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Update on Tumor-Node-Metastasis Staging for Uveal Melanoma
Advances in Ophthalmology and Optometry 1 (2016) 261–272
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
Update on Tumor-NodeMetastasis Staging for Uveal Melanoma Alice Yang Zhang, MD, Sherveen Salek, MD, Mary Aronow, MD* Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 744, Baltimore, MD 21287, USA
Keywords
Uveal melanoma Choroidal melanoma TNM Staging Metastasis Prognosis
Key points
The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification (7th edition) established a universal staging system for uveal melanoma.
Since its development, TNM staging has been validated in uveal melanoma and shown to be of importance for prognostication.
At present, TNM staging takes into account tumor size, ciliary body involvement (CBI), presence of extraocular extension, and distant metastasis.
TNM staging for uveal melanoma does not currently incorporate important prognostic aspects, such as histopathologic features and tumor genetics.
INTRODUCTION Uveal melanoma is the most common primary intraocular malignancy in adults. By definition, it arises from the uveal tract, including iris, ciliary body, and choroid. In a series of 4070 patients with uveal melanoma included in the Surveillance, Epidemiology, and End Results Program database in the United States from 1973 to 2008, the age-adjusted incidence of uveal
The authors have nothing to disclose.
*Corresponding author. Retina Division, Wilmer Eye Institute, 600 North Wolfe Street, Maumenee 744, Baltimore, MD 21287-9277. E-mail address: [email protected] 2452-1760/16/$ – see front matter http://dx.doi.org/10.1016/j.yaoo.2016.03.006
Ó 2016 Elsevier Inc. All rights reserved.
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melanoma was determined to be 5.1 individuals per million population in the United States [1]. This incidence is similar to that reported from other countries worldwide and has remained relatively stable over the past several decades [1]. Uveal melanoma primarily affects persons with light skin complexion, with 97.8% of cases occurring in the white population. In contrast, only 1% of reported cases occur in Hispanics, less than 1% in Asians, and less than 1% in African Americans [1–3]. Diagnosis is frequently in the fifth to seventh decade, with 1 large series reporting a mean age at diagnosis of 60.4 years [4]. Uveal melanoma affects men and women in approximately equal numbers [1]. Uveal melanoma is typically diagnosed on clinical examination with supportive ancillary testing. Typically, features include an elevated, uveal tumor with variable pigmentation, ranging from brownish green to amelanotic. There is frequently overlying orange pigment and associated subretinal fluid. Drusen may be absent, and because they are a feature of chronicity, this finding may help to distinguish long-standing choroidal nevi from melanoma in some cases. B-scan ultrasonography demonstrates an elevated uveal mass, which takes on a mushroom or collar button shape in classic cases. A-scan ultrasonography most frequently demonstrates low to medium internal reflectivity. Intrinsic vascular pulsations, choroidal excavation, and orbital shadowing are supportive features that may be apparent on ultrasonography. Fluorescein angiography, in particular indocyanine green angiography, may reveal intrinsic vasculature. Uveal melanoma may be symptomatic, depending on proximity to the optic nerve or fovea or if significant associated subretinal fluid is present. Ciliary body melanoma is frequently asymptomatic until it reaches a large size, at which point it may compress the lens, leading to blurred vision and astigmatism [5,6]. Although patients may present with decreased visual acuity, metamorphopsia, visual field loss, floaters, photopsias, or other symptoms, many cases are detected on routine examination [7]. Although the ability to accurately diagnose uveal melanoma and to treat with eye-preserving techniques has evolved, survival rates have remained unchanged over the past several decades [1]. In recent years, there has been a trend toward developing standardized staging systems for all forms of cancer. For uveal melanoma, such a system would potentially allow for a universal platform for characterizing these tumors, for understanding the pathophysiology underlying the metastatic process, and for ultimately assessing efficacy of new therapies. A TNM staging system for uveal melanoma has recently been developed [8]. This article reviews the key elements included in the TNM staging system for uveal melanoma, the refinements made to the 7th edition of the AJCC Cancer Staging Manual, and the validation process and challenges involved in classifying uveal melanoma. PROGNOSTIC INDICATORS IN UVEAL MELANOMA Despite excellent local control of the primary tumor with currently available therapies, approximately half of patients with uveal melanoma ultimately
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develop metastases [1,2]. A vast majority of metastases occur within 5 to 10 years after primary treatment, although late onset of metastatic disease is also possible. It is rare to detect metastatic disease at the time of initial diagnosis of the ocular tumor. Uveal melanoma spreads via a hematogenous route, almost uniformly to the liver (93%), followed by the lung (24%) and bone (16%), and less frequently to sites, such as brain and skin [6]. At present, current treatments for metastatic uveal melanoma are minimally effective in prolonging survival. Early on, several clinical features were determined to be of prognostic significance in uveal melanoma. Larger tumor basal diameter and increased thickness, older patient age, presence of extraocular extension (EXE), CBI, and diffuse growth pattern were recognized as poor prognostic indicators [9]. Histopathologic studies demonstrated high-risk features, including epithelioid cell type (in comparison to spindle cell type), increased mitotic activity, presence of tumor vascular loops, and tumor-infiltrating lymphocytes [10–14]. More recently, advances in tumor genetics have revealed that chromosomal abnormalities, in particular aberrations in chromosomes 1, 3, 6, and 8, are correlated with poor survival [15,16]. Among these, loss of 1 copy of chromosome 3 (known as monosomy 3) has emerged as a powerful predictor of metastatic risk. Monosomy 3, which can be detected using a variety of techniques, is found in the majority of metastasizing uveal melanoma [17–21]. Gene expression profiling also has been developed for uveal melanoma risk stratification. Gene expression profiling has been validated in patients with uveal melanoma and has demonstrated that class 1A tumors rarely metastasize, class 1B tumors are associated with intermediate risk, and class 2 tumors are associated with the poor survival [22,23].
CLASSIFICATION OF UVEAL MELANOMA The first classification for uveal melanoma was published in Germany by Knapp in 1869 [24]. Tumors were assigned to 4 stages according to the presence or absence of patient symptoms, extraocular extension, and distant metastasis. In North America, the Collaborative Ocular Melanoma Study created standardized size definitions for uveal melanoma in the 1980s [25]. Mortality was found to generally correlate with increasing tumor size [26,27]. The concept of establishing a universal classification system for uveal melanoma is attractive from several practical standpoints. A more standardized approach to reporting would result in uniformity in the ophthalmic literature, thereby making studies more directly comparable and allowing for possibility of pooled meta-analyses [28]. Once validated, staging designations could be used as a prognostication tool. Furthermore, such a classification scheme could potentially facilitate entry criteria for clinical studies and could ultimately be used to formally assess treatment response, based on initial tumor staging, to new therapies.
