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Melanocytic Proliferations of the Uveal Tract
23 Melanocytic Proliferations of the Uveal Tract Jasmine H. Francis and Klaus J. Busam
OUTLINE Uveal Melanocytic Nevus, 266 Clinical Findings, 266 Histopathologic Features, 266 Uveal Melanoma, 266 Clinical Findings, 266 Histopathologic Features, 267
Molecular Findings, 268 Differential Diagnosis, 268 Prognosis, 272 Treatment, 272 Melanoma in the Orbital Cavity, 272
The uveal tract is the pigmented vascularized soft tissue coat of the eye. It consists of the iris, ciliary body, and choroid. Melanocytic lesions can occur throughout the uveal tract. These invclude nevi, and what may be their malignantly transofrmed courterpart, melanomas. This chapter discusses the clinical findings, histopathological features, molecular findings, differential diagnosis, prognosis and treatment of these lesions.
cytologic features has been reported, ranging from small epithelioid to fusiform. The amount of melanin pigment may vary greatly from none to heavy. Heavily pigmented blue nevus–like melanocytic proliferations of the uveal tract are often referred to as melanocytoma. Many uveal nevi are composed of a mixture of cell types. It has been reported that melanocytic nevi of the iris, in contrast to nevi of the posterior uvea, tend to contain large epithelioid multinucleated cells, as well as melanocytes with nuclear pseudoinclusions.
UVEAL MELANOCYTIC NEVUS The uveal melanocytic nevus is the most common primary intraocular tumor in adults.1,2 It is most often situated in the choroid but may also be found in the iris (Fig. 23.1), ciliary body, or optic disc. Estimates for its frequency range from 10% to 20% of Caucasians older than 50 years. If small melanocytic iris lesions were included, 30% to 50% of eyes would have at least one uveal melanocytic nevus. A uveal melanocytic nevus may be a precursor for uveal melanoma. However, that is a rare event. The rate of for uveal melanocytic nevi to undergo malignant transformation has been estimated at approximately 1 per 6000 to 15,000 per year.
UVEAL MELANOMA Uveal melanoma is the most common primary intraocular malignant neoplasm in adults.1,3,4 Its mean age-adjusted incidence is 4.3 to 5.1 per million. Most tumors affect Caucasians (98%) (Box 23.1). Uveal melanoma affects much less frequently other ethnic groups. Its incidence in Hispanics is approximately 0.9/million and in blacks 0.24/million. Predisposing lesions include congenital melanosis oculi and melanocytic nevi. Most tumors are thought to develop sporadically, but rare familial occurrence has been reported, specifically in families with BRCAassociated protein 1 (BAP1) germline mutations.5
Clinical Findings
Clinical Findings
A choroidal nevus is usually flat and has sharp borders (see Fig. 23.1A). Patients with uveal nevi are usually asymptomatic. Secondary retinal changes can develop overlying the nevus and are typically a sign of chronicity. However, visual loss may result from a macular choroidal nevus. The typical iris nevus appears as a localized melanotic stromal lesion of the iris. It can involve any portion of the iris from the pupillary margin to the iris root. The typical iris nevus is 3 mm or less in diameter and 0.5 mm or less in thickness. Uveal nevi are followed closely in the clinic for signs of growth or potential malignant transformation.
Melanoma may be diagnosed during a routine eye examination in asymptomatic patients or because of symptoms, such as blurred vision, prompting a visit to an ophthalmologist (see Box 23.1). Most symptomatic patients are male. Melanomas of the iris are visible (Fig. 23.2) and typically noted by the patient: due to their anterior location, iris melanomas have the potential of inducing cataract formation or elevated intraocular pressure from angle closure and an impediment of aqueous flow from the eye. The median age at diagnosis of uveal melanoma is 60 years. Clinical diagnosis is made on exam with a slit lamp or indirect ophthalmoscopy and may be aided by ultrasound.6 Computed tomography (CT) and magnetic resonance imaging (MRI) are sometimes useful to assess extraocular extension, although they are not routinely used. Despite 97% to 98% of patients being metastasis free by imaging at diagnosis, approximately half of the patients with primary uveal melanoma will be found to have distant metastatic tumor deposit
Histopathologic Features Uveal melanocytic nevi are usually not biopsied or excised. Knowledge of their pathologic features comes from incidental lesions found in eyes removed for other reasons or autopsy studies. On rare occasion an iris nevus may also be biopsied for reassurance (i.e., to exclude melanoma) (see Fig. 23.1B). Similar to melanocytic nevi at other sites, a range of
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CHAPTER 23 Melanocytic Proliferations of the Uveal Tract
Abstract
Keywords
The uveal tract is the pigmented vascularized soft tissue coat of the eye. It consists of the iris, ciliary body, and choroid. Melanocytic lesions can occur throughout the uveal tract. These invclude nevi, and what may be their malignantly transofrmed courterpart, melanomas. This chapter discusses the clinical findings, histopathological features, molecular findings, differential diagnosis, prognosis and treatment of these lesions.
