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Melanoma, Iris

Squamous Cell Carcinoma, Conjunctival




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AUTHOR AND EDITOR INFORMATION

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Author: Manolette R Roque, MD, MBA, DPBO, FPAO, President and CEO, Chief of Service, Ocular Immunology and Uveitis, Consulting Staff, Cornea and Refractive Surgery, Eye Republic Ophthalmology Clinic; General Manager, Ophthalmic Consultants Philippines Co; Consulting Staff, CME Liaison, Section Chief of Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center

Manolette R Roque, MD, MBA, DPBO, FPAO, is a member of the following medical societies: American Academy of Ophthalmic Executives, 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

Coauthor(s): Barbara L Roque, MD, Full Partner, Ophthalmic Consultants Philippines Co, Chief of Service, Pediatric Ophthalmology and Strabismus, Consulting Staff, Orbit and Eye Plastics, EYE REPUBLIC Ophthalmology Clinic; 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

Editors: Brian A Phillpotts, MD, Former Vitreo-Retinal Service Director, Former Program Director, Clinical Assistant Professor, Department of Ophthalmology, Howard University College of Medicine; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles; Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Hospital; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Author and Editor Disclosure

Synonyms and related keywords: conjunctival melanoma, malignant melanoma of the conjunctiva, malignancy, tumor, exenteration, cryotherapy

INTRODUCTION

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Background

Malignant melanoma of the conjunctiva presents as a raised, pigmented or nonpigmented lesion that appears in adult life. 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).

Pathophysiology

Primary site: Together with mucus-secreting goblet cells within the stratified epithelium, melanocytic cells exist in the basal layer of the conjunctiva. These melanocytic cells are of neuroectodermal origin, and melanocytic tumors may arise from these cells.

Melanomas may arise from junctional and compound nevi. Some uncertainty exists regarding the role of nevi in the histogenesis of malignant melanoma. Previously, compressed cells at the melanoma base have been considered to be nevi, but recent reports suggest that these flattened cells are, in fact, compressed melanoma cells and not nevus cells.

Melanomas also may arise from primary acquired melanosis or de novo.

Regional lymph nodes: The regional lymph nodes are parotid, preauricular, submandibular, and cervical.

For pN (see Staging), histologic examination of a regional lymphadenectomy specimen ordinarily includes 6 or more regional lymph nodes.

Metastatic sites: In addition to spread by lymphatics and the bloodstream, direct extension to the eyeball and orbit occurs.

Frequency

United States

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

International

Denmark: Incidence of primary acquired melanosis (PAM) with atypia or with malignant melanoma of the conjunctiva was estimated to be 0.052 cases a year per 100,000.

Sweden: Only 2 new cases of primary malignant melanoma of the conjunctiva were diagnosed in 1987.

Mortality/Morbidity

The overall tumor-related mortality rate for conjunctival melanoma is 25-26%. This rate increases to 40-44% if the tumor arose from PAM with an intraepithelial pagetoid growth pattern. This tumor tends to spread first to the parotid or submandibular nodes.

  • Tumor thickness, mixed cell type, and lymphatic invasion on histologic examination were found to increase the death rate (3-4 times).
  • Other poor prognostic features, outlined by Jakobiec and associates, include tumor in unfavorable locations (caruncle, palpebral conjunctiva, or fornical conjunctiva), 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 an inflammatory response induced by the tumor.1

Race

This condition occurs predominantly in whites and rarely is seen in blacks.

Sex

No clear sex predilection has been established.

Age

Typically, conjunctival melanoma occurs in patients in their early 50s. It rarely is seen in people younger than 20 years. Strempel reported 3 cases of conjunctival malignant melanoma in children.2


CLINICAL

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History

It is important to elicit a good history of growth characteristics of each lesion. 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 usually are at the limbus and are believed to have, initially, a short horizontal growth phase followed by a rapid vertical growth phase. Melanomas that arise in a preexisting nevus often are characterized by growth of the lesion or by increased vascularity.
  • The onset of malignant degeneration, in the case of PAM, often is 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

The clinical presentation can be variable and is dependent on the antecedent status of the conjunctiva. A melanoma can be distinguished from PAM by its tendency to become fixed to the underlying tissues, which is not a feature of PAM.

  • 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.

Causes

Theoretically, conjunctival melanoma may originate from PAM, from preexisting nevi, and as de novo lesions. It may be difficult to determine the precursor lesion in many cases.