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TUMOR-NODE-METASTASIS STAGING FOR UVEAL MELANOMA The TNM classification scheme is a universal cancer staging system that was first developed by the International Union Against Cancer in 1968. It was not until the recent 4th and 5th editions that TNM staging for ocular cancer was included [29]. For its latest 7th edition, published in 2010, the AJCC appointed an international Ophthalmic Oncology Task Force (OOTF) to revise TNM staging for ocular cancer based on the published literature and acquired evidence [8]. TNM staging for uveal melanoma is designed to use anatomic stage in combination with information on nodal involvement and distant metastases to designate stages I, II, III, and IV. For most ocular cancer, anatomic extent is determined both clinically and, in many cases, histopathologically. Uveal melanoma is an exception, because a majority of tumors are treated with eye-sparing techniques. Histopathology of enucleated globes is available in a minority of cases; therefore, anatomic stage is largely based on clinical factors. The anatomic classification system for uveal melanoma is based on refined data from the collaborative work of the European Ophthalmic Oncology Group [30,31]. The current 7th edition of the TNM staging manual focuses on staging for posterior melanoma, that is, ciliary body and choroidal melanoma. The classification of iris melanoma was not revised due to insufficient data. The tumor size category is denoted by the letter T, followed by a number and a lowercase letter. The number and letter that follow the T encompass 4 clinical variables: largest basal diameter, tumor thickness, CBI, and EXE [8]. The number after the T describes the size of the primary tumor based on a combination of the largest basal diameter and tumor thickness in millimeters. T1 defines the smallest tumors (Fig. 1), and successively larger tumor sizes are classified as T2, T3, and T4 (Table 1) [8]. The lower-case letters, a through d, are used to designate combinations of the presence or absence of CBI (Fig. 2) or EXE as follows [8]:
a—tumors with no CBI or EXE b—tumors with CBI but no EXE c—tumors with no CBI but EXE less than or equal to 5 mm in diameter d—tumors with both CBI and EXE less than or equal to 5 mm in diameter
For example, T1c is the classification given to a uveal melanoma that has a base of 3.0 mm to 9.0 mm with a thickness less than or equal to 6 mm, or a tumor with a base of 9.1 mm to 12.0 mm with thickness less than or equal to 3 mm, with no CBI but with EXE less than 5 mm in diameter. The lower-case e designation uniquely describes any tumor size with EXE greater than 5 mm in diameter and is, therefore, reserved for uveal melanoma classified as T4. The N classification refers to lymph node involvement. An N of 0 or 1 denotes the absence or presence of regional lymph node metastasis, respectively. Because uveal melanoma is known to metastasize via a hematogenous
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Fig. 1. (A) A 77-year-old white woman presented with a superior juxtapapillary choroidal melanoma extending from the 9:00 position to the 3:30 position at the disc margin. There was orange pigment and subretinal fluid overlying the tumor, which measured 2.0 mm in thickness by 6.7 mm laterally by 6.9 mm radially by ultrasonography. No EXE was apparent on ultrasonography. (B) Fluorescein angiography demonstrated intrinsic hyperfluorescence consistent with the intrinsic vascular pulsations that were apparent on ultrasonography. CT scan of the chest, abdomen, and pelvis did not detect any evidence of metastatic disease. This small choroidal melanoma was treated with iodine-125 plaque brachytherapy. This tumor was staged as T1aN0M0.
route, lymph node involvement would be unusual, with the potential exception of very advanced cases. Similarly, M corresponds to metastatic disease; therefore, a 0 or 1 defines the absence or presence of distant metastases, respectively. Table 1 T classification for posterior melanoma based on the 7th edition of the AJCC Cancer Staging Manual Primary tumor (T)
Tumor largest basal diameter and thickness
T1
Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor
T2
T3
T4
base base base base base base base base base base base base base
<3.0 mm–9.0 mm, thickness 6.0 mm 9.1 mm–12.0 mm, thickness 3.0 mm <9.0 mm, thickness 6.0 mm–9.0 mm 9.1 mm–12.0 mm, thickness 3.1 mm–9.0 mm 12.1 mm–15.0 mm, thickness 6.0 mm 15.1 mm–18.0 mm, thickness 3.0 mm 3.1 mm–9.0 mm, thickness 9.1 mm–12.0 mm 9.1 mm–12.0 mm, thickness 9.1 mm–15.0 mm 12.1 mm–15.0 mm, thickness 6.1 mm–15.0 mm 15.1 mm–18.0 mm, thickness 3.1 mm–12.0 mm 12.1 mm–15.0 mm, thickness >15.0 mm 15.1 mm–18.0 mm, thickness >12.0 mm >18.0 mm, any thickness
Adapted from Edge SB, Byrd DR, Compton CC, et al, editors. Malignant melanoma of the uvea. In: AJCC Cancer Staging Manual. 7th edition. New York, NY: Springer;2010:547–9.
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Fig. 2. (A) A 93-year-old white woman was referred for a large ciliochoroidal melanoma. On external examination, sentinel vessels were apparent. (B) B-scan ultrasonography demonstrated a tumor measuring 15.5 mm in thickness by 20.0 mm laterally by 20.0 mm radially. (C) A-scan ultrasonography revealed low internal reflectivity. CT scan of the chest, abdomen, and pelvis did not detect any evidence of metastatic disease. Primary enucleation was performed. Pathology revealed a ciliochoroidal melanoma with a mixed cell population of spindle B and epithelioid cells. There was no evidence of extraocular extension. This tumor was staged as T4bN0M0.
Stages I, II, and III describe increasing extent of local disease, whereas stage IV is reserved for melanoma with distant metastases. Stages I, II, III, and IV are grouped in accordance to subcategories as follows:
Stage I: T1a Stage II: T1b-d, T2a-b, T3a Stage III: T2c-d, T3b-d, T4a-e Stage IV: any T classification with either lymph node involvement or distant metastasis
Staging is further subdivide into stage I, stage II (A and B), stage III (A, B, and C), and stage IV (Table 2) [8]. UPDATES TO THE 7TH EDITION OF TUMOR-NODE-METASTASIS STAGING FOR UVEAL MELANOMA Size category The AJCC 7th edition of TNM staging for uveal melanoma added a fourth size category to the original 3 sizes included in the 6th edition of the staging manual.