uveal melanoma iris nevus ciliary body nevus choroidal nevus choroidal melanoma ciliary body melanoma iris melanoma orbital melanoma
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A
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B Fig. 23.1 Melanocytic Nevus of the Iris. (A) Clinical appearance: discrete, sharply demarcated small area of brown pigmentation affecting a blue iris. (B) Pathology: the lesion is composed of cytologically bland fusiform melanocytes.
BOX 23.1 Uveal Melanoma Clinical Features Predominantly occurs in Caucasians Mean age of diagnosis: 60 years More common in men than women Presentation: asymptomatic; diagnosed on routine eye exam or symptomatic (vision loss, pain) Histopathology Polypoid or diffuse growth pattern Cytology: spindle or epithelioid or mixed Pigmentation: variable Differential Diagnosis Uveal melanocytic nevus Nonmelanocytic tumors Prognosis Adverse prognostic features include • Class 2 gene expression (most powerful prognostic parameter) • Large epithelioid cell type • Extraocular extension • Closed vascular loops Mutations • GNA11 • EIF1AX • CYSLTR2 • SRSF2 • GNAQ • Other
within a few years.7,8 The liver is a preferred target for metastasis and typically the first site of detection of distant spread. Most patients are diagnosed with metastatic disease 2 to 3 years are initial diagnosis of their intraocular tumor. However, patients are at risk for metastatic disease for decades. Metastases have been reported as late as 30 years after the initial diagnosis.
Fig. 23.2 Melanoma of the Iris—Clinical Appearance. Irregular pigmentation of the iris.
Histopathologic Features The vast majority (90%) of uveal melanomas arise in the choroid (Figs. 23.3–23.8), 7% in the ciliary body (Figs. 23.9 and 23.10), and 3% in the iris. Most often, tumors have a polypoid nodular mushroomlike silhouette (see Figs. 23.3 and 23.4), but rare tumors may be diffusely infiltrative and display a ringlike pattern (Fig. 23.11). The diffuse infiltrative variant of uveal melanoma is more likely to invade through the sclera. The majority of uveal melanomas are thought to arise de novo. Rarely, a melanoma is seen in association with a nevus or melanocytoma (see Fig. 23.8). Historically, melanomas of the uveal tract have been classified principally on the basis of their cytologic composition (i.e., the proportion of epithelioid vs. fusiform tumor cells).1,9 Predominantly spindle cell tumors are referred to as type A or spindle cell (see Fig. 23.5). When epithelioid cells predominate, the tumor is classified as type B or epithelioid (see Fig. 23.6). When both cell types are present in significant amounts, the tumor type is called mixed, which is a common scenario. Tumors composed entirely of pure spindle cells are rarely associated with metastatic disease, and it has been suggested that small, purely fusiform tumors should be regarded as indolent or benign (akin to a uveal melanocytic nevus). Uveal
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A
melanomas are often pigmented (see Fig. 23.6) but may be amelanotic or paucimelanotic (see Figs. 23.4 and 23.7). Cytologically there is a range of appearance of spindle and epithelioid cells. The spindle cells may have thin slender elongated narrow nuclei (spindle A cells) or they may be plump with distinct nucleoli (spindle B cells). Likewise, epithelioid tumor cells may be small or large with varying amounts of cytoplasm. The most common epithelioid appearance is that of a tumor cell with large nuclei, vesicular chromatin pattern, and distinct nucleolus (see Fig. 23.5). Melanomas predominantly composed of epithelioid cells tend to be associated with worse outcome. However, there is significant interobserver variability, as well as variability due to sampling that limits the prognostic value of tumor classification by cell type. Metastatic uveal melanoma may be both a therapeutic as well as a diagnostic challenge. In the vast majority of cases, the initial metastasis involves the liver. However, cutaneous metastases may occur and may be diagnostically challenging because of their morphologic overlap with blue nevi, “atypical” blue nevi, and blue nevus–like melanoma (Fig. 23.12). Careful attention to the clinical setting (prior history of uveal or cutaneous melanoma) and cytologic features (presence or absence of epithelioid atypia, mitotic figures) are important to reach the correct diagnosis. In difficult cases, ancillary studies for cytogenetic aberrations commonly associated with uveal melanoma (monosomy 3, abnormalities of chromosomes 6 and/or 8, BAP1 loss, or gene expression profiling) may help (see Figs. 23.11 and 23.12).10,11
Molecular Findings
B Fig. 23.3 Choroidal Melanoma, Pigmented. (A) Pigmented nodular tumor of choroid. (B) The tumor is composed of pigmented plump spindle and epithelioid cells.
