1、Recommendations for Initial Evaluation, Staging, andResponse Assessment of Hodgkin and Non-HodgkinLymphoma: The Lugano ClassificationBruce D. Cheson, Richard I. Fisher, Sally F. Barrington, Franco Cavalli, Lawrence H. Schwartz,Emanuele Zucca, and T. Andrew ListerSee accompanying article on page 3048
2、Bruce D. Cheson, Georgetown Univer-sity Hospital, Lombardi ComprehensiveCancer Center, Washington, DC; Rich-ard I. Fisher, Fox Chase Cancer Center,Philadelphia, PA; Sally F. Barrington, StThomas Hospital; T. Andrew Lister, StBartholomews Hospital, London,United Kingdom; Franco Cavalli andEmanuele Zu
3、cca, Oncology Institute ofSouthern Switzerland, Bellinzona, Swit-zerland; and Lawrence H. Schwartz,Columbia University, New York, NY.Published online ahead of print atwww.jco.org on August 11, 2014.Processed as a Rapid Communicationmanuscript.Written on behalf of the followinggroups: Alliance, Austr
4、alasian Leukae-mia and Lymphoma Group, EasternCooperative Oncology Group, EuropeanMantle Cell Lymphoma Consortium,Italian Lymphoma Foundation, Euro-pean Organisation for Research andTreatment of Cancer/Dutch Hemato-Oncology Group, Grupo Espanol deLinfomas y Trasplantes de MedulaOsea, German High-Gra
5、de LymphomaStudy Group, German Hodgkins StudyGroup, Japanese Lymphoma StudyGroup, Lymphoma Study Association,NCIC Clinical Trials Group, NordicLymphoma Study Group, SouthwestOncology Group, and United KingdomNational Cancer Research Institute.Presented in part at the 12th Interna-tional Conference o
6、n MalignantLymphoma, Lugano, Switzerland, June19-22, 2013.Authors disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.Corresponding author: Bruce D.Cheson, MD, Georgetown UniversityHospital, Lombardi ComprehensiveCancer Center, 3800 Reservoir
7、 Rd, NW,Washington, DC 20007; e-mail:bdc4georgetown.edu. 2014 by American Society of ClinicalOncology0732-183X/14/3227w-3059w/$20.00DOI: 10.1200/JCO.2013.54.8800ABSTRACTAbstractThe purpose of this work was to modernize recommendations for evaluation, staging, and responseassessment of patients with
8、Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshopwas held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, inJune 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists,radiologists, and nuclear medicine physicians
9、, representing major international lymphoma clinical trialsgroups and cancer centers. Clinical and imaging subcommittees presented their conclusions at asubsequent workshop at the 12th International Conference on Malignant Lymphoma, leading torevised criteria for staging and of the International Wor
10、king Group Guidelines of 2007 for response.As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)computed tomogra-phy (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modificationof the Ann Arbor descriptive terminology will be used for anatomic distri
11、bution of disease extent,but the suffixes A or B for symptoms will only be included for HL. A bone marrow biopsy is nolonger indicated for the routine staging of HL and most diffuse large B-cell lymphomas. However,regardless of stage, general practice is to treat patients based on limited (stages I
12、and II, nonbulky)or advanced (stage III or IV) disease, with stage II bulky disease considered as limited or advanceddisease based on histology and a number of prognostic factors. PET-CT will be used to assessresponse in FDG-avid histologies using the 5-point scale. The product of the perpendiculard
13、iameters of a single node can be used to identify progressive disease. Routine surveillance scansare discouraged. These recommendations should improve evaluation of patients with lymphomaand enhance the ability to compare outcomes of clinical trials.J Clin Oncol 32:3059-3067. 2014 by American Societ
14、y of Clinical OncologyINTRODUCTIONThe availability of more effective therapies forlymphoma and the increasingly sensitive and spe-cific technologies for disease assessment providerationale for updated patient evaluation, staging,and response criteria. These should be unambig-uous and universally app
15、licable and facilitate thecomparison of patients and results among studiesand the evaluation of new therapies by regula-tory agencies.Staging defines disease location and extent,suggests prognostic information, allows compari-sons among studies, and provides a baseline againstwhich response or disea
16、se progression can be com-pared. Initial staging criteria were designed primar-ily for Hodgkin lymphoma (HL)1-3and weresuperseded by the Ann Arbor classification,4whichsubdividedHLpatientsintofourstagesandsubclas-sification A and B based on the presence of fevers togreater than 101F (38.3C), weight
17、loss, and nightsweats and which has been the most widely usedclassification since its introduction. The Cotswoldclassification5first formally incorporated computedtomography (CT) scans and introduced “X” forbulky disease and complete remission unconfirmed(CRu)todescribepatientswitharesidualmassafter
