Eye and Orbit





Adult Ocular Lesions


External Lesions


Malignant Melanoma of the Conjunctiva


Clinical Features



Deceased






  • Usually pigmented (may be amelanotic), nodular, elevated lesion with vascularity, anywhere on conjunctiva



  • Usually mobile, but may be fixed to sclera



  • Indistinct edges



  • More common in fair-skinned patients



  • Frequently develops from malignant patches of primary acquired melanosis



  • Metastasize to regional lymph nodes, as well as lungs, liver, brain, bone, and skin through lymphatics



  • Incidence increasing in the United States



Gross Pathology





  • Noncontributory



Histopathology





  • Mixtures of cell types, including small polyhedral cells, spindle cells, epithelioid cells, and balloon cells ( Figure 20.1 )




    Figure 20.1


    Conjunctival melanoma.

    Numerous polyhedral and spindle cells are present in this conjunctival melanoma.



  • Normal polarity is lost



  • Invasion of overlying epithelium by tumor cells



  • May have epithelial cysts if arising from nevus



  • In more aggressive lesions, mitotic figures may be present



  • Often inflammation is found at the base of the lesion



Special Stains and Immunohistochemistry





  • S-100 protein (low specificity, high sensitivity)



  • HMB-45 and HMB-50 combination is less sensitive but more specific for melanomas; can be used to distinguish between benign and malignant lesions



  • Melan-A (MART-1) staining can be used to determine the extent of the lesion



  • Bcl-2 (antiapoptotic cell death protein) is a more robust and consistent marker



  • MIB-1 (Ki-67) used to assess proliferative index and is a marker for aggressive behavior



  • Tumor-suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN), and the heat-shock protein HSP-90 can also aid in differentiating conjunctival nevus from melanoma



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Primary Acquired Melanosis





  • Unique to conjunctiva; analogous to melanoma in situ of skin



  • Primary acquired melanosis (PAM) usually lacks mitotic activity but has varying degrees of atypia



Nevus





  • Usually congenital or acquired during youth, low malignant potential



  • Pigmentation and size may increase during puberty



  • Cysts present on histopathology approximately 50% of the time



  • Rarely located on palpebral conjunctiva



Secondary Melanoma





  • Metastatic from skin or uvea



  • Direct extension of intraocular uveal melanoma



Complexion-Associated Ocular Melanosis





  • Occurs in individuals with darker complexions



  • Histopathologically increased pigmentation without atypical melanocytes



Pearls





  • Two thirds arise from preexisting PAM; one third arise de novo or from preexisting nevi



  • Thickness can predict prognosis: less than 15 mm, excellent prognosis; more than 15 mm, high mortality from metastases



  • Nonbulbar conjunctival locations (e.g., plica semilunaris/caruncle, forniceal or palpebral conjunctiva, palpebral conjunctiva) are associated with the worst prognoses



  • Sentinel node biopsy (preauricular and deep cervical nodes) should be considered in melanomas more than 2-mm thick as well as >10 mm in diameter



  • Fluorescence in situ hybridization (FISH) can be very helpful in aiding the diagnosis of difficult cases of conjunctival malignant melanoma



  • Local recurrence can occur in 36% to 62% of patients; frequency of lymph node metastasis is 36% to 40%



  • Adjuvant radiotherapy can decrease the incidence of local recurrences



  • Anecdotal data of successful treatment using recombinant interferon α-2b as adjuvant therapy



  • Breslow and Clark stain are difficult to apply





Selected References




  • Damato B., Coupland S.E.: Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Experiment Ophthalmol 2008; 36: pp. 786-795.



  • Ophthalmic sites: malignant melanoma of the conjunctiva.Edge S.Byrd D.R.Compton C.C. et. al.AJCC Cancer Staging Manual.2010.SpringerNew York:pp. 538-546.



  • Kurli M., Finger P.T.: Melanocytic conjunctival tumors. Ophthalmol Clin N Am 2005; 18: pp. 15-24.



  • Liesegang T.J.: Pigmented conjunctival and scleral lesions. Mayo Clin Proc 1994; 69: pp. 151-161.



  • Lim L.A., Madigan M.C., Conway R.M.: Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol 2013; 6: pp. 521-531.