The most frequent driver oncogenic mutations in uveal melanoma and nevi are mutations in GNAQ and GNA11, which are seen in the majority of tumors in a mutually exclusive pattern.12,13 Uveal melanomas show several DNA copy number alterations, including loss of one copy of chromosome 3 (monosomy 3), gains of 6p and 8q, and losses of 6q. Gene expression profiling separates uveal melanomas into two distinct groups, termed class 1 and class 2.14–16 Class 1 tumors have a better prognosis and usually possess both copies of chromosome 3, whereas class 2 tumors have poorer outcomes and often exhibit monosomy 3. Class 1 is complicated by involving two groups: class 1A, which are at lower risk for metastases, and class 1B, which are at higher risk for metastases, which typically occur late. Mutations in and deletions of BAP1 have been shown to be common in uveal melanoma, and especially so in metastasizing tumors, over 80% of which harbor BAP1 mutations. Alterations in preferentially expressed antigen in melanoma (PRAME) are believed to occur in the lower-risk tumors that have a tendency to metastasize late (which some term class 1B tumors). Mutually exclusive mutations in EIF1AX and SF3B1 occur in 15% of tumors (typically male patients) and are thought to have more favorable prognostic value.
Differential Diagnosis
Fig. 23.4 Choroidal Melanoma, Amelanotic. Polypoid amelanotic tumor nodule.
The main diagnostic challenge is clinically. The various clinical differential diagnoses and clinical means of diagnosing uveal melanoma are beyond the scope of this chapter. After the eye has been removed, the main purpose of the pathologic examination is the documentation of features relevant for prognosis. Potential diagnostic challenges for pathologists may be posed by uveal nevi, and other tumors (e.g., smooth muscle or peripheral nerve sheath tumors, poorly differentiated carcinomas) simulating the appearance of an amelanotic melanoma. Immunohistochemical studies should lead to the correct diagnosis. Histopathologically, metastatic uveal melanoma to the skin, soft tissue or other sites, may be difficult to diagnose, especially, if the pathologist receiving the issue for review is unaware of the clinical history of uveal melanoma (Box 23.2). We have seen a number of lesions of metastatic uveal melanoma being confused with a primary melanocytic tumor
CHAPTER 23 Melanocytic Proliferations of the Uveal Tract
A
B
Fig. 23.5 Choroidal Melanoma, Epithelioid Cell Type. (A) Heavily pigmented choroidal tumor nodule. (B) The tumor is composed of large epithelioid melanocytes and melanophages.
A Fig. 23.7 Paucimelanotic spindle cell melanoma.
BOX 23.2 Metastatic Uveal Melanoma Differential Diagnosis Melanocytic nevus, especially epithelioid blue nevus Pigmented epithelioid melanocytoma Primary melanoma Metastatic cutaneous melanoma Soft tissue neoplasm (e.g., melanotic schwannian neoplasm)
B Fig. 23.6 Choroidal Melanoma, Predominantly Spindle Cell Type. (A) Small choroidal melanoma. (B) The tumor is predominantly composed of pigmented fusiform melanocytes.
Ancillary Methods for Diagnosis Immunohistochemistry (loss of BAP1 expression) Mutation analysis (e.g., GNA11 vs. BRAFV600E) Cytogenetics (FISH or CGH)
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A B Fig. 23.8 Choroidal Melanoma Associated With a Nevus. (A) Heavily pigmented tumor. (B) The melanoma is composed of atypical spindle and epithelioid cells. It is surrounded by cytologically bland blue nevus–like melanocytes.
B Fig. 23.10 Melanoma of Choroid and Ciliary Body, With Involvement of Iris Root. (A) Cross-sectional profile of tumor. (B) The tumor is composed of pigmented spindle and epithelioid cells with pleomorphic nuclei.
Fig. 23.9 Melanoma of Ciliary Body.
A
Fig. 23.11 Uveal Melanoma With Diffuse Ring-like Pattern. (A) The tumor grows peripherally in a ring-like fashion. (B) It is composed of pigmented spindle and epithelioid melanocytes. There are also sheets of melanophages.
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CHAPTER 23 Melanocytic Proliferations of the Uveal Tract
A
B
C
D Fig. 23.12 Uveal Melanoma Metastatic to Skin. (A) Blue nevus–like small macule (courtesy Dr. M Lacouture.) (B) Small pigmented nodule in the dermis. (C) The nodule is composed of pigmented epithelioid and fusiform melanocytes as well as melanophages. (D) The tumor cells display monosomy 3 by fluorescence in situ hybridization.
