Armed Forces Institute of Pathology Mediastinal Pathology: Mediastinal Pathology: Compartmental Approach Compartmental Approach Teri J. Franks, MD Teri J. Franks, MD Chairman Chairman Department of Pulmonary and Mediastinal Pathology Department of Pulmonary and Mediastinal Pathology
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ChairmanChairmanDepartment of Pulmonary and Mediastinal PathologyDepartment of Pulmonary and Mediastinal Pathology
Faculty Disclosure InformationAt the time of the VTC, At the time of the VTC, Teri J. Franks, MDTeri J. Franks, MD had no significant financial interests had no significant financial interests or relationships to disclose.or relationships to disclose.
As a provider accredited by the Accreditation Council for ContinAs a provider accredited by the Accreditation Council for Continuing uing Medical Education, the Department of Medical Education of The Medical Education, the Department of Medical Education of The Armed Forces Institute of Pathology must insure balance, Armed Forces Institute of Pathology must insure balance, independence, objectivity and scientific rigor in all its indiviindependence, objectivity and scientific rigor in all its individually dually sponsored or jointly sponsored educational activities. All faculsponsored or jointly sponsored educational activities. All faculty ty participating in a sponsored educational activity are expected tparticipating in a sponsored educational activity are expected to o disclose to the activity audience any significant financial intedisclose to the activity audience any significant financial interest or rest or other relationship (1) with the other relationship (1) with the manufacturer(smanufacturer(s) of any commercial ) of any commercial product(sproduct(s) and/or ) and/or provider(sprovider(s) of commercial services discussed in ) of commercial services discussed in an educational presentation and (2) with any commercial an educational presentation and (2) with any commercial supporters of the activity (significant financial interest or otsupporters of the activity (significant financial interest or other her relationship can include such things as grants or research supporelationship can include such things as grants or research support, rt, employee, consultant, major stock holder, member of speakers employee, consultant, major stock holder, member of speakers bureau, etc.). The intent of this disclosure is not to prevent abureau, etc.). The intent of this disclosure is not to prevent aspeaker with a significant financial or other relationship from speaker with a significant financial or other relationship from making a presentation, but rather to provide listeners with making a presentation, but rather to provide listeners with information on which they can make their own judgments. It information on which they can make their own judgments. It remains for the audience to determine whether the speakerremains for the audience to determine whether the speaker’’s s interests or relationships may influence the presentation with interests or relationships may influence the presentation with regard to exposition or conclusion.regard to exposition or conclusion.
Main TopicsMain Topics
•• Clinical featuresClinical features•• Organization of lesionsOrganization of lesions
•• Selected lesionsSelected lesions–– Thymoma and thymic carcinomaThymoma and thymic carcinoma
Mediastinal LesionsMediastinal LesionsClinical featuresClinical features
•• Uncommon, 1% of all tumorsUncommon, 1% of all tumors•• Infant to 83 years, mean 35.4 yearsInfant to 83 years, mean 35.4 years•• No gender biasNo gender bias•• 60% benign, 40% malignant60% benign, 40% malignant•• 60% symptomatic60% symptomatic
–– Chest pain, cough, dyspnea, dysphagia, superior vena cava syndroChest pain, cough, dyspnea, dysphagia, superior vena cava syndromeme
•• 97% can be detected on PA and lateral chest radiographs97% can be detected on PA and lateral chest radiographs•• Surgical resectionSurgical resection
–– Low operative morbidity and mortalityLow operative morbidity and mortality
•• Thymic lesions dominant mediastinal pathologyThymic lesions dominant mediastinal pathology–– 50% of mediastinal lesions occur in the anterior compartment50% of mediastinal lesions occur in the anterior compartment–– Major organ of the anterior mediastinumMajor organ of the anterior mediastinum
ThymusThymusEmbryologyEmbryology
•• 66thth weekweek–– Primordia arise from 3Primordia arise from 3rdrd
pharyngeal pouches pharyngeal pouches
ThymusThymusEmbryologyEmbryology
•• 66thth weekweek–– Primordia arise from 3Primordia arise from 3rdrd
pharyngeal pouchespharyngeal pouches
•• 88thth weekweek–– Primordia elongatePrimordia elongate–– Fragment during migrationFragment during migration
