Melanoma Staging: American Joint Committee On Cancer (AJCC .
Ann Surg Oncol (2018) 513-7EDITORIAL – MELANOMASMelanoma Staging: American Joint Committee on Cancer(AJCC) 8th Edition and BeyondJeffrey E. Gershenwald, MD1,2 and Richard A. Scolyer, MD3,4,51Departments of Surgical Oncology and Cancer Biology, Unit 1484, The University of Texas MD Anderson CancerCenter, Houston, TX; 2Melanoma and Skin Center, The University of Texas MD Anderson Cancer Center, Houston, TX;3Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; 4Department of Tissue Pathology andDiagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; 5Sydney Medical School, TheUniversity of Sydney, Sydney, NSW, AustraliaMelanoma staging is a critical tool for communicationbetween physicians and their patients and also assistsclinical decision-making and prognostic assessment. It isused for clinical trial design, eligibility, stratification, andanalysis. Importantly, it also represents the foundation forreporting in institutional, state, national, and internationaldata registries, which, in turn, facilitate understanding ofthe broader melanoma landscape.The 7th edition AJCC melanoma staging system wasintroduced in 2009 and implemented in 2010. Since thattime, there has been a tremendous improvement in ourunderstanding of the molecular and immune biology ofmelanoma, which has led to the unprecedented introductionand widespread use of a number of effective systemictherapies for patients with advanced disease and in theadjuvant setting.1–6To facilitate an evidence-based approach and to informrevisions for the 8th edition of the AJCC melanoma stagingsystem, we created a contemporary international melanomadatabase: the International Melanoma Database and Discovery Platform (IMDDP).7 Given the recent advances inthe clinical management of patients with advanced andunresectable disease, rapidly evolving treatment options forsuch patients and varying approval for use of these newagents in different parts of the world, the AJCC melanomaexpert panel considered that it was inappropriate to includestage IV patients in their initial data analyses of theIMDDP. Therefore, patients eligible to be included in theIMDDP were those with stages I–III cutaneous melanomadiagnosed since 1998. This approach allowed us to excludepatients diagnosed during the early and mid-1990s, a period of rapid evolution in surgical, pathological, and nuclearmedicine strategies employed to identify, remove, andaccurately assess the sentinel lymph node (SLN) in patientswith cutaneous melanoma who underwent lymphaticmapping and SLN biopsy. In contrast, the database used forthe 7th edition had no restriction on the date of diagnosisand included patients diagnosed as long ago as the 1960s.8In addition, for inclusion in the 8th edition analyses,patients were required to have undergone SLN biopsy iftheir primary was T2 or thicker, and if T1 and a SLNbiopsy had been performed, SLN status was incorporatedfor data analysis and staging purposes.The TNM- or anatomic-based staging system is effectively constrained by the limited type and number offactors that can be included. However, both anatomic andnonanatomic factors can have significant prognosticimportance. As such, the overall 8th edition AJCC strategyembraced inclusion of standard anatomic ‘‘TNM’’ prognostic factors and also considered nonanatomic factors thatcould help further improve staging and prognosticassessment.9T CATEGORY AND STAGES I/II STAGE GROUPSÓ Society of Surgical Oncology 2018First Received: 21 March 2018;Published Online: 30 May 2018J. E. Gershenwald, MDe-mail: jgershen@mdanderson.orgIn the 7th edition, T-category criteria included tumorthickness (measured to the nearest 0.01 mm) and presenceor absence of ulceration across all subcategories; mitosesas a dichotomous variable (\ 1 vs. C 1 mitosis/mm2) also