  • Seregard S.: Conjunctival melanoma. Surv Ophthalmol 1998; 42: pp. 321-350.



  • Shields J.A., Shields C.L.: Eyelid, Conjunctival, and Orbital Tumors: an Atlas and Textbook.3rd ed.2016.Wolters KluwerPhiladelphia


Primary Acquired Melanosis of the Conjunctiva


Clinical Features





  • Characteristically presents as a unilateral, acquired noncystic, flat, patchy, or diffuse tan to brown pigmentation



  • More common in light-skinned patients



  • Can arise anywhere on conjunctiva, slowly enlarges over time



  • Freely mobile



  • Indistinct edges with dusty pigmentation



  • Average age of onset between 40 and 50 years



  • Potential for malignant degeneration into melanoma in approximately 12% of cases



Gross Pathology





  • Noncontributory



Histopathology





  • Atypical melanocytes near basal layer of epithelium ( Figure 20.2 )




    Figure 20.2


    Primary acquired melanosis of the conjunctiva.

    Atypical melanocytes replace many of the deeper layers of the conjunctival epithelium.



  • Usually divided into PAM without atypia and PAM with atypia



  • Malignancy potential increases with degree of cellular atypia



  • Ranges from mild hyperpigmentation of the epithelium (epithelial cells) with no atypical melanocytes to clusters of deep atypical melanocytes (crossover with malignant melanoma), usually arranged in pagetoid configuration



  • Atypical melanocytes will replace basal epithelium in the most aggressive lesions



  • The cells often exhibit epithelioid morphology, with large hyperchromatic nuclei, prominent nucleoli, and moderate to abundant cytoplasm



  • Lacks epithelial cysts of nevi of some melanomas



  • May be arranged in nests, which may indicate poorer prognosis



  • Analogous to melanoma in situ of skin



Special Stains and Immunohistochemistry





  • HMB-45 and HMB-50 combination immunostaining may help distinguish benign from malignant lesions



  • See “Malignant Melanoma of the Conjunctiva” for staining patterns



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Secondary Acquired Melanosis





  • Similar appearance but associated with systemic disease (e.g., Addison disease), previous radiation, pregnancy, or other conjunctival lesion (e.g., papilloma, carcinoma)



  • No significant risk of progression to melanoma



Conjunctival Melanoma





  • More atypia than PAM



  • Loss of normal polarity with mitotic figures



  • Melanocytes invade underlying stroma



Conjunctival Nevus





  • Cells always arranged in nests



  • Benign appearance



  • Congenital



  • Adjacent epithelial cells lack pigmentation



Complexion Associated Melanosis





  • Bilateral



  • Occurs in dark-skinned individuals



Pigmented Papilloma





  • Benign papillomatous lesion with pigmented monolayer of basal cells



  • Lacks malignant features



  • Drug deposits (adrenochrome granules from epinephrine use)



  • Mascara deposits (inadvertent and intentional tattooing)



Pearls





  • About 46% chance of malignant transformation (into melanoma) if atypical melanocytes are in the basal epithelial layer; much greater chance if melanocytes invade the epithelium in a pagetoid manner or are arranged in deep nests (75% to 90%)



  • Three hours or more of conjunctival involvement and caruncular, forniceal, or palpebral conjunctival locations are associated with a worse prognosis



  • Can consider using topical mitomycin C as an alternative treatment for PAM with atypia



  • Some sources advocate biopsy of all PAM lesions; others advocate biopsy only with proven growth or if obviously thick



  • Cellular atypia can only be determined by excisional biopsy



  • A surgeon performing intraocular surgery in a patient with untreated ocular surface neoplasia should exercise care, as violation of Bowman layer can lead to tumor seeding within the corneal stroma and internal structures of the eye




Selected References


Cameron JD, Maltry AC. Melanocytic neoplasms of the conjunctiva. In: Mannis MJ, Holland EJ, eds. Cornea . Vol. 1. 4th ed. Philadelphia: Elsevier; 2017:434–441.


Colby K, Bhat P, Novais G, et al. Recurrent primary acquired melanosis with atypia involving a clear corneal phacoemulsification wound. Cornea . 2011;30(1):114–116.


Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology . 1989;96:147–166.


Kurli M, Finger PT. Melanocytic conjunctival tumors. Ophthalmol Clin N Am . 2005;18:15–24.


Liesegang TJ. Pigmented conjunctival and scleral lesions. Mayo Clin Proc . 1994;69:151–161.


Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. Ophthalmology . 2008;115:511–519.


Pterygium and Pinguecula


Clinical Features





  • A conjunctival or corneal degenerative lesion that appears as an elevated yellowish-white mass overlying sclera (pinguecula) or a wing-shaped fibrovascular growth overlying sclera and cornea (pterygium)



  • Usually over nasal globe, occasionally temporal, usually bilateral in the interpalpebral zone



  • More common in middle and late life



  • Occurs as a result of the effects of aging, UV light exposure, and environmental insults such as dust and wind



Gross Pathology





  • Noncontributory



Histopathology





  • Basophilic (elastotic, actinic, or senile) degeneration of substantia propria ( Figure 20.3 )




    Figure 20.3


    Pterygium and pinguecula.

    Conjunctival epithelium with underlying actinic (elastotic) degeneration.



  • Overlying epithelium may have acanthosis, dyskeratosis, or orthokeratosis



  • Histopathologically similar to each other; however, pterygium invades superficial cornea and demonstrates vascularization, while pinguecula does not



Special Stains and Immunohistochemistry





  • Degenerated collagen stains positively with histochemical stains for elastic fibers such as the Verhoeff–Van Gieson stain



  • Some studies show an abnormal expression of Ki-67 and dysregulation of tumor suppressor genes such as p53 and p63



Modern Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Squamous Cell Carcinoma of Conjunctiva and Cornea (Invasive or In Situ)





  • Easily differentiated by lack of dysplasia in pterygium and pinguecula



  • Epithelial hyperplasia, nuclear hyperchromasia and pleomorphism, and excessive mitotic figures more common in ocular surface squamous neoplasia



  • Pseudopterygium as a result of previous penetrating injury with superficial scar formation



Pearls





  • Surgical removal is indicated if it interferes with contact lens wear, causes significant irritation or astigmatism, or involves the visual axis



  • Antimetabolites such as topical mitomycin C are sometimes used to prevent recurrences



  • Less chance of recurrence if excision is combined with conjunctival autograft or amniotic graft




Selected References


Liu T, Liu Y, Xie L, et al. Progress in the pathogenesis of pterygium. Curr Eye Res . 2013;38(12):1191–1197.


Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral corneal disorders (review). Surv Ophthalmol . 1986;31:1–36.


Squamous Carcinoma of the Conjunctiva and Cornea


Clinical Features





  • Gelatinous, papilliform, or leukoplakic lesion, with superficial vessels



  • May see “corkscrew” vascular pattern and feeder vessels leading to the lesion



  • Usually in the interpalpebral fissure at the corneal limbus; can extend to the corneal center



  • Uncommonly, incompletely excised lesions can invade through corneoscleral lamellae into the anterior chamber



  • Thickened, well-demarcated area



Gross Pathology





  • Noncontributory



Histopathology





  • Hyperplasia and replacement of epithelium by atypical pleomorphic epithelial cells



  • Mitotic figures, loss of goblet cells, loss of cell polarity, and nuclear hyperchromasia and pleomorphism are common



  • Usually will stay within the epithelium (in situ, also known as conjunctival or corneal intraepithelial neoplasia [CIN]), occasionally invades deeper structures, including globe ( Figure 20.4 )




    Figure 20.4


    Squamous carcinoma.

    Nonkeratinized epithelium of conjunctiva with conjunctival intraepithelial neoplasia. The upper arrow indicates a dysplastic region with a sharp line of demarcation to normal-appearing conjunctiva (lower arrow) .