•• 1414thth week to 16week to 16thth weekweek–– Cortex and medulla completeCortex and medulla complete–– Phenotypic characterizationPhenotypic characterization
ThymusThymusLocationLocation
•• Anterior mediastinumAnterior mediastinum–– Base rests on pericardium and Base rests on pericardium and
great vesselsgreat vessels
ThymusThymusLocation Location
•• Anterior mediastinumAnterior mediastinum–– Base rests on pericardium and Base rests on pericardium and
great vesselsgreat vessels–– Upper poles extend along Upper poles extend along
trachea, attach to trachea, attach to corresponding lobe of thyroid corresponding lobe of thyroid via thyrothymic ligamentvia thyrothymic ligament
•• XX-- or Hor H--shapedshaped•• Fibrous capsuleFibrous capsule•• Wide variation in weightWide variation in weight
–– Mainly related to ageMainly related to age–– Affected by state of Affected by state of
healthhealth–– AverageAverage
•• 15 grams at birth15 grams at birth•• 3030--40 grams at puberty40 grams at puberty•• 1010--15 grams at 60 years 15 grams at 60 years
•• Germ cell tumorsGerm cell tumors•• Lymphomas and hematopoietic neoplasmsLymphomas and hematopoietic neoplasms•• Mesenchymal tumorsMesenchymal tumors•• Rare tumorsRare tumors•• MetastasisMetastasis
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaClinical featuresClinical features
•• UncommonUncommon–– Incidence of 1Incidence of 1--5/million population/year5/million population/year–– Incidence has not changed significantly over past three decadesIncidence has not changed significantly over past three decades
•• Wide age range, 7Wide age range, 7--89 years89 years–– Peak 55Peak 55--65 years65 years–– Rare in children and adolescentsRare in children and adolescents
•• No gender biasNo gender bias•• Increased incidence of second cancersIncreased incidence of second cancers
–– Irrespective of histologic type of thymic epithelial tumorIrrespective of histologic type of thymic epithelial tumor
•• Autoimmune diseaseAutoimmune disease–– MG: variable in thymoma (10MG: variable in thymoma (10--80%), rare in thymic carcinoma80%), rare in thymic carcinoma–– Other: common in thymoma, rare in thymic carcinoma Other: common in thymoma, rare in thymic carcinoma
Thymoma and Thymic CarcinomaThymoma and Thymic Carcinoma
•• ThymomasThymomas–– Arise from thymic epithelial cellsArise from thymic epithelial cells–– Exhibit organotypic (thymusExhibit organotypic (thymus--like) architectural featureslike) architectural features
–– No, mild, or moderate atypia of epithelial cellsNo, mild, or moderate atypia of epithelial cells–– CD5, CD70, CD117 negative epithelial cellsCD5, CD70, CD117 negative epithelial cells–– Not observed in organs other than thymusNot observed in organs other than thymus
•• Arise from heterotopic tissue in head, neck, mediastinum, pleuraArise from heterotopic tissue in head, neck, mediastinum, pleura, lung, lung
–– Absent/low to moderate biologic potentialAbsent/low to moderate biologic potential•• Often curable by surgeryOften curable by surgery•• Variable invasion, metastases rareVariable invasion, metastases rare•• Typically long survival due to indolent clinical courseTypically long survival due to indolent clinical course
•• 33 year old male33 year old male•• Three month history Three month history
Thymoma and Thymic CarcinomaThymoma and Thymic Carcinoma
•• Thymic carcinomaThymic carcinoma–– Arise from thymic epithelial cellsArise from thymic epithelial cells–– No or abortive organotypic architectural featuresNo or abortive organotypic architectural features–– ClearClear--cut cytologic atypiacut cytologic atypia–– Frequent CD5, CD70, CD117 expression in epithelial cells, ~ 60%Frequent CD5, CD70, CD117 expression in epithelial cells, ~ 60%–– Resemble carcinomas in other organsResemble carcinomas in other organs–– Malignant Malignant
•• Often unresectableOften unresectable•• Almost always invasive, metastases frequentAlmost always invasive, metastases frequent•• Short survival due to progressive diseaseShort survival due to progressive disease
•• 56 year old male56 year old male•• Two month historyTwo month history
–– Chest painChest pain–– CoughCough
Thymic CarcinomaThymic CarcinomaGrossGross
•• Firm, gritty, grayFirm, gritty, gray--white masswhite mass•• Usually lacks wellUsually lacks well--defined defined
capsule and fibrous bandscapsule and fibrous bands
Thymic CarcinomaThymic CarcinomaGrossGross
•• Firm, gritty, grayFirm, gritty, gray--white masswhite mass•• Usually lacks wellUsually lacks well--defined defined
capsule and fibrous bandscapsule and fibrous bands•• Foci of hemorrhage and Foci of hemorrhage and
–– Typical and atypical carcinoidTypical and atypical carcinoid–– Large cell neuroendocrine and small cell carcinomaLarge cell neuroendocrine and small cell carcinoma
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaTermsTerms
•• EncapsulatedEncapsulated–– Completely surrounded by a fibrous capsuleCompletely surrounded by a fibrous capsule
•• Minimally or microscopically invasiveMinimally or microscopically invasive–– Invasive through the capsule to involve pericapsular tissueInvasive through the capsule to involve pericapsular tissue
•• Usually identified only after microscopic examinationUsually identified only after microscopic examination•• Generally appears encapsulated to surgeonGenerally appears encapsulated to surgeon
•• Widely invasiveWidely invasive–– Spread by direct extension into adjacent structuresSpread by direct extension into adjacent structures
•• ImplantsImplants–– Nodules separate from main mass on pericardium or pleuraNodules separate from main mass on pericardium or pleura
•• Lymph node metastasesLymph node metastases–– Nodes separate from main mass, excludes direct extension into noNodes separate from main mass, excludes direct extension into nodede
•• With distant metastasesWith distant metastases–– Most commonly to lung, liver, skeletal systemMost commonly to lung, liver, skeletal system
Capsular InvasionCapsular Invasion
•• Evaluation of capsule is Evaluation of capsule is essentialessential–– Ink marginsInk margins
•• Adherence to adjacent Adherence to adjacent structuresstructures–– CommonCommon–– DoesnDoesn’’t always indicate true t always indicate true
invasioninvasion
Tumor 400x InvolutionTumor 400x Involution
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaPrinciples of classificationPrinciples of classification
•• ThymomaThymoma–– Two major typesTwo major types
•• Uniformly bland spindle or oval epithelial cells Uniformly bland spindle or oval epithelial cells –– Type AType A•• Predominantly round or polygonal epithelial cells Predominantly round or polygonal epithelial cells –– Type BType B
–– Type B subdivided by extent of lymphoid infiltrates and cellularType B subdivided by extent of lymphoid infiltrates and cellularatypiaatypia•• B1 B1 –– lymphocyte richlymphocyte rich•• B2 and B3 B2 and B3 –– epithelial cell richepithelial cell rich
–– Type A plus B1Type A plus B1--like, and rarely B2like, and rarely B2--like, are designated ABlike, are designated AB
•• Thymic carcinomaThymic carcinoma–– Thymic carcinomas are termed according to differentiationThymic carcinomas are termed according to differentiation–– Combined thymomas are termed by WHO histology and %Combined thymomas are termed by WHO histology and %–– ““Malignant thymomaMalignant thymoma”” is discouragedis discouraged
–– No pattern or storiformNo pattern or storiform–– CystsCysts–– Lobules and bands less Lobules and bands less
conspicuous than other typesconspicuous than other types
•• Spindle or oval epithelial cellsSpindle or oval epithelial cells–– Reticulin fibers surround cellsReticulin fibers surround cells
•• Bland nucleiBland nuclei–– Dispersed chromatinDispersed chromatin–– Inconspicuous nucleoliInconspicuous nucleoli
ThymomaThymomaType ABType AB
•• Mixture of Type A and Type BMixture of Type A and Type B–– Discrete separate nodules orDiscrete separate nodules or
ThymomaThymomaType ABType AB
•• Mixture of Type A and Type BMixture of Type A and Type B–– Discrete separate nodules orDiscrete separate nodules or–– Intermixed A and BIntermixed A and B
ThymomaThymomaType ABType AB
•• Mixture of Type A and Type BMixture of Type A and Type B–– Discrete separate nodules orDiscrete separate nodules or–– Intermixed A and BIntermixed A and B
•• Type B epithelial cells Type B epithelial cells –– Small polygonalSmall polygonal–– Dispersed chromatinDispersed chromatin–– Inconspicuous nucleoliInconspicuous nucleoli
ThymomaThymomaType ABType AB
•• Mixture of Type A and Type BMixture of Type A and Type B–– Discrete separate nodules orDiscrete separate nodules or–– Intermixed A and BIntermixed A and B
•• Type B epithelial cells Type B epithelial cells –– Small polygonalSmall polygonal–– Dispersed chromatinDispersed chromatin–– Inconspicuous nucleoliInconspicuous nucleoli
•• B areasB areas–– Medullary differentiation rareMedullary differentiation rare–– Hassall corpuscles absentHassall corpuscles absent–– Reticulin around B nodulesReticulin around B nodules
•• Not around individual cellsNot around individual cells
ThymomaThymomaType B1Type B1
•• Resembles cortexResembles cortex
ThymomaThymomaType B1Type B1
•• Resembles cortexResembles cortex•• Scant small epithelial cellsScant small epithelial cells
–– Pale nucleiPale nuclei–– Small nucleoliSmall nucleoli
ThymomaThymomaType B1Type B1
•• Resembles cortexResembles cortex•• Scant small epithelial cellsScant small epithelial cells
–– Pale nucleiPale nuclei–– Small nucleoliSmall nucleoli
•• Dispersed epithelial cellsDispersed epithelial cells–– Do not from groupingsDo not from groupings
ThymomaThymomaType B1Type B1