2106was included as a T1 category criterion.8 However, basedon the impracticality of measuring tumor thickness to thenearest 0.01 mm, especially for tumors [ 1 mm in tumorthickness, in the 8th edition, the AJCC recommends thattumor thickness be recorded to the nearest 0.1 mm and hasprovided a formal rounding schema to standardize theapproach.7 For example, patients with melanomas0.75–0.84 mm in tumor thickness will now be rounded to(and reported as) 0.8 mm (i.e., T1b), and melanomasbetween 0.95 mm and 1.04 mm in tumor thickness will bereported as 1.0 mm (i.e., T1b). In the 8th edition, thedefinitions of Tis, T0, and TX have been refined and/orclarified. Tis is used for melanoma in situ (i.e., no invasivecomponent is present). T0 is designated when no evidenceof a primary tumor can be found (e.g., a patient presentingwith an inguinal nodal metastasis of melanoma with noevidence of a primary tumor). TX is used when the tumorthickness cannot be determined (e.g., in a curettage specimen when there is no sectioning of the tumorperpendicular to the skin surface) or there is no informationabout the T category for the primary tumor (e.g., a primarymelanoma that was resected many years previously and theprimary melanoma report cannot be found).Based on previously published studies that reportedpatients with thicker T1 melanomas have a worse prognosis than those with thinner T1 melanomas, the AJCCmelanoma expert panel explored the potential impact ofincluding an additional tumor thickness criterion for subcategorizing T1 melanomas by analyzing our IMDDPmelanoma database.10–13 With the proposal in place torecord tumor thickness measurements to the nearest0.1 mm, a 0.8 mm cut point was explored for patients withT1 melanoma along with ulceration and mitosis (i.e., \ 1vs. C 1 mitosis/mm2). In this analysis, the addition of a0.8-mm tumor thickness stratum was a more powerfulprognostic factor than mitotic rate (as a dichotomousvariable). Principally for this reason, mitotic rate as adichotomous variable was removed as a T1 subcategorycriterion. The subcategorization of T1 melanomas at a 0.8mm threshold has potential clinical relevance, particularlyfor the role of SLN biopsy in patients with T1 melanomas.Overall, SLN metastases are very infrequent (\ 5%) inpatients whose melanoma is \ 0.8 mm in thickness andnonulcerated (i.e., AJCC 8th edition T1a) but occur inapproximately 5–12% of patients with primary melanomas0.8–1.0 mm in thickness (i.e., AJCC 8th edition T1b).14–17Reflective of these data, consensus guidelines have recommended that SLN biopsy may be considered in thislatter group of patients (i.e., patients with a primary tumorthickness 0.8–1.0 mm) and also in patients with thinnerulcerated tumors (i.e., all patients with AJCC 8th editionT1b melanomas).18,19 Although mitosis was removed as aT1 subcategory criterion, analyses performed for both theJ. E. Gershenwald, R. A. Scolyer7th and 8th edition AJCC staging systems demonstratedthat tumor mitotic rate, when explored across its dynamicrange, was a very important prognostic factor and stronglysupports that if interrogated in this fashion, will likely bean important covariate going forward as clinical tools aredeveloped. As emphasized by the AJCC melanoma expertpanel, for these reasons, mitotic rate should be collected forall invasive melanomas.7,13Comparison of stages I and II substage melanomaspecific survival rates between the AJCC 7th and 8th editions demonstrate more favorable survival in the 8thedition compared with the 7th edition. An important contributing factor was the requirement that to be included inthe 8th edition analysis, SLN biopsy had to be performedfor patients with T2 and thicker melanomas, and if performed in patients with a T1 melanoma, the status of theSLN was used.7,8,13,20 This approach ensured that patientswith clinically occult nodal metastases (detected by SLNbiopsy) were designated as stage III in the 8th edition. Incontrast, SLN biopsy was not required for inclusion in the7th edition survival analyses for any tumor thickness (andindeed many patients included in the dataset were managedbefore the era of SLN biopsy). As such, in the 7th editiondatabase, many patients with clinically localized melanomawho did not undergo SLN biopsy were characterized ashaving stage I or II melanoma regardless of whether theyharbored clinically occult regional node metastasis,because only clinical staging of their nodal basin wasperformed. A sequela of this 7th edition approach was thatthe survival outcomes across multiple T subcategories werelikely underestimated and, given the increasing relativerisk of tumor-involvement of SLNs with increasing Tcategory, was most evident when comparing outcomes tothose of the 8th edition for patients with T4b melanomas(Fig. 1a, b).N CATEGORY AND STAGE III STAGE GROUPSFor the N