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B
A
C
Fig. 23.13 Uveal Melanoma Metastatic to Soft Tissue. (A) Melanocytic tumor nodule. (B) The tumor is composed of relatively bland-appearing spindle cells. (C) The tumor cells lack nuclear expression of BAP1 by immunohistochemistry. BAP1 is retained by adjacent normal tissue.
(nevus or melanoma) (see Fig. 23.11) or soft tissue neoplasm (e.g., nerve sheath tumor, Fig. 23.12). In such cases, ancillary cytogenetic, molecular studies or immunohistochemistry may assist in establishing a definitive diagnosis. Loss of BAP1 expression, for example, or monosomy 3 detected by FISH may point to metastatic uveal melanoma (Fig. 23.13).
Prognosis Important adverse prognostic features are larger tumor diameter, ciliary body involvement, transscleral extension, and epithelioid/mixed cell type.17 Refinements of prognostic models have been proposed by including other pathologic features, including tumor mitotic rate, increased tumor infiltrating lymphocytes, and extravascular matrix patterns, such as closed loops and microvessel density.18 More recently, genetic and molecular findings have emerged as the most powerful prognostic predictors.19,20 Monosomy of chromosome 3, class 2 gene expression profile, and mutation of BAP1 have been shown to be associated with poor prognosis. Melanocytic lesions are rarely biopsied for diagnostic purposes, but fine-needle aspiration biopsies can be performed for genetic-based prognostics. Biopsies are not without visually threatening consequences, although the risk of externalization of tumor is believed to be small (in part because radioactive discs are typically placed immediately over the needle site).
Treatment Primary uveal melanoma may be treated by local resection, brachytherapy, or proton beam radiotherapy. Larger tumors frequently necessitate enucleation of the affected eye. Metastatic uveal melanoma has been treated with immunotherapeutic, targeted, and chemotherapeutic agents used in cutaneous melanoma, with variable results. In patients with metastases confined to the liver, debulking of the liver metastases may yield a small but limited survival benefit (although this advantage may be a result of lead-time bias). Studies of the therapeutic efficacy of a
variety of novel agents such as histone deacetylase inhibitors, other targeted molecules, and immunotherapies in uveal melanoma are still at early stages.
MELANOMA IN THE ORBITAL CAVITY Primary melanoma in the periocular soft tissue is exceedingly rare but may occur, such as cellular blue nevus–like melanoma associated with a nevus of Ota (melanosis oculi). More often, melanoma detected in the orbital cavity indicates direct extension by ocular or sinonasal melanoma or a metastasis from a uveal, conjunctival, or cutaneous melanoma. If the melanoma is amelanotic, it needs to be distinguished from various benign or malignant, predominantly soft tissue tumors of the orbit. The clinical setting (e.g., history of melanoma or carcinoma) and/or immunohistochemical studies should permit a correct diagnosis.
REFERENCES 1. McLean IW, et al. Atlas of Tumor Pathology. Tumors of the Eye and Ocular Adnexa. Washington, DC: America Registry of Pathology, Armed Forces Institute of Pathology; 1994. 2. Ganley JP, Comstock GW. Benign nevi and malignant melanomas of the choroid. Am J Ophthalmol. 1973;76:19–23. 3. Shields CL, et al. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina. 2012;32:1363–1372. 4. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011;118:1881–1885. 5. Höiom V, et al. Hereditary uveal melanoma: a report of a germline mutation in BAP1. Genes Chromosomes Cancer. 2013;52:378–384. 6. Shields JA, et al. Diagnosis and treatment of uveal melanoma. Semin Oncol. 1996;23:763–767. 7. Singh AD, Topham A. Survival rates with uveal melanoma in the United States: 1973-1997. Ophthalmology. 2003;110:962–965.
CHAPTER 23 Melanocytic Proliferations of the Uveal Tract 8. Shields CL, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 2009;127:989–998. 9. Gamel JW, et al. Uveal melanomas: correlation of cytologic features with prognosis. Cancer. 1978;41:1897–1901. 10. Busam KJ, et al. Diagnosis of blue nevus-like metastatic uveal melanoma confirmed by fluorescence in situ hybridization (FISH) for monosomy 3. J Cutan Pathol. 2012;39:621–625. 11. Fang Y, et al. Use of fluorescence in situ hybridization to distinguish metastatic uveal from cutaneous melanoma. Int J Surg Pathol. 2012;20:246–251. 12. Van Raamsdonk CD, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602. 13. Van Raamsdonk CD, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191–2199. 14. Onken MD, et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64:7205–7209.
