer Science and Business Media LLC; 2010. 20. Lim LA, Madigan MC, Conway RM. Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol. 2013;6:521-31. [Medline]. [Full Text]. 21. Finger PT, Czechonska G, Liarikos S. Topical mitomycin C chemotherapy for conjunctival melanoma and PAM with atypia. Br J Ophthalmol. May 1998;82(5):476-9. [Medline]. [Full Text]. 22. Cunneen TS, Conway RM, Madigan MC. In vitro effects of histone deacetylase inhibitors and mitomycin C on tenon capsule fibroblasts and conjunctival melanoma cells. Arch Ophthalmol. Apr 2009;127(4):414-20. [Medline]. 23. Damato B, Coupland SE. An audit of conjunctival melanoma treatment in Liverpool. Eye (Lond). Apr 2009;23(4):801-9. [Medline]. 24. Paridaens AD, McCartney AC, Minassian DC, Hungerford JL. Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol. Jul 1994;78(7):520-8. [Medline]. [Full Text]. 25. Aronow ME, Singh AD. Radiation therapy: conjunctival and eyelid tumors. Dev Ophthalmol. 2013;52:8593. [Medline]. Medscape Reference 2011 WebMD, LLC
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