- - AJCC AJCC CAROL L. SHIELDS, MD MD CAROL L. SHIELDS, and Fundus evaluation OD revealed a jux a revealed OD evaluation Fundus tapapillary pigmented choroidal masschoroidal pigmented tapapillary mm3.5 and base in mm 10 measuring subretinaloverlying with thickness, in (lipofuscin)pigment orange and fluid hyperautofluo Lipofuscin A). (Figure, opticaland documented, was rescence revealed(OCT) tomography coherence D,B, (Figure, fluid subretinal shallow tumorthe ultrasonography, On E). and measuredand hollow acoustically was ClinicalC). thickness(Figure, in mm 3.5 consistentwere features imaging and juxtapapillaryof diagnosis the with wastumor The . choroidal normal in each eye (OU). Anterior(OU). eye each in normal fundusand OU examination segment unremarkable. were OS examination - includes a new subcategory to the N category that the N category that to a new subcategory includes In this installment, we furtherwe installment, this In 5 AT A GLANCE The posterior uveal melanoma section in the latest edition of the in the latest edition The posterior uveal melanoma section Uveal melanoma is the most common primary intraocular malignancy in malignancy in Uveal melanoma is the most common primary intraocular serious with posterior uveal melanoma than Systemic prognosis is more Cancer Staging Manual with those with extrascleral extension and between patients differentiates contiguous with the eye. regional spread into the orbit not with melanoma. adults and is more likely to develop in white individuals than in people of of than in people in white individuals to develop more likely adults and is other races.    A case example of a patient with choroidal melanoma is discussed in in is discussed melanoma with choroidal a patient A case example of of this cancer staging manual. light of the latest edition BS; MAURA DI NICOLA, MD; BY EVAN D. BARON,

A 54-year-old white woman withwoman white 54-year-old A s s s CASE REPORT CASE REPORT wasfloaters of history 1-month a pigmenteda of evaluation for referred (OD).eye right her in mass choroidal acuityvisual examination, ocular On left the in 20/20 and OD 20/60 was werepressures Intraocular (OS). eye installment of this column, wecolumn, this of installment classification updated the discussed edition8th the in melanoma uveal for mela iris to attention particular with noma. forclassification updated the discuss inedition 8th the in melanoma uveal choroidalwith patient a of context the melanoma. - -

The 1 1 1 2-4 - AJCC , providing, 2018

4 MAY/JUNE

|

Systemic prognosis is moreis prognosis Systemic

he American Joint Committee Joint American he the updates (AJCC) Cancer on Manual Staging Cancer AJCC a as serve to years 8 to 6 every classifica for universalstandard 3,4 In January 2017, the AJCC releasedAJCC the 2017, January In

Uveal melanoma is the most com most the is melanoma Uveal T melanoma. the of edition 8th updated the Manual Staging Cancer clas tumor for guidelines revised earlieran In staging. and sification melanoma represents only 4% of newof 4% only represents melanoma cases. melanomauveal posterior with serious rate10-year the as melanoma, iris than choroidal,for 25% was of irisfor 7% and body, ciliary for 34% in adults, with a mean age-adjustedmean a with adults, in casesnew million per 5.1 of incidence withand States United the in annually whites. in occurring cases of 98% tosite common most the is representingmelanoma, uveal develop iris comparison, By cases. new of 90% uveal melanoma, , melanoma, uveal conjunctival melanoma, conjunctival adnexal ocular carcinoma, eyelid and sarcoma. orbital and lymphoma, malignancyintraocular primary mon Since the release of the first edition edition first the of release the Since staging this 1977, in manual the of and developed been has system sites. anatomic many for updated neoplasms, ocular to regard With for classifications provides AJCC the tion of cancer extent using clinical, using extent cancer of tion measures. genetic and pathologic,

POSTERIOR UVEAL MELANOMA UVEAL POSTERIOR UPDATED AJCC CLASSIFICATION FOR FOR CLASSIFICATION AJCC UPDATED TODAY

30 s OCULAR OCULAR ONCOLOGY s

A B followed for 4 years with no evidence of systemic metastasis.