category, which includes regional lymph nodeas well as non-nodal regional disease (i.e., satellites, intransit metastasis, and microsatellites), the AJCC melanoma expert panel grouped nonnodal regional diseasetogether for staging purposes (because they each had asimilar impact on prognosis) and revised the N categorycriteria.7 Previously used terms of ‘‘microscopic’’ and‘‘macroscopic’’ regional disease in the 7th edition havebeen replaced by ‘‘clinically occult’’ (i.e., detected by SLNbiopsy) and ‘‘clinical evident’’ (i.e., detected by clinicalexamination or radiographic imaging) regional disease toenhance clarity. These correspond to N category designations ‘‘a’’ and ‘‘b’’, respectively. The presence ofmicrosatellites, satellites, or in-transit metastases is now
ab1.00.90.80.70.60.50.4N5-YR 10-YR5225 99% 98%5749 97% 94%2338 94% 88%1688 87% 82%691 82% 75%IAIBIIAIIBIIC0.30.20.10123456721071.0Survival Rate (proportion)Melanoma-Specific Survival ProbabilityMelanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond0.9IA (n 9,452)0.8IB (n 8,918)0.7IIA (n 4,644)0.60.50.4IIB (n 3,228)0.3IIC (n 1,397)0.20.1890102.55.07.5Years Since Diagnosisd1.00.90.80.70.60.50.4N 5-YR 10-YRIIIA 1006 93% 88%IIIB 1170 83% 77%IIIC 2201 69% 60%IIID 205 32% 24%0.20.10123456712.515.017.520.01.0Survival Rate (proportion)Melanoma-Specific Survival Probabilityc0.310.0Time (years)0.90.80.7IIIA (n 1,196)0.60.5IIIB (n 1,391)0.40.3IIIC (n 720)0.20.18910Years Since Diagnosis02.55.07.510.012.515.017.520.0Time (years)FIG. 1 Comparison of survival curves for 8th edition and 7th editionAJCC stages I, II, and III. a 8th edition stages I and II stage groups;b 7th edition stages I and II stage groups; c 8th edition stage III stagegroups; and d 7th edition stages III stage groups. Figures a and c usedwith permission from Gershenwald, J.E., Scolyer, R.A., Hess, K.R.,et al. Melanoma staging: Evidence-based changes in the AmericanJoint Committee on Cancer eighth edition cancer staging manual. CACancer J Clin. 2017;67:472–92. Figures b and d used withpermission from Balch CM, Gershenwald JE, Soong SJ, et al. Finalversion of 2009 AJCC melanoma staging and classification. J ClinOncol. 2009;27:6199–206categorized as N1c, N2c, or N3c, based on the number oftumor-involved regional lymph nodes, if any.7 Importantly,the definition of a microsatellite was refined and clarified; amicrosatellite is a microscopic cutaneous and/or subcutaneous metastasis adjacent or deep to, but discontinuousfrom, a primary melanoma detected on pathologicalexamination of the primary tumor site.Recent clinical trial data, demonstrating no clear survival benefit for patients with a tumor-involved SLN whounderwent completion lymph node dissection (CLND)compared with those who did not, has already begun totransform surgical approaches for patients with tumor-involved SLNs—i.e., fewer patients undergo completionlymph node dissection (CLND) after detection of a tumorinvolved SLN.21,22 It is worth noting that the 8th editionAJCC Cancer Staging Manual provides specific recommendations for documentation of the now commonscenario when SLN biopsy identifies tumor-involved SLNsbut CLND is not performed.9 To distinguish patients whohave had a CLND from those who have not, the ‘‘(sn)’’suffix should be appended to the N category for those whodid not undergo CLND—i.e., a patient with a single tumorinvolved SLN who does not undergo CLND ispN1a(sn).7,8,13 This approach will likely improve datacapture and facilitate future planned analyses in this newera of a more selective approach to CLND.Recognizing the importance of tumor thickness as apotential prognostic factor among patients with regionaldisease and expanding on prior analyses demonstrating theimportance of primary tumor ulceration among thesepatients, the AJCC explored the prognostic impact of primary tumor factors (e.g., tumor thickness and ulcerationstatus), as well as regional factors via a T-category- andN-category-based analysis. Based on recursive partitioninganalysis, the expert panel agreed on four stage III substagesto capture the significant heterogeneity among the stage IIIpopulation.13 It is important to note that no direct comparison or ‘‘mapping’’ of the 7th edition and 8th edition