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Table 2 Staging for posterior melanoma based on the 7th edition of the AJCC Cancer Staging Manual Stage
Primary tumor (T)
Lymph node (N)
Metastasis (M)
Stage I Stage II Stage IIA Stage IIB Stage III Stage IIIA Stage IIIB Stage IIIC Stage IV
T1a T1b-d, T2a-b, T3a T1b-d, T2a T2b, T3a T2c-d, T3b-d, T4a-e T2c-d, T3b-c, T4a T3d, T4b-c T4d-e Any T Any T
N0 N0 N0 N0 N0 N0 N0 N0 N1 Any N
M0 M0 M0 M0 M0 M0 M0 M0 M0 M1
Adapted from Edge SB, Byrd DR, Compton CC, et al, editors. Malignant melanoma of the uvea. In: AJCC Cancer Staging Manual. 7th edition. New York, NY: Springer;2010:547–9.
The rationale was that tumor size was considered a predominant clinical predictor of mortality in uveal melanoma. As a result of the addition of the fourth size category, the distribution of tumors within each size designation were more uniform: 24% classified as T1, 34% as T2, 30% as T3, and 12% as T4 [30]. Ciliary body involvement The prognostic importance of CBI was recognized in the 7th edition of TNM staging for uveal melanoma. In previous editions, there were separate classifications for ciliary body melanoma depending on extension to the iris or the choroid [32]. In clinical practice, it may be difficult to determine whether the primary tumor originated from the ciliary body or the choroid [30]. The 6th edition of TNM staging addressed tumors with or without CBI in the same category, separated only by size differences. The newer 7th edition classification is more efficient and incorporates valuable information about both tumor size and CBI. Extraocular extension EXE was classified exclusively in category 4 in the 5th edition of the TNM system. The 6th edition included EXE as a separate subcategory that differentiated various sizes of melanoma with EXE but without subgrouping by size of the EXE [32]. More recently, EXE greater than 5 mm has been associated with a higher mortality rate [30,33]. The 7th edition, therefore, includes a separate subcategory T4e for any tumor with EXE greater than 5 mm regardless of tumor size. VALIDATION OF TUMOR-NODE-METASTASIS STAGING FOR UVEAL MELANOMA Since its initial development and subsequent refinements, there have been several studies aimed at validating aspects of the AJCC TNM classification system for uveal melanoma. Tumor size, corresponding anatomic stage, presence
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of high risk features (EXE and CBI) have been correlated with survival based on TNM classification [30,31,34–36]. Survival based on size Increasing tumor category (T designation) has been demonstrated to be associated with older patient age, large tumor, greater incidence of subretinal fluid, hemorrhage, and EXE [37]. Posterior uveal melanoma classified at T2, T3, and T4 had a 2-fold, 4-fold, and 8-fold greater incidence of metastasis, respectively, compared with melanoma classified at T1 [34]. The OOTF independently confirmed that increasing tumor size designation is significantly related to higher risk of metastases [31,38]. The OOTF determined metastasis-free survival estimates at 10 years’ follow-up to be 94% for T1, 80% for T2, and 68% for T3; there were no data for T4 [31]. Survival based on ciliary body involvement and extraocular extension Validation studies support the finding that tumors designated with the letter a (no CBI or EXE) have the best prognosis, and those with category d (both CBI and EXE) have the poorest prognosis [30]. Survival as a function of subcategories (a through d) based on the presence of CBI and EXE has been examined. In 1 series, of 3251 primary uveal melanomas with known CBI and EXE, 71% of tumors were classified as category a, 23% as category b, 3% as category c, and 3% as category d [30]. The 10-year survival rates were, 78%, 51%, 40%, and 19%, respectively. By 15 years, survival rates were 68% for category a, 41% for category b, and unknown for categories c and d (fewer than 10 patients combined were at risk in these categories) [30]. The OOTF reported a similar distribution of each tumor subcategory based on the presence of CBI and EXE, although 10-year metastasis-free survival estimates were slightly higher for each category: 84% for category a, 67% for category b, again not calculated for category c, and 33% for category d [31]. The presence of CBI and EXE and the degree (size) of EXE have been associated with increased risk of metastasis. Only a few reports discuss the issue of EXE and its size relative to the risk of mortality [30,33]. The OOTF analyses showed that metastasis-free survival estimates at 5 years were 87% for non-EXE, 43% for EXE 5.0 mm or smaller, and 42% for EXE greater than 5.0 mm [31]. The relative paucity of data with regard to the size of EXE and resulting impact on prognosis require further validation. Survival based on overall stage In the Shields [35] series, a majority of patients were classified as either stage I (36%) or stage II (48%), whereas a small percentage were classified as stage III (16%) or stage IV (less than 1%). Compared with patients with stage I posterior uveal melanoma, hazard ratio for metastasis was 3.1 times higher in stage II disease and 9.3 times higher in stage III disease [34]. Kaplan-Meier estimates of death at 10 years were 12% for stage I, 29% for stage II, 61% for stage III, and 100% for stage IV [37]. The OOTF revealed a similar trend. The 10-year metastasis-free survival estimates from Kaplan-Meier curves were 94% for stage I, 84% for stage
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IIA, 70% for stage IIB, 60% for stage IIIA, and 50% for stage IIIB. Estimates for stage IIIC and higher could not be calculated due to small sample size at 10 years [31]. Iris melanoma Iris melanoma was not addressed in the 7th edition of the AJCC TNM staging system for uveal melanoma. OOTF reported that iris melanoma involves the ciliary body in 51.9% of patients and the choroid in 3.8% of patients [31]. When classified by tumor size category, a majority of these cases were T2 (41.3%). Of these, a total of 5 of 160 patients developed metastases and all had T2 tumors with either ciliary body or choroidal involvement. KaplanMeier estimates were not calculated due to small sample size [31]. FUTURE DIRECTIONS The latest revisions in TNM staging for uveal melanoma included in the 7th edition of the AJCC Cancer Staging Manual reflect a collaborative undertaking based on all available existing evidence. This staging system improves significantly on the anatomic classification of uveal melanoma, resulting in a more efficient framework with relevant prognostic information. Although more precise anatomic classification has been achieved in the newer system, there are several important prognostic variables not accounted for in the 7th edition. For example, histopathologic features (such as epithelioid or spindle cell type, mitotic rate, vascular mimicry patterns, tumor-infiltrating lymphocytes, and others) are not currently integrated into TNM staging. With increased advances in understanding of tumor genetics, it has become common practice to biopsy