  • Three types of invasive conjunctival squamous cell carcinoma have been reported




    • Spindle cell: spindle-shaped cells are difficult to distinguish from fibroblasts; tends to invade the corneoscleral region



    • Mucoepidermoid carcinoma: yellow globular cystic component secondary to mucous-secreting cells within cysts; in older patients, more aggressive



    • Adenoid squamous carcinoma: extracellular hyaluronic acid but no intracellular mucin; aggressive form and may invade globe or orbit




  • Cells can gain access to blood vessels and lymphatics but rarely metastasize



Special Stains and Immunohistochemistry





  • Pancytokeratin and epithelial membrane antigen (EMA) staining to support surface ectodermal lineage



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Sebaceous Carcinoma





  • More common in conjunctiva and eyelid than squamous cell carcinoma



  • Similar dysplasia but tends to have a more malignant appearance with a high proportion of cells that display intracytoplasmic vacuolization (sebaceous differentiation)



  • Tends to invade overlying conjunctiva in “pagetoid” pattern of spread; AR441 positivity can be helpful in detecting pagetoid spread



Pterygium and Pinguecula





  • No dysplasia in pterygium and pinguecula



Squamous Papilloma





  • Typical finger-like projections with fibrovascular cores



  • Goblet cells common



  • Often associated with human papillomavirus (HPV)



  • CK17 negative squamous cells and low p53 nuclear positivity



Oncocytoma





  • Rare tumor of the caruncle



  • Cystic cavities lined by proliferating epithelium



Lipodermoid





  • Congenital lesion with typical clinical appearance



  • Histopathologically similar to dermoid cyst



Pearls





  • Ultraviolet light exposure, aging, HPV infection, smoking, fair complexion, and immunosuppression are known risk factors



  • Diagnosis is usually known before excision



  • Neoplasia may be graded as mild, moderate, or severe depending on degree of atypia



  • May recur but usually stays in situ if the primary tumor was in situ




Selected References


Mittal R, Rath S, Vemuganti GK. Ocular surface squamous neoplasia. Review of etio-pathogenesis and an update on clinico-pathological diagnosis. Saudi J Ophthalmol . 2013;27(3):177–186.


Pe’er J. Ocular surface squamous neoplasia. Ophthalmol Clin N Am . 2005;18:1–13.


Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral corneal disorders (review). Surv Ophthalmol . 1986;31:1–36.


Shields JA, Shields CL. Premalignant and malignant lesions of the conjunctival epithelium. In: Eyelid, Conjunctival, and Orbital Tumors: An Atlas and Textbook . 3rd ed. Philadelphia: Wolters Kluwer; 2016:283–306.


Stagner AM, Jakobiec FA, Chi A, et al. Conjunctival inverted squamous papilloma: a case report with immunohistochemical analysis and review of the literature. Surv Ophthalmol . 2015;60:263–268.


Waring III GO, Roth AM, Ekins MB. Clinical and pathological descriptions of 17 cases of corneal intraepithelial neoplasia. Am J Ophthalmol . 1984;97:547–549.


Sebaceous Carcinoma


Clinical Features





  • More common in female patients 60 to 80 years of age



  • Genetic factors: Muir Torre syndrome, p53, LEF1 mutations



  • Represents 5% of all malignant eyelid tumors



  • Second most common eyelid tumor after basal cell carcinoma (more common than squamous cell carcinoma of the eyelid)



  • Wide range of presentations, from a small, firm nodule resembling chalazion to diffuse plaquelike thickening of the tarsus to unilateral chronic diffuse blepharitis, conjunctivitis, loss of cilia, superior limbal keratitis, or corneal pannus



  • Overall mortality of about 20%



  • May spread through direct extension into adjacent structures (orbit, nasal cavity, sinuses, intracranial cavity) or by the intraepithelial route (pagetoid invasion), lending an impression of multiple primary tumors



  • Originates from sebaceous glands of the eyelid and conjunctiva, usually meibomian glands of the tarsus, and from the glands of Zeis (accessory lacrimal glands in conjunctival fornix)



  • More common in upper eyelid



  • If conjunctival epithelium is involved, almost always superior tarsal and forniceal conjunctiva



  • Regional metastasis through lymphatics with the upper eyelid lesions spreading to the preauricular and parotid lymph nodes and the lower eyelid lesions spreading to the submandibular and cervical lymph nodes



Gross Pathology





  • Noncontributory



Histopathology





  • Irregular lobular masses of cells with sebaceous differentiation indicated by prominent cytoplasmic vacuolization giving foamy appearance ( Figure 20.5 )




    Figure 20.5


    Sebaceous carcinoma with typical comedo pattern.