DISCUSSION The AJCC Cancer Staging Manual provides uniform guidance for cancer staging and assessing anatomic dimen- sions, anatomic structure involvement, and histopathologic factors utilizing the available evidence.1 The 7th edition of the AJCC staging of posterior uveal C D melanoma, released in 2009, was rede- signed based on a recent study6 using clinical evidence from a collaborative database of 7,369 patients to create the year-plus old 8th edition AJCC E staging system. Multiple studies have validated the 7th edition AJCC classification for uveal melanoma.7-10 Shields et al independently analyzed 7,731 patients Figure. AJCC category T2a N0 M0 melanoma. Subtle juxtapapillary pigmented choroidal melanoma with overlying and found that the case distribution subretinal fluid and orange pigment (A), fundus autofluorescence imaging revealing hyperautofluorescence of lipofuscin (B), ultrasound depicting hollow tumor with thickness of 3.5 mm (C), and OCT showing melanoma with included stage 1 in 2,767 patients overlying subretinal fluid (D) extending into the fovea (E). (36%), stage 2 in 3,735 (48%), stage 3 in 1,220 (16%), and stage 4 in nine (<1%).7 Compared with uveal mela- clinically classified using the AJCC 8th At 18 months after treatment, noma classified as AJCC stage 1, the edition as T2a N0 M0. circumpapillary recurrence and optic rate of metastasis and/or death was Treatment of choice was iodine-125 nerve edema were detected, and enu- three times greater for stage 2, nine to (I-125) plaque radiotherapy combined cleation was advised and performed. 10 times greater for stage 3, and not with two sessions of transpupillary Histopathology of the tumor revealed assessable for stage 4.7 thermotherapy. At 1-year follow-up, choroidal melanoma, mixed cell type, Furthermore, the AJCC Ophthalmic the tumor demonstrated complete with AJCC 8th edition histologic Task Force released a validation study regression. grade G2. The patient has been of 3,217 patients from 10 other ocular TABLE 1. AJCC CLASSIFICATION OF POSTERIOR UVEAL MELANOMA (CHOROIDAL AND ), T CATEGORY Thickness (mm) >15.0 4 4 4 4 4 4 4 12.1 to 15.0 3 3 3 3 3 4 4 9.1 to 12.0 3 3 3 3 3 3 4 6.1 to 9.0 2 2 2 2 3 3 4 3.1 to 6.0 1 1 1 2 2 3 4 ≤ 3.0 1 1 1 1 2 2 4 ≤ 3.0 3.1-6.0 6.1-9.0 9.1-12.0 12.1-15.0 15.1-18.0 >18.0 Largest basal diameter (mm) Source: Adapted from the AJCC Cancer Staging Manual, 8th ed.1

MAY/JUNE 2018 | RETINA TODAY 31 1 , 8th ed. AJCC Cancer Staging Manual 2018 Tumor size category 3 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter Tumor base 12.1-15 mm with thickness >15 mm Tumor base 15.1-18 mm with thickness >12 mm Tumor base >18 mm with any thickness Tumor size category 4 without ciliary body involvement and extraocular extension Tumor size category 4 with ciliary body involvement diameter Tumor size category 4 without ciliary body involvement but with extraocular extension ≤5 mm in largest Tumor size category 4 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter Any tumor size category with extraocular extension >5 mm in largest diameter Tumor size category 2 with ciliary body involvement but with extraocular extension ≤5 mm in largest diameter Tumor size category 2 without ciliary body involvement and extraocular extension ≤5 mm in largest diameter Tumor size category 2 with ciliary body involvement Tumor base 3.1-9 mm with thickness 9.1-12 mm Tumor base 9.1-12 mm with thickness 9.1-15 mm Tumor base 12.1-15 mm with thickness 6.1-15 mm Tumor base 15.1-18 mm with thickness 3.1-12 mm and extraocular extension Tumor size category 3 without ciliary body involvement Tumor size category 3 with ciliary body involvement diameter Tumor size category 3 without ciliary body involvement but with extraocular extension ≤5 mm in largest Tumor size category 1 without ciliary body involvement and extraocular extension Tumor size category 1 without Tumor size category 1 with ciliary body involvement but with extraocular extension ≤5 mm in largest diameter Tumor size category 1 without ciliary body involvement and extraocular extension ≤5 mm in largest diameter Tumor size category 1 with ciliary body involvement Tumor base ≤9 mm with thickness 6.1-9 mm Tumor base 9.1-12 mm with thickness 3.1-9 mm Tumor base 12.1-15 mm with thickness ≤6 mm Tumor base 15.1-18 mm with thickness ≤3 mm and extraocular extension Tumor size category 2 without ciliary body involvement T Criteria Primary tumor cannot be assessed No evidence of primary tumor ≤6 mm Tumor base ≤9 mm with thickness thickness ≤3 mm Tumor base 9.1-12 mm with MAY/JUNE

|

T4d T4e Source: Adapted from the T4a T4b T4c T3b T3c T3d T4 T2d T3 T3a T2a T2b T2c T1c T1d T2 T1 T1a T1b AND CILIARY BODY), T CATEGORY SUBCLASSIFICATION BODY), T CATEGORY CILIARY AND T Category TX T0 TABLE 2. AJCC CLASSIFICATION OF POSTERIOR UVEAL MELANOMA (CHOROIDAL (CHOROIDAL MELANOMA UVEAL OF POSTERIOR 2. AJCC CLASSIFICATION TABLE RETINA TODAY