uveal melanoma for prognostication purposes. Neither chromosomal abnormalities, notably monosomy 3, nor gene expression profiling are at present included in the TNM classification system. One histopathologic study of uveal melanoma enucleation specimens concluded that metastatic death was more significantly correlated with largest basal diameter, predominance of epithelioid cell type, mitotic rate, and closed loops than with extraocular extension, again emphasizing the importance of several features not currently considered in the latest TNM classification [39]. Although anatomic classification has become precise in the 7th edition, there are specific challenges related to size determination. For example, when measuring tumor size, there may be discrepancy between clinical size estimates, preoperative ultrasonography measurements, and histopathologic size measurements in cases of eyes that have been enucleated. When compared with ultrasonographic measurements, histopathologic basal diameter and thickness measurements may be artificially smaller due to tissue shrinkage artifact that may occur during processing of specimens [30,40]. It is possible that individuals with tumors on the threshold of size cutoffs may be down-graded, resulting in assignment to a lower T category. Additionally, iris melanoma, although it may not comprise a majority of intraocular uveal melanomas, is still an important component of the spectrum
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of uveal melanoma. The present AJCC TNM system does not include iris melanoma, and it may be that a separate system is warranted for iris melanoma, given that it has a unique set of clinical features distinct from choroidal melanoma and a less aggressive propensity to metastasize. As newer evidence and information become available, subsequent updates to TNM staging for uveal melanoma will ideally incorporate such findings in an effort to continue to improve on the present staging capabilities. SUMMARY Although uveal melanoma is an uncommon disease affecting 5.1 individuals per million population in the United States, it carries a high risk of mortality. Standardization of anatomic classification and staging of the primary tumor using the AJCC TNM system is a forward step in communicating a universal language in ophthalmic oncology. The ultimate goal is to develop worldwide collaborations to advance understanding of the underlying pathophysiology and treatment approaches to this rare cancer. The 7th edition of the TNM staging system successfully incorporates tumor basal diameter, thickness, presence of CBI, and degree of extraocular extension, along with information on lymph node involvement and distant metastases. Several studies have demonstrated that larger tumor size, CBI, and larger extent of EXE are all high-risk features associated with increased risk of metastasis. Increasing tumor size, denoted by the T stage (number 1 through 4), seems particularly associated with increasing risk of metastasis. This correlation is mirrored by successive categories, a through d (and e in exceptional cases), which reflect the presence of CBI and extent of EXE, where d (and e) carry the poorest prognosis for survival. Finally, each successive stage has been shown associated with an increased risk of metastasis and death. The 7th edition of TNM staging for uveal melanoma provides early evidence of the importance of early detection and treatment, because smaller tumor size and absence of EXE are associated with a better overall prognosis. Subsequent editions of the AJCC TNM staging for uveal melanoma may take advantage of known histopathologic high-risk features and genetic information of prognostic significance. As it becomes increasingly common to biopsy uveal melanoma, the repository of information related to tumor genetics will increase understanding in this realm. Such information may be added to the existing TNM staging to improve the accuracy of prognostication. Ultimately, the ability to identify high-risk patients will increase understanding the disease mechanisms underlying the development and spread of uveal melanoma and facilitating studies aimed at evaluating the efficacy of newly developed therapies. References [1] Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 2011;118(9):1881–5. [2] Singh AD, Topham A. Survival rates with uveal melanoma in the United States: 1973-1997. Ophthalmology 2003;110(5):962–5.
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[25] Design and methods of a clinical trial for a rare condition: the Collaborative Ocular Melanoma Study. COMS report no. 3. Control Clin Trials 1993;14(5):362–91. [26] Diener-West M, Earle JD, Fine SL, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS report no. 17. Arch Ophthalmol 2001;119(7):951–65. [27] Diener-West M, Earle JD, Fine SL, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS report no. 18. Arch Ophthalmol 2001;119(7):969–82. [28] Finger PT. Do you speak ocular tumor? Ophthalmology 2003;110(1):13–4. [29] Sobin L, Wittekind CH. International union against cancers (UICC) TNM classification of malignant tumors. 5th edition. New York: John Wiley & Sons; 1997. [30] Kujala E, Damato B, Coupland SE, et al. Staging of ciliary body and choroidal melanomas based on anatomic extent. J Clin Oncol 2013;31(22):2825–31. [31] AJCC Ophthalmic Oncology Task Force. International validation of the American Joint Committee on cancer’s 7th edition classification of uveal melanoma. JAMA Ophthalmol 2015;133(4):376–83. [32] Kujala E, Kivela T. Tumor, node, metastasis classification of malignant ciliary body and choroidal melanoma evaluation of the 6th edition and future directions. Ophthalmology 2005;112(6):1135–44. [33] Pach JM, Robertson DM, Taney BS, et al. Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension. Am J Ophthalmol 1986;101(3):325–31. [34] Shields CL, Kaliki S, Furuta M, et al. American Joint Committee on cancer classification of uveal melanoma (anatomic stage) predicts prognosis in 7,731 patients: the 2013 Zimmerman lecture. Ophthalmology 2015;122(6):1180–6. [35] Damato BE, Heimann H, Kalirai H, et al. Age, survival predictors, and metastatic death in patients with choroidal melanoma: tentative evidence of a therapeutic effect on survival. JAMA Ophthalmol 2014;132(5):605–13. [36] Kivela T, Kujala E. Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond. Eye (Lond) 2013;27(2):243–52. [37] Shields CL, Kaliki S, Furuta M, et al. American Joint Committee on cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients. Ophthalmology 2013;120(10):2066–71. [38] The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol 1998;125(6):779–96. [39] Coupland SE, Campbell I, Damato B. Routes of extraocular extension of uveal melanoma: risk factors and influence on survival probability. Ophthalmology 2008;115(10): 1778–85. [40] Collaborative Ocular Melanoma Study Group. Comparison of clinical, echographic, and histopathological measurements from eyes with medium-sized choroidal melanoma in the collaborative ocular melanoma study: COMS report no. 21. Arch Ophthalmol 2003;121(8):1163–71.