    Notice numerous cells with vacuolated cytoplasm, many mitotic figures, and the presence of necrosis.



  • Frequent mitoses, nuclear atypia, and pleomorphism



  • Varies from highly differentiated to poorly differentiated (which may resemble anaplastic carcinoma)



  • Four histologic patterns have been identified




    • Lobular: neoplastic cells form well-demarcated lobules



    • Comedocarcinoma: large lobules with central necrotic foci



    • Papillary: fronds of neoplastic cells, sometimes mistaken for squamous carcinoma or squamous papilloma, although careful examination reveals sebaceous differentiation



    • Mixed: mixture of previous three




  • Small biopsies may identify strictly intraepithelial tumors, which may be manifestations of pagetoid spread; full thickness biopsy is usually advised



Special Stains and Immunohistochemistry





  • Oil red O stain and Sudan Black B may reveal lipid within the cytoplasm of tumor cells but is typically not necessary



  • BRST1 marker is positive in sebaceous carcinoma, negative in basal cell carcinoma and squamous carcinoma



  • AR441 positivity can be helpful in detecting pagetoid spread



  • EMA, CK7, and Cam 5.2 are typically expressed



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Chalazion (Stye)





  • Lipogranulomatous inflammation on biopsy



  • Consider biopsy if chalazion recurs after multiple excisions



Basal Cell Carcinoma





  • Spreads only through direct extension (unifocal)



  • Lacks sebaceous differentiation



Squamous Cell Carcinoma





  • Can be difficult to differentiate histopathologically



  • Lacks sebaceous differentiation



  • Hyperkeratosis, parakeratosis, keratin inclusions, and dyskeratosis



  • Immunohistochemistry can be useful to differentiate from sebaceous carcinoma



Sebaceous Adenoma





  • Sometimes associated with visceral malignancy (Muir-Torre syndrome)



  • Solitary benign, yellow, circumscribed nodule



  • Predilection for the eyebrow and eyelid



Pearls





  • Poor prognosis is indicated by location in the upper lid, size of 10 mm or more, duration greater than 6 months, infiltrative growth pattern, and moderate to poor sebaceous differentiation



  • Early diagnosis and treatment with wide local excision may improve prognosis



  • Sometimes referred to as “the great masquerader” because it can mimic many other conditions



  • Can be found in younger patients who have undergone orbital irradiation (e.g., for retinoblastoma or rhabdomyosarcoma) as well as patients who are immunosuppressed



  • Biopsy tissue should not be placed in alcohol, which will dissolve the fat from the specimen and make the diagnosis more difficult




Selected References


Kass LG, Hornblass A. Sebaceous carcinoma of the ocular adnexa. Surv Ophthalmol . 1989;33:477–490.


Rao NA, Hidayat AA, McLean IW, et al. Sebaceous gland carcinoma of the ocular adnexa: a clinicopathologic study of 104 cases with five-year follow-up data. Hum Pathol . 1982;13:113–122.


Schmitz EJ, Herwig-Carl MC, Holz FG, et al. Sebaceous gland carcinoma of the ocular adnexa – variability in clinical and histological appearance with analysis of immunohistochemical staining patterns. Graefes Arch Clin Exp Ophthalmol . 2017;255:2277–2285.


Shields JA, Saktanasate J, Lally SE, et al. Sebaceous carcinoma of the ocular region: the 2014 Professor Winifred Mao lecture. Asia Pac J Ophthalmol (Phila) . 2015;4:221–227.