  • Primary acquired melanosis
    • Approximately 50-75% of cases of conjunctival melanoma arise in a setting of PAM. Typically, it is a lesion found in middle-aged whites, and, along with malignant melanomas, it is extremely rare in the younger population.
    • The natural history of PAM begins with the development of superficial epithelial pigmentation, with a typical peppered distribution of pigment. These lesions can evolve slowly over years, waxing and waning, extending in a radial manner over larger areas of conjunctiva and skin.
  • Nevus
    • Approximately 20-25% of patients with conjunctival melanoma had a history or microscopic evidence of a benign conjunctival nevus.
    • Malignant melanomas arising from 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.
  • De novo (without any histologic or clinical evidence of a preexisting lesion)
    • Approximately 25% of cases of conjunctival melanoma come from de novo lesions.
    • These lesions can be ulcerative, amelanotic, papillary, or fungating.
  • Occasional reports of cases showing the presence of both acquired melanosis and a nevus have been documented.


DIFFERENTIALS

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Melanoma, Choroidal
Melanoma, Ciliary Body
Melanoma, Iris
Squamous Cell Carcinoma, Conjunctival

Other Problems to be Considered

Conjunctival nevi
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


WORKUP

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Imaging Studies

  • Ultrasound biomicroscopy (UBM)
    • Extrascleral extension of a ciliary body melanoma can simulate a conjunctival melanoma in some cases. 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.

Procedures

  • Conjunctival excision biopsy: Conjunctiva is an easily accessible tissue source for diagnostic biopsy. A biopsy of a malignant melanoma does not seem to increase its lethality, and it may prevent unnecessary, mutilating surgery.

Histologic Findings

Invasive melanoma cells may be small polyhedral, epithelioid, spindled, or ballooned.

The Callender classification for melanoma does not apply to conjunctival melanomas (see Histopathologic Type). 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.

Staging

This classification applies only to melanoma. Histologic verification of the melanocytic lesion should occur.

Clinical staging: 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.

Pathologic staging: 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.

  • Clinical classification (cTNM)
    • Primary tumor (T)
      • 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
    • Regional lymph nodes (N)
      • NX - Regional lymph nodes cannot be assessed.
      • N0 - No regional lymph node metastasis
      • N1 - Regional lymph node metastasis
    • Distant metastasis (M)
      • MX - Distant metastasis cannot be assessed.
      • M0 - No distant metastasis
      • M1 - Distant metastasis
  • Pathologic classification (pTNM)
    • Primary tumor (pT)
      • pTX - Primary tumor cannot be assessed.
      • pT0 - No evidence of primary tumor
      • pT1 - Tumor(s) of bulbar conjunctiva occupying 1 quadrant or less and 2 mm or less in thickness
      • pT2 - Tumor(s) of bulbar conjunctiva occupying more than 1 quadrant and 2 mm or less in thickness
      • pT3 - Tumor(s) of the conjunctival fornix, and/or palpebral, and/or caruncle or tumor(s) of the bulbar conjunctiva, more than 2 mm in thickness
      • pT4 - Tumor invades eyelid, cornea, and/or orbit
    • Regional lymph nodes (pN)
      • pNX - Regional lymph nodes cannot be assessed.
      • pN0 - No regional lymph node metastasis
      • pN1 - Regional lymph node metastasis
    • Distant metastasis
      • pMX - Distant metastasis cannot be assessed.
      • pM0 - No distant metastasis
      • pM1 - Distant metastasis
  • Stage group: No stage grouping is recommended at this time.
  • Histopathologic type: This categorization applies only to melanoma of the conjunctiva.
  • Histopathologic grade: This grade represents the origin of the primary tumor.
    • GX - Origin cannot be assessed.
    • G0 - PAM
    • G1 - Malignant melanoma arises from a nevus
    • G2 - Malignant melanoma arises from a PAM
    • G3 - Malignant melanoma arises de novo


TREATMENT

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Medical Care

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

  • The treatment of conjunctival melanoma is primarily surgical.
  • Finger et al presented a more conservative approach with topical mitomycin-C as an option.3 They concluded that topical mitomycin-C chemotherapy was tolerated as a treatment for conjunctival melanoma and PAM with atypia (10 patients with 2.5-year follow-up care).3

Surgical Care

The treatment of conjunctival melanoma is surgical, with complete removal of the tumor, if possible.

  • 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 usually can be accomplished with initial localized absolute alcohol epitheliectomy.
  • This treatment is followed with wide (2-3 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 by a specific technique (lifting the conjunctiva). It is important to treat the entire area of the lesion because untreated areas may lead to spread through local lymphatic channels. Laser therapy after excision also has been used.
  • 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 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 with increased patient survival. The use of radical neck dissection at the period of exenteration is not without controversy.
  • The poor survival rate, in spite of 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 to determine 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. Nodal involvement indicates extensive metastatic disease, but, occasionally, cases in which lesions were limited to regional nodes and cured by node resection have occurred.

Consultations

Radiation-oncologist


MEDICATION

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Drug Category: Antimetabolites

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 (PRK) haze management, and conjunctival melanoma management.