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
Update on Tumor-NodeMetastasis Staging for Uveal Melanoma Alice Yang Zhang, MD, Sherveen Salek, MD, Mary Aronow, MD* Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 744, Baltimore, MD 21287, USA
Keywords
Uveal melanoma Choroidal melanoma TNM Staging Metastasis Prognosis
Key points
The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification (7th edition) established a universal staging system for uveal melanoma.
Since its development, TNM staging has been validated in uveal melanoma and shown to be of importance for prognostication.
At present, TNM staging takes into account tumor size, ciliary body involvement (CBI), presence of extraocular extension, and distant metastasis.
TNM staging for uveal melanoma does not currently incorporate important prognostic aspects, such as histopathologic features and tumor genetics.
INTRODUCTION Uveal melanoma is the most common primary intraocular malignancy in adults. By definition, it arises from the uveal tract, including iris, ciliary body, and choroid. In a series of 4070 patients with uveal melanoma included in the Surveillance, Epidemiology, and End Results Program database in the United States from 1973 to 2008, the age-adjusted incidence of uveal
The authors have nothing to disclose.
*Corresponding author. Retina Division, Wilmer Eye Institute, 600 North Wolfe Street, Maumenee 744, Baltimore, MD 21287-9277. E-mail address: [email protected] 2452-1760/16/$ – see front matter http://dx.doi.org/10.1016/j.yaoo.2016.03.006
Ó 2016 Elsevier Inc. All rights reserved.
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melanoma was determined to be 5.1 individuals per million population in the United States [1]. This incidence is similar to that reported from other countries worldwide and has remained relatively stable over the past several decades [1]. Uveal melanoma primarily affects persons with light skin complexion, with 97.8% of cases occurring in the white population. In contrast, only 1% of reported cases occur in Hispanics, less than 1% in Asians, and less than 1% in African Americans [1–3]. Diagnosis is frequently in the fifth to seventh decade, with 1 large series reporting a mean age at diagnosis of 60.4 years [4]. Uveal melanoma affects men and women in approximately equal numbers [1]. Uveal melanoma is typically diagnosed on clinical examination with supportive ancillary testing. Typically, features include an elevated, uveal tumor with variable pigmentation, ranging from brownish green to amelanotic. There is frequently overlying orange pigment and associated subretinal fluid. Drusen may be absent, and because they are a feature of chronicity, this finding may help to distinguish long-standing choroidal nevi from melanoma in some cases. B-scan ultrasonography demonstrates an elevated uveal mass, which takes on a mushroom or collar button shape in classic cases. A-scan ultrasonography most frequently demonstrates low to medium internal reflectivity. Intrinsic vascular pulsations, choroidal excavation, and orbital shadowing are supportive features that may be apparent on ultrasonography. Fluorescein angiography, in particular indocyanine green angiography, may reveal intrinsic vasculature. Uveal melanoma may be symptomatic, depending on proximity to the optic nerve or fovea or if significant associated subretinal fluid is present. Ciliary body melanoma is frequently asymptomatic until it reaches a large size, at which point it may compress the lens, leading to blurred vision and astigmatism [5,6]. Although patients may present with decreased visual acuity, metamorphopsia, visual field loss, floaters, photopsias, or other symptoms, many cases are detected on routine examination [7]. Although the ability to accurately diagnose uveal melanoma and to treat with eye-preserving techniques has evolved, survival rates have remained unchanged over the past several decades [1]. In recent years, there has been a trend toward developing standardized staging systems for all forms of cancer. For uveal melanoma, such a system would potentially allow for a universal platform for characterizing these tumors, for understanding the pathophysiology underlying the metastatic process, and for ultimately assessing efficacy of new therapies. A TNM staging system for uveal melanoma has recently been developed [8]. This article reviews the key elements included in the TNM staging system for uveal melanoma, the refinements made to the 7th edition of the AJCC Cancer Staging Manual, and the validation process and challenges involved in classifying uveal melanoma. PROGNOSTIC INDICATORS IN UVEAL MELANOMA Despite excellent local control of the primary tumor with currently available therapies, approximately half of patients with uveal melanoma ultimately
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develop metastases [1,2]. A vast majority of metastases occur within 5 to 10 years after primary treatment, although late onset of metastatic disease is also possible. It is rare to detect metastatic disease at the time of initial diagnosis of the ocular tumor. Uveal melanoma spreads via a hematogenous route, almost uniformly to the liver (93%), followed by the lung (24%) and bone (16%), and less frequently to sites, such as brain and skin [6]. At present, current treatments for metastatic uveal melanoma are minimally effective in prolonging survival. Early on, several clinical features were determined to be of prognostic significance in uveal melanoma. Larger tumor basal diameter and increased thickness, older patient age, presence of extraocular extension (EXE), CBI, and diffuse growth pattern were recognized as poor prognostic indicators [9]. Histopathologic studies demonstrated high-risk features, including epithelioid cell type (in comparison to spindle cell type), increased mitotic activity, presence of tumor vascular loops, and tumor-infiltrating lymphocytes [10–14]. More recently, advances in tumor genetics have revealed that chromosomal abnormalities, in particular aberrations in chromosomes 1, 3, 6, and 8, are correlated with poor survival [15,16]. Among these, loss of 1 copy of chromosome 3 (known as monosomy 3) has emerged as a powerful predictor of metastatic risk. Monosomy 3, which can be detected using a variety of techniques, is found in the majority of metastasizing uveal melanoma [17–21]. Gene expression profiling also has been developed for uveal melanoma risk stratification. Gene expression profiling has been validated in patients with uveal melanoma and has demonstrated that class 1A tumors rarely metastasize, class 1B tumors are associated with intermediate risk, and class 2 tumors are associated with the poor survival [22,23].
CLASSIFICATION OF UVEAL MELANOMA The first classification for uveal melanoma was published in Germany by Knapp in 1869 [24]. Tumors were assigned to 4 stages according to the presence or absence of patient symptoms, extraocular extension, and distant metastasis. In North America, the Collaborative Ocular Melanoma Study created standardized size definitions for uveal melanoma in the 1980s [25]. Mortality was found to generally correlate with increasing tumor size [26,27]. The concept of establishing a universal classification system for uveal melanoma is attractive from several practical standpoints. A more standardized approach to reporting would result in uniformity in the ophthalmic literature, thereby making studies more directly comparable and allowing for possibility of pooled meta-analyses [28]. Once validated, staging designations could be used as a prognostication tool. Furthermore, such a classification scheme could potentially facilitate entry criteria for clinical studies and could ultimately be used to formally assess treatment response, based on initial tumor staging, to new therapies.