Internal Lesions


Malignant Melanoma


Clinical Features





  • Most common primary malignant intraocular tumor



  • Incidence of 5 to 7 per 1 million general population per year



  • Incidence of 20 per million per year in Caucasians older than 50 years



  • Unlike cutaneous melanomas, incidence rates do not vary by latitude



  • Lifetime risk of 1 in 2500 for whites



  • Median age at presentation is in the sixth decade



  • Less than 1% occur in patients younger than 18 years



  • Slightly more prevalent in men and patients with light complexions, blond hair, and blue eyes



  • No known hereditary component, although a few familial occurrences have been reported



  • Pregnancy is suggested to enhance growth of melanoma and metastases



  • With oculodermal melanocytosis (nevus of Ota) in a white person, there is a lifetime risk of 1 in 400



  • About 50% harbor mutations in GNAQ gene, which is also seen in precursor lesions



  • BAP1, GNA11, EIF1AX, and SF3B1 germline mutations are other driver-mutated genes associated with increased risk



  • Patient may be asymptomatic or may complain of blurred vision because of direct tumor involvement of macula, detachment of retina from subretinal fluid produced by tumor, vitreous hemorrhage, or massive size of tumor obscuring vision



  • Variably pigmented, elevated, initially flat or dome-shaped lesion noted in fundus, sometimes with orange pigment on its surface



  • Slow growing



  • Anterior (ciliary body) position may be associated with segmental cataract



  • Anterior (ciliary body) tumors




    • More difficult to visualize



    • Can attain a large size before clinically recognized



    • Associated with ≥1 dilated episcleral blood vessels, epibulbar pigmented lesion, cataractous lens, and secondary glaucoma



    • Can be dome shaped or have a diffuse circumferential growth pattern (ring melanoma)



    • High-frequency ultrasound biomicroscopy allows for better imaging of the ciliary body




  • Choroidal melanomas can be flat and diffuse, making clinical diagnosis more difficult



  • Ultrasonography demonstrates solid tumor with low to medium internal reflectivity



  • CT and MRI are used to evaluate extrascleral extension and differentiate intraocular hemorrhage and atypical vascular lesions from melanoma



Gross Pathology





  • Mushroom-shaped or dome-shaped pigmented mass in choroid or ciliary body



  • When these tumors arise in the choroid (as opposed to the ciliary body), they may rupture through the overlying Bruch membrane and extend into the subretinal space (giving a mushroom or collar-button shape)



  • Size and location are important prognostic factors (size greater than 1 cm 3 and location at the ciliary body or over the optic nerve are poor prognosticators)



  • Extrascleral extension can be seen, usually through scleral canals with vortex veins; this too is an important poor prognosticator



  • Occasionally may extend into the subconjunctival space and be mistaken for a primary conjunctival lesion



Histopathology


See Figure 20.6 .




  • Most tumors probably arise from preexisting nevi in the choroid (not retinal pigment epithelium); others arise de novo



  • Cell types (Callender histologic classification is most commonly used)




    • Spindle A




      • About 5% of melanomas (second least common)



      • Highly cohesive cells with spindle-shaped nuclei having a central stripe of chromatin (caused by nuclear fold)



      • Spindle cells grow as a syncytium, making cell boundaries difficult to identify



      • Rare mitoses



      • High survival rate (>90%)



      • Pure spindle A tumors are now considered benign and incapable of metastasis




    • Spindle B




      • Nuclei are larger and plumper than spindle A nuclei and contain prominent nucleoli rather than nuclear folds



      • Common type (about 35% to 40% of all melanomas)



      • Indistinct cell boundaries



      • Mitotic figures are rare, although more common than in spindle A



      • Often arranged in fascicular (herringbone) pattern



      • Moderate survival rate (about 75%)




    • Epithelioid




      • Rarest type (about 3%)



      • Noncohesive large cells with large nuclei and abundant cytoplasm



      • High degree of pleomorphism



      • Mitoses more common



      • Poor prognosis; survival of about 28%




    • Mixed




      • Most common type (about 45%)



      • By definition contains a mixture of epithelioid and spindle cell types



      • Usually spindles predominate, but the presence of epithelioid cells classifies the tumor as mixed and portends a worse prognosis



      • Survival rate about 40%




    • Necrotic




      • Rare



      • Tumor is so necrotic as to be unidentifiable in cell type



      • Survival approximates that of mixed-cell type



      • Most tumors have some necrosis



      • Balloon cells commonly found and may represent aging apoptotic cells



      • Inflammatory infiltrates commonly seen within tumor, composed mostly of T-cell lymphocytes



      • Macrophages (melanophages) are commonly seen scattered throughout melanomas



      • Degree of pigmentation varies between tumors and even within an individual tumor (varies from amelanotic to deeply pigmented)