•• Resembles cortexResembles cortex•• Scant small epithelial cellsScant small epithelial cells
–– Pale nucleiPale nuclei–– Small nucleoliSmall nucleoli
•• Dispersed epithelial cellsDispersed epithelial cells–– Do not from groupingsDo not from groupings
•• Small cell and large cell neuroendocrineSmall cell and large cell neuroendocrine
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaPrognosisPrognosis
•• Most important prognostic factorsMost important prognostic factors–– Tumor stageTumor stage
•• MasaokaMasaoka stage is the most important and statistically most significant stage is the most important and statistically most significant independent prognostic indicator of survival in most studiesindependent prognostic indicator of survival in most studies
–– WHO histologic typeWHO histologic type–– Completeness of resectionCompleteness of resection
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaPrognosisPrognosis
•• T1 T1 –– tumor completely encapsulatedtumor completely encapsulated•• T2 T2 –– tumor invades pericapsular connective tissuetumor invades pericapsular connective tissue•• T3 T3 –– tumor invades into neighboring structures, such as tumor invades into neighboring structures, such as
pericardium, mediastinal pleura, thoracic wall, great vessels pericardium, mediastinal pleura, thoracic wall, great vessels and lungand lung
•• T4 T4 –– tumor with pleural or pericardial disseminationtumor with pleural or pericardial dissemination
•• Currently no authorized TNM system for thymic epithelial or Currently no authorized TNM system for thymic epithelial or neuroendocrine tumorsneuroendocrine tumors
StagingStagingModified Masaoka Modified Masaoka
•• Stage 1:Stage 1: intact capsule or growth within capsuleintact capsule or growth within capsule•• Stage 2a:Stage 2a: microscopic invasion through capsulemicroscopic invasion through capsule
2b:2b: gross and microscopic invasiongross and microscopic invasion•• Stage 3:Stage 3: invasion into surrounding structuresinvasion into surrounding structures•• Stage 4a:Stage 4a: pleural or pericardial disseminationpleural or pericardial dissemination
4b:4b: lymphatic or hematogenous metastaseslymphatic or hematogenous metastases
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaDiagnosisDiagnosis
•• ThymomaThymoma–– EncapsulatedEncapsulated–– Invasive (term malignant thymoma is discourage)Invasive (term malignant thymoma is discourage)
•• Up to 20% in some studies incorrectly diagnosedUp to 20% in some studies incorrectly diagnosed
–– Assessment of surgical marginsAssessment of surgical margins•• Requires inkingRequires inking
–– Determination of invasivenessDetermination of invasiveness•• Multiple sections through capsuleMultiple sections through capsule
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaDiagnosisDiagnosis
•• Thymic carcinomaThymic carcinoma–– Separation from metastatic carcinoma may be difficultSeparation from metastatic carcinoma may be difficult
•• Lung, thyroid, breast, prostate are most commonLung, thyroid, breast, prostate are most common
–– May only be able to suggest or favor diagnosis May only be able to suggest or favor diagnosis •• Clinical history and radiologic studies are essentialClinical history and radiologic studies are essential
Thymoma and Thymic CarcinomaThymoma and Thymic CarcinomaDiagnosisDiagnosis
TumorTumor Thymic primaryThymic primary Lung or head/neckLung or head/neck
–– 2003 WHO Classification of Germ Cell Tumors2003 WHO Classification of Germ Cell Tumors•• TeratomaTeratoma•• SeminomaSeminoma
•• Lymphomas and hematopoietic neoplasmsLymphomas and hematopoietic neoplasms•• Mesenchymal tumorsMesenchymal tumors•• Rare tumorsRare tumors•• MetastasisMetastasis
Tumors of the Thymus and Mediastinum Tumors of the Thymus and Mediastinum WHO ClassificationWHO Classification
•• Epithelial tumorsEpithelial tumors•• Germ cell tumorsGerm cell tumors•• Lymphomas and hematopoietic neoplasmsLymphomas and hematopoietic neoplasms
–– 2001 WHO Classification of Hematopoietic and Lymphoid Tumors2001 WHO Classification of Hematopoietic and Lymphoid Tumors•• NS Classical HLNS Classical HL•• PMLBPMLB--CLCL•• TT--lymphoblastic leukemia/lymphomalymphoblastic leukemia/lymphoma•• MALT lymphomaMALT lymphoma
–– Ectopic tumors of the thymusEctopic tumors of the thymus•• Ectopic thyroid tumorsEctopic thyroid tumors•• Ectopic parathyroid tumorsEctopic parathyroid tumors
–– Thymus and anterior (middle) mediastinumThymus and anterior (middle) mediastinum•• Lung, thyroid, breast, prostate are most commonLung, thyroid, breast, prostate are most common
•• Three compartmentsThree compartments•• Mediastinal lesionsMediastinal lesions
–– 50% of lesions50% of lesions•• Anterior compartmentAnterior compartment
–– ThymicThymic lesions dominatelesions dominate–– Organization by compartmentOrganization by compartment