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TUMOR-NODE-METASTASIS STAGING FOR UVEAL MELANOMA The TNM classification scheme is a universal cancer staging system that was first developed by the International Union Against Cancer in 1968. It was not until the recent 4th and 5th editions that TNM staging for ocular cancer was included [29]. For its latest 7th edition, published in 2010, the AJCC appointed an international Ophthalmic Oncology Task Force (OOTF) to revise TNM staging for ocular cancer based on the published literature and acquired evidence [8]. TNM staging for uveal melanoma is designed to use anatomic stage in combination with information on nodal involvement and distant metastases to designate stages I, II, III, and IV. For most ocular cancer, anatomic extent is determined both clinically and, in many cases, histopathologically. Uveal melanoma is an exception, because a majority of tumors are treated with eye-sparing techniques. Histopathology of enucleated globes is available in a minority of cases; therefore, anatomic stage is largely based on clinical factors. The anatomic classification system for uveal melanoma is based on refined data from the collaborative work of the European Ophthalmic Oncology Group [30,31]. The current 7th edition of the TNM staging manual focuses on staging for posterior melanoma, that is, ciliary body and choroidal melanoma. The classification of iris melanoma was not revised due to insufficient data. The tumor size category is denoted by the letter T, followed by a number and a lowercase letter. The number and letter that follow the T encompass 4 clinical variables: largest basal diameter, tumor thickness, CBI, and EXE [8]. The number after the T describes the size of the primary tumor based on a combination of the largest basal diameter and tumor thickness in millimeters. T1 defines the smallest tumors (Fig. 1), and successively larger tumor sizes are classified as T2, T3, and T4 (Table 1) [8]. The lower-case letters, a through d, are used to designate combinations of the presence or absence of CBI (Fig. 2) or EXE as follows [8]:
a—tumors with no CBI or EXE b—tumors with CBI but no EXE c—tumors with no CBI but EXE less than or equal to 5 mm in diameter d—tumors with both CBI and EXE less than or equal to 5 mm in diameter
For example, T1c is the classification given to a uveal melanoma that has a base of 3.0 mm to 9.0 mm with a thickness less than or equal to 6 mm, or a tumor with a base of 9.1 mm to 12.0 mm with thickness less than or equal to 3 mm, with no CBI but with EXE less than 5 mm in diameter. The lower-case e designation uniquely describes any tumor size with EXE greater than 5 mm in diameter and is, therefore, reserved for uveal melanoma classified as T4. The N classification refers to lymph node involvement. An N of 0 or 1 denotes the absence or presence of regional lymph node metastasis, respectively. Because uveal melanoma is known to metastasize via a hematogenous
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Fig. 1. (A) A 77-year-old white woman presented with a superior juxtapapillary choroidal melanoma extending from the 9:00 position to the 3:30 position at the disc margin. There was orange pigment and subretinal fluid overlying the tumor, which measured 2.0 mm in thickness by 6.7 mm laterally by 6.9 mm radially by ultrasonography. No EXE was apparent on ultrasonography. (B) Fluorescein angiography demonstrated intrinsic hyperfluorescence consistent with the intrinsic vascular pulsations that were apparent on ultrasonography. CT scan of the chest, abdomen, and pelvis did not detect any evidence of metastatic disease. This small choroidal melanoma was treated with iodine-125 plaque brachytherapy. This tumor was staged as T1aN0M0.
route, lymph node involvement would be unusual, with the potential exception of very advanced cases. Similarly, M corresponds to metastatic disease; therefore, a 0 or 1 defines the absence or presence of distant metastases, respectively. Table 1 T classification for posterior melanoma based on the 7th edition of the AJCC Cancer Staging Manual Primary tumor (T)
Tumor largest basal diameter and thickness
T1
Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor
T2
T3
T4
base base base base base base base base base base base base base
<3.0 mm–9.0 mm, thickness 6.0 mm 9.1 mm–12.0 mm, thickness 3.0 mm <9.0 mm, thickness 6.0 mm–9.0 mm 9.1 mm–12.0 mm, thickness 3.1 mm–9.0 mm 12.1 mm–15.0 mm, thickness 6.0 mm 15.1 mm–18.0 mm, thickness 3.0 mm 3.1 mm–9.0 mm, thickness 9.1 mm–12.0 mm 9.1 mm–12.0 mm, thickness 9.1 mm–15.0 mm 12.1 mm–15.0 mm, thickness 6.1 mm–15.0 mm 15.1 mm–18.0 mm, thickness 3.1 mm–12.0 mm 12.1 mm–15.0 mm, thickness >15.0 mm 15.1 mm–18.0 mm, thickness >12.0 mm >18.0 mm, any thickness
Adapted from Edge SB, Byrd DR, Compton CC, et al, editors. Malignant melanoma of the uvea. In: AJCC Cancer Staging Manual. 7th edition. New York, NY: Springer;2010:547–9.
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Fig. 2. (A) A 93-year-old white woman was referred for a large ciliochoroidal melanoma. On external examination, sentinel vessels were apparent. (B) B-scan ultrasonography demonstrated a tumor measuring 15.5 mm in thickness by 20.0 mm laterally by 20.0 mm radially. (C) A-scan ultrasonography revealed low internal reflectivity. CT scan of the chest, abdomen, and pelvis did not detect any evidence of metastatic disease. Primary enucleation was performed. Pathology revealed a ciliochoroidal melanoma with a mixed cell population of spindle B and epithelioid cells. There was no evidence of extraocular extension. This tumor was staged as T4bN0M0.
Stages I, II, and III describe increasing extent of local disease, whereas stage IV is reserved for melanoma with distant metastases. Stages I, II, III, and IV are grouped in accordance to subcategories as follows:
Stage I: T1a Stage II: T1b-d, T2a-b, T3a Stage III: T2c-d, T3b-d, T4a-e Stage IV: any T classification with either lymph node involvement or distant metastasis
Staging is further subdivide into stage I, stage II (A and B), stage III (A, B, and C), and stage IV (Table 2) [8]. UPDATES TO THE 7TH EDITION OF TUMOR-NODE-METASTASIS STAGING FOR UVEAL MELANOMA Size category The AJCC 7th edition of TNM staging for uveal melanoma added a fourth size category to the original 3 sizes included in the 6th edition of the staging manual.