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15. Coupland SE, et al. Molecular pathology of uveal melanoma. Eye (Lond). 2013;27:230–242. 16. Griewank KG, Murali R. Pathology and genetics of uveal melanoma. Pathology. 2013;45:18–27. 17. Gill HS, Char DH. Uveal melanoma prognostication: from lesion size and cell type to molecular class. Can J Ophthalmol. 2012;47:246–253. 18. Folberg R, et al. Microcirculation patterns other than loops and networks in choroidal and ciliary body melanomas. Ophthalmology. 2001;108:996–1001. 19. Harbour JW, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–1413. 20. Onken MD, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119:1596–1603.
OUTLINE Uveal Melanocytic Nevus, 266 Clinical Findings, 266 Histopathologic Features, 266 Uveal Melanoma, 266 Clinical Findings, 266 Histopathologic Features, 267
Molecular Findings, 268 Differential Diagnosis, 268 Prognosis, 272 Treatment, 272 Melanoma in the Orbital Cavity, 272
The uveal tract is the pigmented vascularized soft tissue coat of the eye. It consists of the iris, ciliary body, and choroid. Melanocytic lesions can occur throughout the uveal tract. These invclude nevi, and what may be their malignantly transofrmed courterpart, melanomas. This chapter discusses the clinical findings, histopathological features, molecular findings, differential diagnosis, prognosis and treatment of these lesions.
cytologic features has been reported, ranging from small epithelioid to fusiform. The amount of melanin pigment may vary greatly from none to heavy. Heavily pigmented blue nevus–like melanocytic proliferations of the uveal tract are often referred to as melanocytoma. Many uveal nevi are composed of a mixture of cell types. It has been reported that melanocytic nevi of the iris, in contrast to nevi of the posterior uvea, tend to contain large epithelioid multinucleated cells, as well as melanocytes with nuclear pseudoinclusions.
UVEAL MELANOCYTIC NEVUS The uveal melanocytic nevus is the most common primary intraocular tumor in adults.1,2 It is most often situated in the choroid but may also be found in the iris (Fig. 23.1), ciliary body, or optic disc. Estimates for its frequency range from 10% to 20% of Caucasians older than 50 years. If small melanocytic iris lesions were included, 30% to 50% of eyes would have at least one uveal melanocytic nevus. A uveal melanocytic nevus may be a precursor for uveal melanoma. However, that is a rare event. The rate of for uveal melanocytic nevi to undergo malignant transformation has been estimated at approximately 1 per 6000 to 15,000 per year.
UVEAL MELANOMA Uveal melanoma is the most common primary intraocular malignant neoplasm in adults.1,3,4 Its mean age-adjusted incidence is 4.3 to 5.1 per million. Most tumors affect Caucasians (98%) (Box 23.1). Uveal melanoma affects much less frequently other ethnic groups. Its incidence in Hispanics is approximately 0.9/million and in blacks 0.24/million. Predisposing lesions include congenital melanosis oculi and melanocytic nevi. Most tumors are thought to develop sporadically, but rare familial occurrence has been reported, specifically in families with BRCAassociated protein 1 (BAP1) germline mutations.5
Clinical Findings
Clinical Findings
A choroidal nevus is usually flat and has sharp borders (see Fig. 23.1A). Patients with uveal nevi are usually asymptomatic. Secondary retinal changes can develop overlying the nevus and are typically a sign of chronicity. However, visual loss may result from a macular choroidal nevus. The typical iris nevus appears as a localized melanotic stromal lesion of the iris. It can involve any portion of the iris from the pupillary margin to the iris root. The typical iris nevus is 3 mm or less in diameter and 0.5 mm or less in thickness. Uveal nevi are followed closely in the clinic for signs of growth or potential malignant transformation.
Melanoma may be diagnosed during a routine eye examination in asymptomatic patients or because of symptoms, such as blurred vision, prompting a visit to an ophthalmologist (see Box 23.1). Most symptomatic patients are male. Melanomas of the iris are visible (Fig. 23.2) and typically noted by the patient: due to their anterior location, iris melanomas have the potential of inducing cataract formation or elevated intraocular pressure from angle closure and an impediment of aqueous flow from the eye. The median age at diagnosis of uveal melanoma is 60 years. Clinical diagnosis is made on exam with a slit lamp or indirect ophthalmoscopy and may be aided by ultrasound.6 Computed tomography (CT) and magnetic resonance imaging (MRI) are sometimes useful to assess extraocular extension, although they are not routinely used. Despite 97% to 98% of patients being metastasis free by imaging at diagnosis, approximately half of the patients with primary uveal melanoma will be found to have distant metastatic tumor deposit
Histopathologic Features Uveal melanocytic nevi are usually not biopsied or excised. Knowledge of their pathologic features comes from incidental lesions found in eyes removed for other reasons or autopsy studies. On rare occasion an iris nevus may also be biopsied for reassurance (i.e., to exclude melanoma) (see Fig. 23.1B). Similar to melanocytic nevi at other sites, a range of
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CHAPTER 23 Melanocytic Proliferations of the Uveal Tract
Abstract
Keywords
The uveal tract is the pigmented vascularized soft tissue coat of the eye. It consists of the iris, ciliary body, and choroid. Melanocytic lesions can occur throughout the uveal tract. These invclude nevi, and what may be their malignantly transofrmed courterpart, melanomas. This chapter discusses the clinical findings, histopathological features, molecular findings, differential diagnosis, prognosis and treatment of these lesions.