  • The most recent TNM classification system for uveal melanomas is published in the 8th Edition AJCC Cancer Staging Manual and is based on the size of the primary tumor and the extent of systemic metastases




Figure 20.6


A, Typical spindle B choroidal melanoma. The white arrow indicates a spindle A cell, whereas most of the cells are of the spindle B variety. B, Epithelioid melanoma. Large flat cells with prominent nucleoli and marked pleomorphism. This histopathologic appearance is an ominous prognosticator. C, Cross section of whole globe with choroidal melanoma. Arrow indicates a dome-shaped mass under the retina (arrowhead) . D, Choroidal melanoma with extraocular extension. Choroidal tumor is indicated by the white arrow, extraocular tumor by the black arrow.


Special Stains and Immunohistochemistry





  • Frequently HMB-45 positive (about 50%), more specific



  • Commonly S-100 positive (>90%), very sensitive



  • Melan-A, tyrosinase, and microphthalmia transcription factor (MITF) are additional melanocytic markers



Other Techniques for Diagnosis





  • Gene expression profile (GEP) using a 12-gene expression classifier identified two classes of tumors:




    • Class 1 melanoma resembles melanocytes, and <5% of these metastasize



    • Class 1 is further divided into Class 1A (2% 5-year metastatic risk) and Class 1B (21% 5-year metastatic risk)



    • Class 2 melanoma resembles primitive neural or ectodermal stem cells, and 90% of these metastasize (72% 5-year metastatic risk)




Differential Diagnosis


Choroidal Nevus








    • Smaller than melanoma; majority are asymptomatic



    • Exclusively spindle cell type (usually spindle A)



    • Uncommonly associated with serous subretinal fluid



    • Never extends out of globe



    • Mitoses not present




Cavernous Hemangioma of the Choroid








    • Hamartoma that may occur in isolation or in association with Sturge-Weber syndrome (encephalotrigeminal angiomatosis)



    • Round or oval, slightly elevated orange-red lesion, usually 3 to 15 mm in diameter



    • Cluster of grapes appearance



    • Occasional leakage of fluid, similar to melanoma



    • Ultrasound helpful in differentiating from melanoma (high vs. medium internal reflectivity)



    • Histopathologically characterized by many large cavernous blood-filled spaces



    • Fluorescein angiography may reveal plasma–erythrocyte separation within the vascular spaces of the cavernous hemangioma, diagnostic of this lesion




Metastatic Carcinoma








    • Most common intraocular tumor



    • Usually in posterior pole, near vascular arcades



    • Fast growing



    • May be multifocal



    • Ultrasonography may help to differentiate from melanoma



    • Breast (in women) and lung (in men) are the two most common metastatic tumors to the eye



    • Up to 12% of all carcinomas may metastasize to choroid (based on autopsy studies)



    • In 20% to 45% of cases, ocular findings precede the diagnosis of the primary tumor



    • Histopathology varies depending on site of primary tumor




Choroidal Melanocytoma (Magnocellular Nevus)








    • Deeply pigmented (jet-black), usually peripapillary, benign tumor of choroidal melanocytes



    • Tends to be flat or minimally elevated



    • More common in heavily pigmented people



    • Probably has the same low malignant potential as nevus



    • Histologically composed of deeply pigmented plump polyhedral nevus cells containing large melanosomes, small nuclei, and abundant cytoplasm




Subretinal Hemorrhage








    • Deep red, may appear brown or black



    • Ultrasonography useful in differentiating from melanoma




Schwannoma








    • Rare tumor of Schwann cells surrounding ciliary nerves



    • Can be solitary or associated with neurofibromatosis



    • Clinically and ultrasonographically similar to choroidal melanoma



    • Histologically difficult to differentiate from spindle cell melanoma, although characteristically lacks the prominent nucleoli of melanoma



    • Electron microscopy may be helpful in making diagnosis (Antoni patterns)



    • Immunohistochemistry is typically positive for S-100 protein, vimentin, and CD68




Choroidal Osteoma








    • An unusual benign osseous, creamy-white lesion of the posterior pole



    • Usually relatively flat



    • Ultrasonography shows calcification



Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Eye and Orbit
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