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Table 2 Staging for posterior melanoma based on the 7th edition of the AJCC Cancer Staging Manual Stage
Primary tumor (T)
Lymph node (N)
Metastasis (M)
Stage I Stage II Stage IIA Stage IIB Stage III Stage IIIA Stage IIIB Stage IIIC Stage IV
T1a T1b-d, T2a-b, T3a T1b-d, T2a T2b, T3a T2c-d, T3b-d, T4a-e T2c-d, T3b-c, T4a T3d, T4b-c T4d-e Any T Any T
N0 N0 N0 N0 N0 N0 N0 N0 N1 Any N
M0 M0 M0 M0 M0 M0 M0 M0 M0 M1
Adapted from Edge SB, Byrd DR, Compton CC, et al, editors. Malignant melanoma of the uvea. In: AJCC Cancer Staging Manual. 7th edition. New York, NY: Springer;2010:547–9.
The rationale was that tumor size was considered a predominant clinical predictor of mortality in uveal melanoma. As a result of the addition of the fourth size category, the distribution of tumors within each size designation were more uniform: 24% classified as T1, 34% as T2, 30% as T3, and 12% as T4 [30]. Ciliary body involvement The prognostic importance of CBI was recognized in the 7th edition of TNM staging for uveal melanoma. In previous editions, there were separate classifications for ciliary body melanoma depending on extension to the iris or the choroid [32]. In clinical practice, it may be difficult to determine whether the primary tumor originated from the ciliary body or the choroid [30]. The 6th edition of TNM staging addressed tumors with or without CBI in the same category, separated only by size differences. The newer 7th edition classification is more efficient and incorporates valuable information about both tumor size and CBI. Extraocular extension EXE was classified exclusively in category 4 in the 5th edition of the TNM system. The 6th edition included EXE as a separate subcategory that differentiated various sizes of melanoma with EXE but without subgrouping by size of the EXE [32]. More recently, EXE greater than 5 mm has been associated with a higher mortality rate [30,33]. The 7th edition, therefore, includes a separate subcategory T4e for any tumor with EXE greater than 5 mm regardless of tumor size. VALIDATION OF TUMOR-NODE-METASTASIS STAGING FOR UVEAL MELANOMA Since its initial development and subsequent refinements, there have been several studies aimed at validating aspects of the AJCC TNM classification system for uveal melanoma. Tumor size, corresponding anatomic stage, presence
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of high risk features (EXE and CBI) have been correlated with survival based on TNM classification [30,31,34–36]. Survival based on size Increasing tumor category (T designation) has been demonstrated to be associated with older patient age, large tumor, greater incidence of subretinal fluid, hemorrhage, and EXE [37]. Posterior uveal melanoma classified at T2, T3, and T4 had a 2-fold, 4-fold, and 8-fold greater incidence of metastasis, respectively, compared with melanoma classified at T1 [34]. The OOTF independently confirmed that increasing tumor size designation is significantly related to higher risk of metastases [31,38]. The OOTF determined metastasis-free survival estimates at 10 years’ follow-up to be 94% for T1, 80% for T2, and 68% for T3; there were no data for T4 [31]. Survival based on ciliary body involvement and extraocular extension Validation studies support the finding that tumors designated with the letter a (no CBI or EXE) have the best prognosis, and those with category d (both CBI and EXE) have the poorest prognosis [30]. Survival as a function of subcategories (a through d) based on the presence of CBI and EXE has been examined. In 1 series, of 3251 primary uveal melanomas with known CBI and EXE, 71% of tumors were classified as category a, 23% as category b, 3% as category c, and 3% as category d [30]. The 10-year survival rates were, 78%, 51%, 40%, and 19%, respectively. By 15 years, survival rates were 68% for category a, 41% for category b, and unknown for categories c and d (fewer than 10 patients combined were at risk in these categories) [30]. The OOTF reported a similar distribution of each tumor subcategory based on the presence of CBI and EXE, although 10-year metastasis-free survival estimates were slightly higher for each category: 84% for category a, 67% for category b, again not calculated for category c, and 33% for category d [31]. The presence of CBI and EXE and the degree (size) of EXE have been associated with increased risk of metastasis. Only a few reports discuss the issue of EXE and its size relative to the risk of mortality [30,33]. The OOTF analyses showed that metastasis-free survival estimates at 5 years were 87% for non-EXE, 43% for EXE 5.0 mm or smaller, and 42% for EXE greater than 5.0 mm [31]. The relative paucity of data with regard to the size of EXE and resulting impact on prognosis require further validation. Survival based on overall stage In the Shields [35] series, a majority of patients were classified as either stage I (36%) or stage II (48%), whereas a small percentage were classified as stage III (16%) or stage IV (less than 1%). Compared with patients with stage I posterior uveal melanoma, hazard ratio for metastasis was 3.1 times higher in stage II disease and 9.3 times higher in stage III disease [34]. Kaplan-Meier estimates of death at 10 years were 12% for stage I, 29% for stage II, 61% for stage III, and 100% for stage IV [37]. The OOTF revealed a similar trend. The 10-year metastasis-free survival estimates from Kaplan-Meier curves were 94% for stage I, 84% for stage
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IIA, 70% for stage IIB, 60% for stage IIIA, and 50% for stage IIIB. Estimates for stage IIIC and higher could not be calculated due to small sample size at 10 years [31]. Iris melanoma Iris melanoma was not addressed in the 7th edition of the AJCC TNM staging system for uveal melanoma. OOTF reported that iris melanoma involves the ciliary body in 51.9% of patients and the choroid in 3.8% of patients [31]. When classified by tumor size category, a majority of these cases were T2 (41.3%). Of these, a total of 5 of 160 patients developed metastases and all had T2 tumors with either ciliary body or choroidal involvement. KaplanMeier estimates were not calculated due to small sample size [31]. FUTURE DIRECTIONS The latest revisions in TNM staging for uveal melanoma included in the 7th edition of the AJCC Cancer Staging Manual reflect a collaborative undertaking based on all available existing evidence. This staging system improves significantly on the anatomic classification of uveal melanoma, resulting in a more efficient framework with relevant prognostic information. Although more precise anatomic classification has been achieved in the newer system, there are several important prognostic variables not accounted for in the 7th edition. For example, histopathologic features (such as epithelioid or spindle cell type, mitotic rate, vascular mimicry patterns, tumor-infiltrating lymphocytes, and others) are not currently integrated into TNM staging. With increased advances in understanding of tumor genetics, it has become common practice to biopsy uveal melanoma for prognostication purposes. Neither chromosomal abnormalities, notably monosomy 3, nor gene expression profiling are at present included in the TNM classification system. One histopathologic