uveal melanoma iris nevus ciliary body nevus choroidal nevus choroidal melanoma ciliary body melanoma iris melanoma orbital melanoma
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A
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B Fig. 23.1 Melanocytic Nevus of the Iris. (A) Clinical appearance: discrete, sharply demarcated small area of brown pigmentation affecting a blue iris. (B) Pathology: the lesion is composed of cytologically bland fusiform melanocytes.
BOX 23.1 Uveal Melanoma Clinical Features Predominantly occurs in Caucasians Mean age of diagnosis: 60 years More common in men than women Presentation: asymptomatic; diagnosed on routine eye exam or symptomatic (vision loss, pain) Histopathology Polypoid or diffuse growth pattern Cytology: spindle or epithelioid or mixed Pigmentation: variable Differential Diagnosis Uveal melanocytic nevus Nonmelanocytic tumors Prognosis Adverse prognostic features include • Class 2 gene expression (most powerful prognostic parameter) • Large epithelioid cell type • Extraocular extension • Closed vascular loops Mutations • GNA11 • EIF1AX • CYSLTR2 • SRSF2 • GNAQ • Other
within a few years.7,8 The liver is a preferred target for metastasis and typically the first site of detection of distant spread. Most patients are diagnosed with metastatic disease 2 to 3 years are initial diagnosis of their intraocular tumor. However, patients are at risk for metastatic disease for decades. Metastases have been reported as late as 30 years after the initial diagnosis.
Fig. 23.2 Melanoma of the Iris—Clinical Appearance. Irregular pigmentation of the iris.
Histopathologic Features The vast majority (90%) of uveal melanomas arise in the choroid (Figs. 23.3–23.8), 7% in the ciliary body (Figs. 23.9 and 23.10), and 3% in the iris. Most often, tumors have a polypoid nodular mushroomlike silhouette (see Figs. 23.3 and 23.4), but rare tumors may be diffusely infiltrative and display a ringlike pattern (Fig. 23.11). The diffuse infiltrative variant of uveal melanoma is more likely to invade through the sclera. The majority of uveal melanomas are thought to arise de novo. Rarely, a melanoma is seen in association with a nevus or melanocytoma (see Fig. 23.8). Historically, melanomas of the uveal tract have been classified principally on the basis of their cytologic composition (i.e., the proportion of epithelioid vs. fusiform tumor cells).1,9 Predominantly spindle cell tumors are referred to as type A or spindle cell (see Fig. 23.5). When epithelioid cells predominate, the tumor is classified as type B or epithelioid (see Fig. 23.6). When both cell types are present in significant amounts, the tumor type is called mixed, which is a common scenario. Tumors composed entirely of pure spindle cells are rarely associated with metastatic disease, and it has been suggested that small, purely fusiform tumors should be regarded as indolent or benign (akin to a uveal melanocytic nevus). Uveal
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A
melanomas are often pigmented (see Fig. 23.6) but may be amelanotic or paucimelanotic (see Figs. 23.4 and 23.7). Cytologically there is a range of appearance of spindle and epithelioid cells. The spindle cells may have thin slender elongated narrow nuclei (spindle A cells) or they may be plump with distinct nucleoli (spindle B cells). Likewise, epithelioid tumor cells may be small or large with varying amounts of cytoplasm. The most common epithelioid appearance is that of a tumor cell with large nuclei, vesicular chromatin pattern, and distinct nucleolus (see Fig. 23.5). Melanomas predominantly composed of epithelioid cells tend to be associated with worse outcome. However, there is significant interobserver variability, as well as variability due to sampling that limits the prognostic value of tumor classification by cell type. Metastatic uveal melanoma may be both a therapeutic as well as a diagnostic challenge. In the vast majority of cases, the initial metastasis involves the liver. However, cutaneous metastases may occur and may be diagnostically challenging because of their morphologic overlap with blue nevi, “atypical” blue nevi, and blue nevus–like melanoma (Fig. 23.12). Careful attention to the clinical setting (prior history of uveal or cutaneous melanoma) and cytologic features (presence or absence of epithelioid atypia, mitotic figures) are important to reach the correct diagnosis. In difficult cases, ancillary studies for cytogenetic aberrations commonly associated with uveal melanoma (monosomy 3, abnormalities of chromosomes 6 and/or 8, BAP1 loss, or gene expression profiling) may help (see Figs. 23.11 and 23.12).10,11
Molecular Findings
B Fig. 23.3 Choroidal Melanoma, Pigmented. (A) Pigmented nodular tumor of choroid. (B) The tumor is composed of pigmented plump spindle and epithelioid cells.