2108pathological stage III stage groups is possible. First, tumorthickness was included as a component of stage III stagegroups for the 8th edition but was not employed as a stageIII stage group criterion in the 7th edition melanomastaging system. Furthermore, the N category criteria differin the 7th and 8th editions and, in several instances, thevarious N subcategories map to different stage III groupings in the 8th edition. With these important caveats inmind, melanoma-specific survival (MSS) for both AJCC8th edition stage IIIA and stage IIIB patients was morefavorable compared to 7th edition stage IIIA patients(Fig. 1). These observations translate into significantimplications for patient counseling, management, andcontemporary clinical trial design, stratification, and analysis, because patients in the 8th edition cohort had a morefavorable survival profile across stages IIIA, IIIB, and IIICdisease compared with patients with similar stage groupings in the 7th edition (Figs. 1c and d). To facilitateaccurate and efficient 8th edition stage III stage groupdetermination, particularly in busy patient clinics, clinic-,desktop-, and phone-friendly stage III subgroup grids areavailable for download in the supporting information section of reference13 (reproduced in Fig. 2).In recent years, multiple studies of patients with tumorinvolved SLNs have demonstrated that SLN tumor burdenprovides important prognostic information.23,24 SLN tumorburden can be quantitated by a variety of parameters, suchas the maximum size of the largest metastasis, the maximum subcapsular depth of extension of the tumor deposit(also known as the tumor penetrative depth), the location ofthe deposit(s) within the SLN, and the percentage crosssectional area of the SLN involved by tumor.25,26 Microscopic tumor burden has already been implemented as aninclusion criterion in some clinical trials of adjuvant therapy.5 Based on available data and practical considerations,the AJCC melanoma expert panel recommends that thesingle largest maximum dimension (measured in millimeters using an ocular micrometer) of the largest discretemetastatic melanoma deposit in any tumor-involved SLNbe recorded in pathology reports. Although thishistopathological parameter is not currently a formalstaging criterion, SLN tumor burden will be included inand will likely guide the development of future prognosticmodels and ultimately validated clinical tools (e.g., calculators, nomograms, etc.) for patients with regionalmetastatic disease.J. E. Gershenwald, R. A. ScolyerAJCC Eighth EditionMelanoma Stage III SubgroupsT CategoryNCategory T0 T1a T1b T2a T2b T3a T3b T4a CCCCDN3cCCCCCCCCDLegendInstructions(1) Select patient’s N category at left chart.(2) Select patient’s T category at top of chart.(3) Note letter at the intersection of T&N on grid.(4) Determine patient’s AJCC stage using legend.N/A Not assignedAStage IIIABStage IIIBCStage IIICDStage IIIDFIG. 2 American Joint Committee on Cancer (AJCC) eighth editionstage III subgroups based on T and N categories. Used withpermission from Gershenwald JE, Scolyer RA, Hess KR, SondakVK, et al. Melanoma staging: evidence-based changes in theAmerican Joint Committee on Cancer eighth edition cancer stagingmanual. CA Cancer J Clin. 2017; 67:472–491the importance of central nervous system (CNS) disease inprognosis, clinical management, and clinical trial design,stratification, and analysis, a new M1d designation fordistant metastasis to the CNS has been added; M1c nolonger includes patients with CNS metastasis. In addition,M1c is no longer defined by any patient with distantmetastasis and elevated LDH. Nevertheless, as elevatedLDH has been demonstrated to be an adverse prognosticfactor both in the 7th edition analyses and recent clinicaltrials, it remains an M category criterion in the 8th edition.2,3,7 The revised M category now includes a suffix tosignify the absence or presence of an elevated LDH foreach M1 subcategory.M CATEGORYBEYOND TNM, ASSESSMENT OF CLINICALPROGNOSTIC TOOLS, AND NEXT STEPSPatients with distant metastasis continue to be definedby anatomic site of distant metastases and serum lactatedehydrogenase (LDH) level. In the 8th edition, reflective ofAdditional prognostic factors that are not staging criteriabut are recommended for recording clinical care, emergingprognostic factors for clinical care, as well as
Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyondrecommendations for clinical trial stratification are alsopresented in the 8th edition AJCC Cancer Staging Manualand/or on the AJCC website.7,27Despite its success over the past several decades, TNM/anatomic-based staging systems have been constrained intheir ability to accommodate prognostic factors that mayemerge from an improved understanding of cancer biology.To be useful, any staging system needs to be clinicallyrelevant, reflect contemporary practice, and be refined asour understanding of the disease matures. In an effort tofoster clinical relevance, the AJCC has expanded its principles of cancer staging to include nonanatomic-basedfactors. Nevertheless, it is essential that before such factorsare introduced as staging criteria (and therefore adopted inroutine clinical settings), they are demonstrated to haveindependent prognostic significance, are validated inindependent patient cohorts, and are practical to measure inroutine clinical practice. Using a systematic search of thepublished literature, a priori criteria were used to evaluatequality and clinical relevance of 17 clinical prognostictools for primary cutaneous melanoma; a principal conclusion was that there ‘‘is a great opportunity to improvethese tools and to foster the development of new, validatedtools by the inclusion of contemporary clinicopathologicalcovariates and by using improved statistical and methodological approaches.’’28 Formal criteria also have beenrecently developed by the AJCC 8th edition PrecisionMedicine Core to serve as a framework for approval ofcontemporary risk models by the AJCC.29 These changesare overall reflective of a strategic evolution from population-based staging to a more personalized approach.29,30Given the ongoing advances in our understanding of theclinical, pathological, molecular, and immunologicalunderpinnings of melanoma, a less ‘‘staccato’’ approach tocancer staging is likely to be embraced and implementedby the AJCC. Strategically configured iterative or ‘‘rolling’’updates can more efficiently exploit integration of clinically relevant advances into the cancer staging arena. It isimportant to note that while there is tremendous enthusiasm to integrate molecular and/or immune-basedbiomarkers into melanoma staging and other clinicalprognostic tools, there are as yet no formally validatedschema. In addition, some biomarkers may have predictivesignifican
ulcerated tumors (i.e., all patients with AJCC 8th edition T1b melanomas).18,19 Although mitosis was removed as a T1 subcategory criterion, analyses performed for both the 7th and 8th edition AJCC staging systems demonstrated that tumor mitotic rate, when explored across its dynamic range, was a very important prognostic factor and strongly
This measure is to be reported a minimum of . once per reporting period. for patients with a current diagnosis of melanoma or a history of melanoma seen during the reporting period. It is anticipated that eligible clinicians providing care for patients with melanoma or a history of melanoma will submit this measure. Measure Reporting:
study aims to screen medicinal plants fromacross the world against skin cancer melanoma. 26 medicinal plants were extracted with chloroform and methanol. 52 extracts of 26 plants were screened for anti-proliferation against human skin cancer melanoma cell line A375 and mice skin cancer melanoma cell line B16, using a colorimetric assay MTT. Plants like Horsetail and officinalis have .
Questions 1.3 million people are living with melanoma in the US . melanoma is more than 1mm thick. Newer studies have found that SLNB status is the most important prognostic factor even in thin melanoma (up to 1mm
ISSUE 20 HORIZONS AUGUST 2015 Neoadjuvant clinical trials: a new paradigm for melanoma treatment By Michael A. Davies, M.D., Ph.D., Deputy Chair and Associate Professor, Melanoma Medical Oncology T he treatment of melanoma patients with distant metastases, which is also called stage IV disease, has changed dramatically in recent years.
Changes from AJCC Staging Manual, 7th ed. 13 AJCC 8th Edition Staging Rules –Chapter 1 Entire 30 pages devoted to Staging Rules and is Table-Driven with User Notes Definitions are included for vocabulary related to cancer staging Clarification on Use of “X”, and Zero (0) Clarification on Use of Staging Descriptors
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