Drug NameMitomycin and/or mitomycin-C (Mutamycin)
DescriptionAn antibiotic isolated from the broth of Streptomyces caespitosus that has been shown to have antitumor activity. The primary preparation is meant for injection. Has since been used in ophthalmology as a topical adjunct to antifibrosis management.
Adult DoseTopical preparation: 0.02% (0.2 mg/mL) and 0.04% (0.4 mg/mL)
For glaucoma: Apply once with a cellulose sponge during the procedure for 2-4 min, and wash copiously with BSS
For pterygium: Apply once with a cellulose sponge during the procedure for 2-4 min, and wash copiously with BSS and/or apply topically 1 gtt bid to qid for a variable length of time
For conjunctival melanoma: Apply topically 1 gtt bid to qid for a variable length of time
Pediatric DoseNot established
ContraindicationsPatients who have demonstrated a hypersensitive or idiosyncratic reaction to it in the past; if used systemically, contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes; recent chicken pox, herpes zoster, and impaired renal function
InteractionsSystemically administered, interactions have been reported with bone marrow depressants, doxorubicin, live viral vaccines, and vinca alkaloids
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsSeveral precautions exist when using mitomycin systemically, to include shortness of breath and severe bronchospasm reported following administration of vinca alkaloids in patients who had previously or simultaneously received mitomycin; a few cases of adult respiratory distress syndrome have been reported in patients receiving mitomycin in combination with other chemotherapy and maintained at FIO2 concentrations greater than 50% perioperatively; in ophthalmology, precautions on its prolonged topical use may lead to nonhealing ulcers and/or scleral melting


FOLLOW-UP

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Further Outpatient Care

  • Radiotherapy as needed

Complications

  • Metastasis: 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.4 Gastric metastases are frequently seen in cutaneous melanoma.
  • Intumescent lens: Applied topically, mitomycin-C has reportedly resulted in an intumescent lens, requiring surgical intervention.

Prognosis

  • In several studies, the 5-year survival rate after surgery and/or radiotherapy was 83-84%, and the 10-year survival rate was 69-80%. The 5-year recurrence rate in both studies was 39%.
  • Paridaens et al listed the following prognostic factors associated with a higher mortality (in increasing order of mortality risk)5:
    • 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


MISCELLANEOUS

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Medical/Legal Pitfalls

  • In an adult, all elevated or enlarged pigmented lesions with a history of change should be excised as suspected malignant melanoma. Any nevus that has increased in vascularity, size, or solidity or that has become fixed to the underlying sclera (nevi always are freely movable over the sclera, except at the fixation point at the limbus) should be suspected of being a malignant melanoma.
  • Note that metastatic melanomas from anywhere in the body and extensions from ciliary body melanomas may first become apparent in the conjunctiva.

Special Concerns

  • 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. Amelanotic melanomas can even puzzle the pathologist; staining with the S-100 protein stain and the more specific homatropine methylbromide (HMB-45) antibody stain can assist in diagnosis. Since 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 it may prevent needless, mutilating surgery.


ACKNOWLEDGMENTS

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The author was a fellow and affiliated with the Ocular Immunology and Uveitis Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, while performing this work.


MULTIMEDIA

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Media file 1:  Conjunctival melanomas may be associated with primary acquired melanosis (75%) or may arise from a preexisting nevus or de novo. Reprinted from University of Utah, Peter DeBry, Kwok Li, and Nick Mamalis, MD, Ophthalmic Pathology: An Internet Ocular Pathology Archive, with permission from University of Utah Ophthalmic Pathology.
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Media type:  Photo

Media file 2:  Dysplastic melanocytes may invade beyond the epithelium into the substantia propria or into the globe or lids. Reprinted from University of Utah, Peter DeBry, Kwok Li, and Nick Mamalis, MD, Ophthalmic Pathology: An Internet Ocular Pathology Archive, with permission from University of Utah Ophthalmic Pathology.
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Media type:  Photo

Media file 3:  Conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media type:  Photo

Media file 4:  Conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media type:  Photo

Media file 5:  Tarsal conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media file 6:  Conjunctival nevus. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media type:  Photo

Media file 7:  An aggressive conjunctival melanoma with lid involvement. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media type:  Photo

Media file 8:  Large conjunctival melanoma that has invaded the orbit. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media type:  Photo

Media file 9:  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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Media type:  Photo

Media file 10:  Conjunctival melanomas. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Media file 11:  Invasive conjunctival melanoma. Courtesy of Peter Rubin, MD, Director, Eye Plastics Service, Massachusetts Eye & Ear Infirmary, Boston, MA.
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Melanoma, Conjunctival excerpt

Article Last Updated: Dec 27, 2007