The most frequent driver oncogenic mutations in uveal melanoma and nevi are mutations in GNAQ and GNA11, which are seen in the majority of tumors in a mutually exclusive pattern.12,13 Uveal melanomas show several DNA copy number alterations, including loss of one copy of chromosome 3 (monosomy 3), gains of 6p and 8q, and losses of 6q. Gene expression profiling separates uveal melanomas into two distinct groups, termed class 1 and class 2.14–16 Class 1 tumors have a better prognosis and usually possess both copies of chromosome 3, whereas class 2 tumors have poorer outcomes and often exhibit monosomy 3. Class 1 is complicated by involving two groups: class 1A, which are at lower risk for metastases, and class 1B, which are at higher risk for metastases, which typically occur late. Mutations in and deletions of BAP1 have been shown to be common in uveal melanoma, and especially so in metastasizing tumors, over 80% of which harbor BAP1 mutations. Alterations in preferentially expressed antigen in melanoma (PRAME) are believed to occur in the lower-risk tumors that have a tendency to metastasize late (which some term class 1B tumors). Mutually exclusive mutations in EIF1AX and SF3B1 occur in 15% of tumors (typically male patients) and are thought to have more favorable prognostic value.
Differential Diagnosis
Fig. 23.4 Choroidal Melanoma, Amelanotic. Polypoid amelanotic tumor nodule.
The main diagnostic challenge is clinically. The various clinical differential diagnoses and clinical means of diagnosing uveal melanoma are beyond the scope of this chapter. After the eye has been removed, the main purpose of the pathologic examination is the documentation of features relevant for prognosis. Potential diagnostic challenges for pathologists may be posed by uveal nevi, and other tumors (e.g., smooth muscle or peripheral nerve sheath tumors, poorly differentiated carcinomas) simulating the appearance of an amelanotic melanoma. Immunohistochemical studies should lead to the correct diagnosis. Histopathologically, metastatic uveal melanoma to the skin, soft tissue or other sites, may be difficult to diagnose, especially, if the pathologist receiving the issue for review is unaware of the clinical history of uveal melanoma (Box 23.2). We have seen a number of lesions of metastatic uveal melanoma being confused with a primary melanocytic tumor
CHAPTER 23 Melanocytic Proliferations of the Uveal Tract
A
B
Fig. 23.5 Choroidal Melanoma, Epithelioid Cell Type. (A) Heavily pigmented choroidal tumor nodule. (B) The tumor is composed of large epithelioid melanocytes and melanophages.
A Fig. 23.7 Paucimelanotic spindle cell melanoma.
BOX 23.2 Metastatic Uveal Melanoma Differential Diagnosis Melanocytic nevus, especially epithelioid blue nevus Pigmented epithelioid melanocytoma Primary melanoma Metastatic cutaneous melanoma Soft tissue neoplasm (e.g., melanotic schwannian neoplasm)
B Fig. 23.6 Choroidal Melanoma, Predominantly Spindle Cell Type. (A) Small choroidal melanoma. (B) The tumor is predominantly composed of pigmented fusiform melanocytes.
Ancillary Methods for Diagnosis Immunohistochemistry (loss of BAP1 expression) Mutation analysis (e.g., GNA11 vs. BRAFV600E) Cytogenetics (FISH or CGH)
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A
A B Fig. 23.8 Choroidal Melanoma Associated With a Nevus. (A) Heavily pigmented tumor. (B) The melanoma is composed of atypical spindle and epithelioid cells. It is surrounded by cytologically bland blue nevus–like melanocytes.
B Fig. 23.10 Melanoma of Choroid and Ciliary Body, With Involvement of Iris Root. (A) Cross-sectional profile of tumor. (B) The tumor is composed of pigmented spindle and epithelioid cells with pleomorphic nuclei.
Fig. 23.9 Melanoma of Ciliary Body.
A
Fig. 23.11 Uveal Melanoma With Diffuse Ring-like Pattern. (A) The tumor grows peripherally in a ring-like fashion. (B) It is composed of pigmented spindle and epithelioid melanocytes. There are also sheets of melanophages.