18、treatment that was most likely fibrous tissue.The first universally accepted response criteriafor non-Hodgkin lymphoma (NHL), used also forHL, were published in 1999 by the National CancerInstituteWorkingGroup6andrevisedin2007bytheInternational Working Group (IWG)7to incorpo-ratepositronemissiontomo
19、graphy(PET)andbonemarrow immunohistochemistry and flow cytom-etry in response assessment, eliminating CRu.JOURNAL OF CLINICAL ONCOLOGYSPECIAL ARTICLEVOLUME 32 H18528 NUMBER 27 H18528 SEPTEMBER 20 2014 2014 by American Society of Clinical Oncology 3059Downloaded from jco.ascopubs.org on December 17,
20、2014. For personal use only. No other uses without permission.Copyright 2014 American Society of Clinical Oncology. All rights reserved.Afterextensiveexperiencewiththesecriteria,andrecognizingtheprogress made after their publication, particularly in imaging tech-niques, a workshop was held at the 11
21、th International Conferenceon Malignant Lymphoma in Lugano, Switzerland, in June 2011,which was attended by leading hematologists, oncologists, radia-tion oncologists, pathologists, radiologists, and nuclear medicinephysicians, representing major lymphoma clinical trials groupsand cancer centers in
22、North America, Europe, Japan, and Austral-asia. The aim was to develop improved staging and responsecriteria for HL and NHL, relevant for community physicians,investigator-led trials, cooperative groups, and registration trials.Subcommittees focused on clinical and imaging issues, and a sub-sequent
23、workshop at the 12th International Conference on Malig-nant Lymphoma in 2013 led to the following revisions.INITIAL EVALUATIONDiagnosisLymphoma diagnosis depends on morphology, immunohisto-chemistry,andflowcytometryreviewedbyanexperiencedlymphomapathologist and, where appropriate, molecular studies
24、to accuratelycategorize the lymphoma.8A fine-needle aspirate is inadequate forinitial diagnosis. An incisional or excisional biopsy is preferred toprovide adequate tissue for these examinations, but a core-needlebiopsy can be considered when excisional biopsy is not possible9,10and to document relap
25、se; however, a nondiagnostic sample must befollowed by an incisional or excisional biopsy. With consent, addi-tional paraffin-embedded, fresh-frozen tissue, or cell suspensionsshould be stored for future research.Patient EvaluationClinical evaluation requires a comprehensive history includingage; se
26、x; absence/presence of fevers to more than 101F (38.3C),chills, drenching night sweats, or unexplained weight loss more than10%ofbodymassover6months;andhistoryofmalignancy.Fatigue,pruritus,andalcohol-inducedpaininpatientswithHLshouldalsobenoted. Whereas these factors rarely direct treatment, their r
27、ecurrencemay herald disease relapse.Physical examination includes measurement of accessible nodalgroups and the size of the spleen and liver in centimeters below theirrespective costal margins in the midclavicular line. However, the sen-sitivity of physical examination is variable among observers. T
28、here-fore, organomegaly is formally defined by CT imaging (Table 1).Laboratory tests and other investigations necessary for the deter-mination of the prognostic indices for the different lymphoma sub-types and general patient management, including assessment ofcomorbidities, must be recorded.Anatomi
29、c StagingHistorical series and prospective clinical trials have used theAnn Arbor staging system5to select patients and report outcomes.Now, stage is only one component of factors in prognostic indicesincreasingly used for pretreatment risk stratification and selectionof therapy.11-15PET-CT scanning
30、 has become the standard for assessment ofresponse in most lymphomas.7For HL and fluorodeoxyglucose(FDG) -avid NHL subtypes, PET and PET-CT improve the accuracyof staging compared with CT scans for nodal and extranodal sites.16PET-CTleadstochangeinstagein10%to30%ofpatients,moreoftenupstaging, althou
31、gh alteration in management occurs in fewer pa-tients, with no demonstrated impact on overall outcome. However,improving staging accuracy ensures that fewer patients are under-treated or overtreated.16PET-CT is particularly important for stagingbefore consideration of radiation therapy.17,18Although
32、 most lym-phomas are FDG avid, because of greater variability in FDG uptake,metabolic imaging is less reliable in other lymphomas.19-24Whereasmantle-celllymphomaisroutinelyFDGavid,limiteddatasuggestthatthesensitivityandspecificityofidentifyingbowelinvolvementarelowand should not replace other invest
33、igative measures.25,26RECOMMENDATION FOR REVISIONS TO STAGING CRITERIAPET-CT is already widely used for pretreatment assessment, oftenoutside of clinical trials, to assign stage and has already been incorpo-rated into response assessment.7Although physical examination re-mainsimportant,anddespitecon