32 s OCULAR ONCOLOGY OCULAR ONCOLOGY s

oncology centers internationally, reveal- ing case distribution of stage 1 in 1,030 TABLE 3. AJCC CLASSIFICATION OF POSTERIOR UVEAL (32%), stage 2 in 1,805 (56%), stage 3 in 382 (12%), and stage 4 in 67 patients (2%).8 These authors independently MELANOMA (CHOROIDAL AND CILIARY BODY), found the risk of metastasis at 10 years to increase by approximately twofold REGIONAL LYMPH NODES AND DISTANT METASTASIS for each AJCC stage.8 N Category N Criteria Bagger et al evaluated the prog- NX Regional lymph nodes cannot be assessed nostic effect of AJCC 7th edition staging combined with genetic status N0 No regional lymph node involvement in patients with posterior uveal mela- N1 Regional lymph node metastasis or discrete tumor deposits in the orbit noma and concluded that a normal N1a Metastasis in one or more regional lymph node(s) genetic status of chromosomes 3 and 8 minimized the prognostic effect of N1b No regional lymph nodes are positive, but there are discrete tumor deposits in the AJCC staging, while a combination of orbit that are not contiguous to the eye genetic status and AJCC staging pro- M Category M Criteria vided accurate prediction of survival in those with abnormal chromosome M0 No distant metastasis by clinical classification 3 and 8 status.9 M1 Distant metastasis Additionally, the European M1a Largest diameter of the largest metastasis ≤3.0 cm Ophthalmic Oncology Group con- ducted a study of pediatric choroidal M1b Largest diameter of the largest metastasis 3.1-8.0 cm and , collecting M1c Largest diameter of the largest metastasis ≥8.1 cm data on 299 patients from 24 centers Source: Adapted from the AJCC Cancer Staging Manual, 8th ed.1 (114 children age <18 and 185 young adults age 18-25 at the time of diag- nosis).10 In individuals aged 25 years TABLE 4. AJCC CLASSIFICATION OF POSTERIOR UVEAL and younger, they found that increas- ing AJCC stage was associated with poorer survival at 10 years from diag- MELANOMA (CHOROIDAL AND CILIARY BODY), nosis, with stage 1 at 100% survival, stage 2 at 86% survival, and stage 3 at STAGING 76% survival.10 They concluded that When T is … And N is … And M is … Then the stage group is … children younger than 18 years have T1a N0 M0 I a more favorable survival rate than T1b-d N0 M0 IIA young adults aged 18 to 25 years, adjusting for TNM stage and sex.10 T2a N0 M0 IIA The 8th edition of the AJCC Cancer T2b N0 M0 IIB Staging Manual guides users in assessing T3a N0 M0 IIB the extent of the primary tumor (T), the presence or absence of lymph node T2c-d N0 M0 IIIA involvement (N), and the presence or T3b-c N0 M0 IIIA absence of distant metastasis (M).1 More specifically, T is organized based T4a N0 M0 IIIA on the tumor’s largest basal diameter T3d N0 M0 IIIB and thickness into increasing size cat- T4b-c N0 M0 IIIB egories and then subclassified accord- ing to ciliary body involvement and T4d-e N0 M0 IIIC extraocular extension (Tables 1 and 2). Any T N1 M0 IV N is classified by regional lymph node Any T N1 M1a-c IV involvement (Table 3). Similarly, M is 1 classified by distant metastasis and Source: Adapted from the AJCC Cancer Staging Manual, 8th ed.