B
CHAPTER 23 Melanocytic Proliferations of the Uveal Tract
A
B
C
D Fig. 23.12 Uveal Melanoma Metastatic to Skin. (A) Blue nevus–like small macule (courtesy Dr. M Lacouture.) (B) Small pigmented nodule in the dermis. (C) The nodule is composed of pigmented epithelioid and fusiform melanocytes as well as melanophages. (D) The tumor cells display monosomy 3 by fluorescence in situ hybridization.
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B
A
C
Fig. 23.13 Uveal Melanoma Metastatic to Soft Tissue. (A) Melanocytic tumor nodule. (B) The tumor is composed of relatively bland-appearing spindle cells. (C) The tumor cells lack nuclear expression of BAP1 by immunohistochemistry. BAP1 is retained by adjacent normal tissue.
(nevus or melanoma) (see Fig. 23.11) or soft tissue neoplasm (e.g., nerve sheath tumor, Fig. 23.12). In such cases, ancillary cytogenetic, molecular studies or immunohistochemistry may assist in establishing a definitive diagnosis. Loss of BAP1 expression, for example, or monosomy 3 detected by FISH may point to metastatic uveal melanoma (Fig. 23.13).
Prognosis Important adverse prognostic features are larger tumor diameter, ciliary body involvement, transscleral extension, and epithelioid/mixed cell type.17 Refinements of prognostic models have been proposed by including other pathologic features, including tumor mitotic rate, increased tumor infiltrating lymphocytes, and extravascular matrix patterns, such as closed loops and microvessel density.18 More recently, genetic and molecular findings have emerged as the most powerful prognostic predictors.19,20 Monosomy of chromosome 3, class 2 gene expression profile, and mutation of BAP1 have been shown to be associated with poor prognosis. Melanocytic lesions are rarely biopsied for diagnostic purposes, but fine-needle aspiration biopsies can be performed for genetic-based prognostics. Biopsies are not without visually threatening consequences, although the risk of externalization of tumor is believed to be small (in part because radioactive discs are typically placed immediately over the needle site).
Treatment Primary uveal melanoma may be treated by local resection, brachytherapy, or proton beam radiotherapy. Larger tumors frequently necessitate enucleation of the affected eye. Metastatic uveal melanoma has been treated with immunotherapeutic, targeted, and chemotherapeutic agents used in cutaneous melanoma, with variable results. In patients with metastases confined to the liver, debulking of the liver metastases may yield a small but limited survival benefit (although this advantage may be a result of lead-time bias). Studies of the therapeutic efficacy of a
variety of novel agents such as histone deacetylase inhibitors, other targeted molecules, and immunotherapies in uveal melanoma are still at early stages.
MELANOMA IN THE ORBITAL CAVITY Primary melanoma in the periocular soft tissue is exceedingly rare but may occur, such as cellular blue nevus–like melanoma associated with a nevus of Ota (melanosis oculi). More often, melanoma detected in the orbital cavity indicates direct extension by ocular or sinonasal melanoma or a metastasis from a uveal, conjunctival, or cutaneous melanoma. If the melanoma is amelanotic, it needs to be distinguished from various benign or malignant, predominantly soft tissue tumors of the orbit. The clinical setting (e.g., history of melanoma or carcinoma) and/or immunohistochemical studies should permit a correct diagnosis.
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CHAPTER 23 Melanocytic Proliferations of the Uveal Tract 8. Shields CL, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 2009;127:989–998. 9. Gamel JW, et al. Uveal melanomas: correlation of cytologic features with prognosis. Cancer. 1978;41:1897–1901. 10. Busam KJ, et al. Diagnosis of blue nevus-like metastatic uveal melanoma confirmed by fluorescence in situ hybridization (FISH) for monosomy 3. J Cutan Pathol. 2012;39:621–625. 11. Fang Y, et al. Use of fluorescence in situ hybridization to distinguish metastatic uveal from cutaneous melanoma. Int J Surg Pathol. 2012;20:246–251. 12. Van Raamsdonk CD, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602. 13. Van Raamsdonk CD, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191–2199. 14. Onken MD, et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64:7205–7209.
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15. Coupland SE, et al. Molecular pathology of uveal melanoma. Eye (Lond). 2013;27:230–242. 16. Griewank KG, Murali R. Pathology and genetics of uveal melanoma. Pathology. 2013;45:18–27. 17. Gill HS, Char DH. Uveal melanoma prognostication: from lesion size and cell type to molecular class. Can J Ophthalmol. 2012;47:246–253. 18. Folberg R, et al. Microcirculation patterns other than loops and networks in choroidal and ciliary body melanomas. Ophthalmology. 2001;108:996–1001. 19. Harbour JW, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–1413. 20. Onken MD, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119:1596–1603.