34、cernsthatmoresensitivestagingcanTable 1. Criteria for Involvement of SiteTissue Site Clinical FDG Avidity Test Positive FindingLymph nodes Palpable FDG-avid histologies PET-CT Increased FDG uptakeNonavid disease CT Unexplained node enlargementSpleen Palpable FDG-avid histologies PET-CT Diffuse uptak
35、e, solitary mass, miliary lesions, nodulesNonavid disease CT H11022 13 cm in vertical length, mass, nodulesLiver Palpable FDG-avid histologies PET-CT Diffuse uptake, massNonavid disease CT NodulesCNS Signs, symptoms CT Mass lesion(s)MRI Leptomeningeal infiltration, mass lesionsCSF assessment Cytolog
36、y, flow cytometryOther (eg, skin, lung, GI tract,bone, bone marrow)Site dependent PET-CTH11569, biopsy Lymphoma involvementAbbreviations: CSF, cerebrospinal fluid; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography.H11569PET-CT is ade
37、quate for determination of bone marrow involvement and can be considered highly suggestive for involvement of other extralymphatic sites. Biopsyconfirmation of those sites can be considered if necessary.Cheson et al3060 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGYDownlo
38、aded from jco.ascopubs.org on December 17, 2014. For personal use only. No other uses without permission.Copyright 2014 American Society of Clinical Oncology. All rights reserved.result in stage migration, impairing the use of historically controlleddata, PET-CT is critical as a baseline measurement
39、 before therapy toincrease the accuracy of subsequent response assessment27,28(Table1). Therefore, the consensus was that PET-CT should be recom-mended for routine staging of FDG-avid, nodal lymphomas (essen-tially all histologies except chronic lymphocytic leukemia/smalllymphocytic lymphoma, lympho
40、plasmacytic lymphoma/Walden-stroms macroglobulinemia, mycosis fungoides, and marginal zoneNHLs, unless there is a suspicion of aggressive transformation) as thegold standard.24The following recommendations are intended for lymphomaswithprimarilynodalinvolvement,althoughtheyarealsoapplicabletoprimary
41、extranodaldiffuselargeB-celllymphoma(DLBCL).Separatecriteria have been proposed for primary extranodal29,30and cutane-ous lymphomas.31ImagingPET-CTispreferredforstagingofFDG-avidlymphomas,andCT scan is preferred in the other lymphomas. A chest x-ray is nolonger required in lymphoma staging because i
42、t less accurate thanCT.32Moreover, CT identifies more hilar nodes and may betterdiscriminate between a single large nodal mass and an aggregate ofindividual nodes. Bulk is a negative prognostic factor,11,13-15butthere is little agreement on its definition, which is disease, stage,and treatment speci
43、fic.These criteria strongly recommend PET-CT for staging ofroutinelyFDG-avidhistologies,especiallyinclinicaltrials.Acontrast-enhanced CT scan should be included for a more accurate measure-mentofnodalsizeifrequiredfortrials;ifnecessary,tomoreaccuratelydistinguish bowel from lymphadenopathy; and in t
44、he setting of com-pression/thrombosis of central/mediastinal vessels. Contrast-enhanced CT is also preferred for radiation planning. Variably FDG-avid histologies should be staged with a CT scan.For patients staged with PET-CT, focal uptake in nodal andextranodal sites that is in keeping with lympho
45、ma, according to thedistributionand/orCTcharacteristics,isconsideredinvolvementwithlymphoma, including spleen, liver, bone, thyroid, and so on. Forpatients staged with CT, up to six of the largest target nodes, nodalmasses, or other lymphomatous lesions that are measurable in twodiameters (longest d
46、iameter LDi and shortest diameter) shouldbe identified from different body regions representative of thepatientsoveralldiseaseburdenandincludemediastinalandretro-peritoneal disease, if involved. A measurable node must have anLDi greater than 1.5 cm. Measurable extranodal disease (eg, he-patic nodule
47、s) may be included in the six representative, measuredlesions.AmeasurableextranodallesionshouldhaveanLDigreaterthan 1.0 cm. All other lesions (including nodal, extranodal, andassessable disease) should be followed as nonmeasured disease (eg,cutaneous, GI, bone, spleen, liver, kidneys, pleural or per
48、icardialeffusions, ascites). In patients in whom a discordant histology ormalignant transformation is suspected, a PET-CT may identify theoptimal site to biopsy for confirmation.20,21Tumor BulkA single nodal mass, in contrast to multiple smaller nodes, of 10cm or greater than a third of the transtho
49、racic diameter at any level ofthoracic vertebrae as determined by CT is retained as the definition ofbulky disease for HL.5A chest x-ray is not required to determine bulkbecauseofitshighconcordancewithCT.32However,avarietyofsizeshave been suggested for NHL,15,33with limited evidence suggesting 6cm as best for follicular lymphoma15and 6 to 10 cm in the rituximabera for DLBCL.34However, none of the proposed sizes have beenvalidated in the current therapeutic era. Therefore, the recommenda-tion for HL and NHL is to record the longest measurement by CTscan, with the ter