MAY/JUNE 2018 | RETINA TODAY 33 J . . . 2017;12(5):40-43. Invest Ophthalmol Ophthalmology Ophthalmology . 8th ed. New York, NY: Retina Today AJCC Cancer Staging Manual . 3rd ed. Philadelphia, PA: Wolters Kluwer; 2016. . 2016;123(4):898-907. . 2015;133(4):376-383. n editorial advisory board . 2012;32(7):1363-1372. Ophthalmology Retina JAMA Ophthalmol Retina Today Intraocular Tumors: An Atlas and Textbook . 2013;31(22):2825-2831. . 2015;56(1):438-444. The AJCC cancer staging system for posterior uveal posterior for system staging cancer AJCC The Medical student at Sidney Kimmel Medical College and graduate student graduate student Medical student at Sidney Kimmel Medical College and [email protected] Research fellow, Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson [email protected] Director of the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson Member of the [email protected] researcher, Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson Thomas Jefferson researcher, Ocular Oncology Service, Wills Eye Hospital, University, Philadelphia, Pennsylvania University, Philadelphia, Pennsylvania University, Philadelphia, Pennsylvania     6. Kujala E, Damato B, Coupland SE, et al. Staging of ciliary body and choroidal based on anatomic extent. 6. Kujala E, Damato B, Coupland SE, et al. Staging of ciliary body and choroidal Clin Oncol on Cancer classification of 7. Shields CL, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields JA. American Joint Committee Zimmerman Lecture. uveal melanoma (anatomic stage) predicts prognosis in 7731 patients: The 2013 2015;122(6):1180-1186. Joint Committee on Cancer’s 7th edition 8. AJCC Ophthalmic Oncology Task Force. International validation of the American classification of uveal melanoma. edition, the previous edition did not differentiate patients patients differentiate not did edition previous the edition, to adherent typically is which extension, extrascleral with not orbit the into spread regional with those from eye, the eye. the with contiguous STAY IN THE KNOW and years, recent in validated largely been has melanoma this of prognosis the of understanding improve to helps it utilize to oncologists ocular all encourage We malignancy. of method uniform a maintain to system classification this outcomes. predicting et al. Uveal melanoma. In: 1. Kivelä T, Simpson RE, Grossniklaus HE, Springer; 2016:805-817. and survival. 2. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, 2011;118(9):1181-1185. 3. Shields JA, Shields CL. prognosis of uveal melanoma based on 4. Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and age at presentation in 8,033 cases. melanoma. 5. Bekerman VP, Di Nicola M, Shields JA, Shields CL. Updated classification for primary iris No conflicting relationship exists for any author. Support provided by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania. (CLS). The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. 9. Bagger M, Andersen MT, Andersen KK, Heegaard S, Andersen MK, Kiilgaard JF. The prognostic effect of American Joint 9. Bagger M, Andersen MT, Andersen KK, Heegaard S, Andersen MK, Kiilgaard JF. ciliary body melanoma. Committee on Cancer staging and genetic status in patients with choroidal and Vis Sci body melanoma study: A survey by the 10. Al-Jamal RT, Cassoux N, Desjardins L, et al. The pediatric choroidal and ciliary European ophthalmic oncology group. EVAN D. BARON, BS n n MAURA DI NICOLA, MD n n CAROL L. SHIELDS, MD n n n - - 1 , 8th ed. AJCC Cancer Staging Manual 2018 Epithelioid cell melanoma (>90% epithelioid cells) G Criteria Grade cannot be assessed spindle cells) Spindle cell melanoma (>90% epithelioid cells and <90% Mixed cell melanoma (>10% spindle cells) MAY/JUNE

|

(G) should be assessed (Table 5). Grading includes Grading 5). (Table assessed be should (G) For posterior uveal melanoma, the 8th edition of the of edition 8th the melanoma, uveal posterior For When available following enucleation, histologic histologic enucleation, following available When The AJCC classification system for uveal melanoma addi melanoma uveal for system classification AJCC The G3 Source: Adapted from the G Category G Category GX G1 G2 OF POSTERIOR UVEAL MELANOMA MELANOMA UVEAL OF POSTERIOR AND CILIARY BODY), (CHOROIDAL GRADE HISTOLOGIC TABLE 5. AJCC CLASSIFICATION 5. AJCC CLASSIFICATION TABLE tumor deposits in the orbit that are not contiguous to contiguous not are that orbit the in deposits tumor This involvement. node lymph regional without eye the 8th manual AJCC the in stated as because, important is ing, it may be incorporated in the future. the in incorporated be may it ing, but category, N the to subcategory a added manual AJCC edition. 7th the from unchanged largely otherwise is it to subcategories N1b and N1a has now category N1 The discrete from involvement node lymph regional separate increasing stage indicates increasingly higher risk for metastasisriskfor higher increasingly indicates stage increasing mortality. and grading types cell epithelioid and (G2), cell mixed (G1), cell spindle stag prognostic in used currently not is G Although (G3). metastatic tumor dimension (Table 3). (Table dimension tumor metastatic individualthe of combination specific each organizes tionally Each4). (Table stages(stages1-4) prognostic into M and N, T, IMPROVE UNDERSTANDING OF THE IMPROVE UNDERSTANDING OF THE PROGNOSIS OF THIS MALIGNANCY. FOR POSTERIOR UVEAL MELANOMA FOR POSTERIOR UVEAL MELANOMA HAS BEEN LARGELY VALIDATED IN RECENT YEARS, AND IT HELPS TO THE AJCC CANCER STAGING SYSTEM THE AJCC CANCER STAGING SYSTEM RETINA TODAY

34 s OCULAR ONCOLOGY