study of uveal melanoma enucleation specimens concluded that metastatic death was more significantly correlated with largest basal diameter, predominance of epithelioid cell type, mitotic rate, and closed loops than with extraocular extension, again emphasizing the importance of several features not currently considered in the latest TNM classification [39]. Although anatomic classification has become precise in the 7th edition, there are specific challenges related to size determination. For example, when measuring tumor size, there may be discrepancy between clinical size estimates, preoperative ultrasonography measurements, and histopathologic size measurements in cases of eyes that have been enucleated. When compared with ultrasonographic measurements, histopathologic basal diameter and thickness measurements may be artificially smaller due to tissue shrinkage artifact that may occur during processing of specimens [30,40]. It is possible that individuals with tumors on the threshold of size cutoffs may be down-graded, resulting in assignment to a lower T category. Additionally, iris melanoma, although it may not comprise a majority of intraocular uveal melanomas, is still an important component of the spectrum
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of uveal melanoma. The present AJCC TNM system does not include iris melanoma, and it may be that a separate system is warranted for iris melanoma, given that it has a unique set of clinical features distinct from choroidal melanoma and a less aggressive propensity to metastasize. As newer evidence and information become available, subsequent updates to TNM staging for uveal melanoma will ideally incorporate such findings in an effort to continue to improve on the present staging capabilities. SUMMARY Although uveal melanoma is an uncommon disease affecting 5.1 individuals per million population in the United States, it carries a high risk of mortality. Standardization of anatomic classification and staging of the primary tumor using the AJCC TNM system is a forward step in communicating a universal language in ophthalmic oncology. The ultimate goal is to develop worldwide collaborations to advance understanding of the underlying pathophysiology and treatment approaches to this rare cancer. The 7th edition of the TNM staging system successfully incorporates tumor basal diameter, thickness, presence of CBI, and degree of extraocular extension, along with information on lymph node involvement and distant metastases. Several studies have demonstrated that larger tumor size, CBI, and larger extent of EXE are all high-risk features associated with increased risk of metastasis. Increasing tumor size, denoted by the T stage (number 1 through 4), seems particularly associated with increasing risk of metastasis. This correlation is mirrored by successive categories, a through d (and e in exceptional cases), which reflect the presence of CBI and extent of EXE, where d (and e) carry the poorest prognosis for survival. Finally, each successive stage has been shown associated with an increased risk of metastasis and death. The 7th edition of TNM staging for uveal melanoma provides early evidence of the importance of early detection and treatment, because smaller tumor size and absence of EXE are associated with a better overall prognosis. Subsequent editions of the AJCC TNM staging for uveal melanoma may take advantage of known histopathologic high-risk features and genetic information of prognostic significance. As it becomes increasingly common to biopsy uveal melanoma, the repository of information related to tumor genetics will increase understanding in this realm. Such information may be added to the existing TNM staging to improve the accuracy of prognostication. Ultimately, the ability to identify high-risk patients will increase understanding the disease mechanisms underlying the development and spread of uveal melanoma and facilitating studies aimed at evaluating the efficacy of newly developed therapies. References [1] Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 2011;118(9):1881–5. [2] Singh AD, Topham A. Survival rates with uveal melanoma in the United States: 1973-1997. Ophthalmology 2003;110(5):962–5.
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[3] Shields CL, Kaliki S, Cohen MN, et al. Prognosis of uveal melanoma based on race in 8100 patients: the 2015 Doyne lecture. Eye (Lond) 2015;29(8):1027–35. [4] Shields CL, Kaliki S, Furuta M, et al. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina 2012;32(7):1363–72. [5] Shields CL, Kels JG, Shields JA. Melanoma of the eye: revealing hidden secrets, one at a time. Clin Dermatol 2015;33(2):183–96. [6] Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, et al. Ocular melanoma: an overview of the current status. Int J Clin Exp Pathol 2013;6(7):1230–44. [7] Kanski JJ, Bowling B. Clinical ophthalmology: a systemic approach. 7th edition. Edinburgh (United Kingdom): Elsevier; 2011. [8] Malignant melanoma of the uvea. In: Edge DB, Byrd DR, Compton CC, et al, editors. AJCC Cancer Staging Manual. 7th edition. New York: Springer; 2010. p. 547–9. [9] Seddon JM, Albert DM, Lavin PT, et al. A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol 1983;101(12): 1894–9. [10] Makitie T, Summanen P, Tarkkanen A, et al. Tumor-infiltrating macrophages (CD68(þ) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 2001;42(7): 1414–21. [11] Makitie T, Summanen P, Tarkkanen A, et al. Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas. J Natl Cancer Inst 1999;91(4): 359–67. [12] McLean MJ, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol 1977;95(1):48–58. [13] Shammas HF, Blodi FC. Prognostic factors in choroidal and ciliary body melanomas. Arch Ophthalmol 1977;95(1):63–9. [14] Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999;155(3):739–52. [15] Sisley K, Rennie IG, Cottam DW, et al. Cytogenetic findings in six posterior uveal melanomas: involvement of chromosomes 3, 6, and 8. Genes Chromosomes Cancer 1990;2(3):205–9. [16] Sisley K, Cottam DW, Rennie IG, et al. Non-random abnormalities of chromosomes 3, 6, and 8 associated with posterior uveal melanoma. Genes Chromosomes Cancer 1992;5(3):197–200. [17] Scholes AG, Damato BE, Nunn J, et al. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003;44(3): 1008–11. [18] Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996;347(9010):1222–5. [19] Aalto Y, Eriksson L, Seregard S, et al. Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma. Invest Ophthalmol Vis Sci 2001;42(2):313–7. [20] Horsthemke B, Prescher G, Bornfeld N, et al. Loss of chromosome 3 alleles and multiplication of chromosome 8 alleles in uveal melanoma. Genes Chromosomes Cancer 1992;4(3): 217–21. [21] Prescher G, Bornfeld N, Horsthemke B, et al. Chromosomal aberrations defining uveal melanoma of poor prognosis. Lancet 1992;339(8794):691–2. [22] Onken MD, Worley LA, Ehlers JP, et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res 2004;64(20):7205–9. [23] Onken MD, Worley LA, Tuscan MD, et al. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 2010;12(4):461–8. [24] Knapp H. A Treatise on intraocular tumors from original clinical observations and anatomical investigations [Cole S, trans]. New York: William Wood & Co; 1869.
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