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Second Edition

Nosé, MD, PhD

Associate Chief of Pathology

Director of Anatomic and Molecular Pathology

Massachusetts General Hospital

Professor of Pathology

Harvard Medical School

Boston, Massachusetts

1600 John F. Kennedy Blvd.

Ste 1800 Philadelphia, PA 19103-2899

DIAGNOSTIC PATHOLOGY: FAMILIAL CANCER SYNDROMES, SECOND EDITION ISBN: 978-0-323-71204-0

Inkling: 978-0-323-71206-4

Copyright © 2020 by Elsevier. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Previous edition copyrighted 2013.

Library of Congress Control Number: 2019956687

Printed in Canada by Friesens, Altona, Manitoba, Canada

Dedication

Developing a comprehensive book like this could only be accomplished with high levels of amazing teamwork. I would like to acknowledge and thank so many remarkable people for their support and contributions to this book. I will start with my parents, Dalva and Antonio Nosé, for their support, invaluable teaching and guidance, and for being my life examples. To my wonderful sons and best friends, Gustave, Erick, and Phillip, and their wives, Carla, Suzana, and Bianca, and to my grandsons, Nicolas, Leonardo, and Lucas Antonio, you all make my life so lovely and complete. To my brothers, Dalton and Walton, and their families for their love and continuous support. To the outstanding and dedicated contributing authors of this book for their hard work and contributions to this unique project. To the wonderful Elsevier team for their extraordinary work in making this book a reality. My final thanks are to all my family, friends, residents, fellows, colleagues, and everyone who shares our love and commitment to a better understanding of familial cancer diseases.

TABLEOFCONTENTS

PartI:DiagnosesAssociatedWith SyndromesbyOrgan

AcuteLymphoblasticLeukemiaandNon-Hodgkin

Nardi,MD

BloodandBoneMarrowTable

ValentinaNardi,MD

G.PeturNielsen,MDandYinRexHung,MD,PhD

G.PeturNielsen,MDandYinRexHung,MD,PhD

18 MalignantPeripheralNerveSheathTumor

G.PeturNielsen,MDandYinRexHung,MD,PhD

G.PeturNielsen,MDandYinRexHung,MD,PhD 28 Rhabdomyosarcoma

G.PeturNielsen,MDandYinRexHung,MD,PhD

32 Schwannoma

G.PeturNielsen,MDandYinRexHung,MD,PhD

36 BoneandSoftTissueTable

G.PeturNielsen,MDandYinRexHung,MD,PhD

SECTION3:BREAST 46 BreastCarcinoma

SusanC.Lester,MD,PhDandDavidG.Hicks,MD 54 BreastTable

DavidG.Hicks,MDandSusanC.Lester,MD,PhD

SECTION4:ENDOCRINE

ADRENALCORTEX

58 AdrenalCorticalAdenoma

VaniaNosé,MD,PhD

62 AdrenalCorticalCarcinoma

VaniaNosé,MD,PhDandJulieGuilmette,MD

70 AdrenalCorticalNeoplasmsinChildren

VaniaNosé,MD,PhD

78 PrimaryPigmentedNodularAdrenocorticalDisease

VaniaNosé,MD,PhD

84 AdrenalCortexTable

VaniaNosé,MD,PhD

ADRENALMEDULLAANDPARAGANGLIA

88 AdrenalMedullaryHyperplasia

VaniaNosé,MD,PhD

92 NeuroblasticTumorsofAdrenalGland

VaniaNosé,MD,PhD

104 PheochromocytomaandParaganglioma

VaniaNosé,MD,PhDandArthurS.Tischler,MD

114 AdrenalMedullaandParagangliaTable

VaniaNosé,MD,PhD

PANCREAS

118 PancreaticNeuroendocrineNeoplasms

VaniaNosé,MD,PhD

128 EndocrinePancreasTable

VaniaNosé,MD,PhD

PARATHYROID

130 ParathyroidAdenoma

VaniaNosé,MD,PhDandLoriA.Erickson,MD

136 ParathyroidCarcinoma

VaniaNosé,MD,PhDandLoriA.Erickson,MD

142 PrimaryParathyroidHyperplasia

LoriA.Erickson,MDandVaniaNosé,MD,PhD

152 ParathyroidTable

VaniaNosé,MD,PhD

PITUITARY

158 PituitaryAdenoma

M.BeatrizS.Lopes,MD,PhDandVaniaNosé,MD,PhD

164 PituitaryHyperplasia

M.BeatrizS.Lopes,MD,PhD

166 PituitaryTable

VaniaNosé,MD,PhD

THYROID,MEDULLARY

170 C-CellHyperplasia

VaniaNosé,MD,PhD

176 MedullaryThyroidCarcinoma

VaniaNosé,MD,PhD

186 Thyroid,MedullaryCarcinomaTable

VaniaNosé,MD,PhD

THYROID,NONMEDULLARY

188 FamilialThyroidCarcinoma

VaniaNosé,MD,PhD

200 FollicularThyroidCarcinoma

VaniaNosé,MD,PhD

TABLEOFCONTENTS

208 Thyroid,NonmedullaryCarcinomaTable

VaniaNosé,MD,PhD

SECTION5:GASTROINTESTINAL

HEPATOBILIARYANDPANCREAS

212 Hepatoblastoma

LarissaV.Furtado,MDandKarenS.Thompson,MD

218 HepatocellularCarcinoma

AmitabhSrivastava,MD

222 PancreaticAdenocarcinoma

AmitabhSrivastava,MDandVonSamedi,MD,PhD

226 BiliaryTract/Liver/PancreasTable

AmitabhSrivastava,MD

TUBULARGUT

228 ColonicAdenomas

Ying-HsiaChu,MDandVikramDeshpande,MD

234 EsophagealAdenocarcinoma

Ying-HsiaChu,MDandVikramDeshpande,MD

236 EsophagealSquamousCellCarcinoma

Ying-HsiaChu,MDandVikramDeshpande,MD

238 GastricAdenocarcinoma

Ying-HsiaChu,MDandVikramDeshpande,MD

244 GastrointestinalStromalTumor

Ying-HsiaChu,MDandVikramDeshpande,MD

252 HamartomatousPolyposisSyndromes

VaniaNosé,MD,PhDandAmitabhSrivastava,MD

262 SmallBowelAdenocarcinoma

Ying-HsiaChu,MDandVikramDeshpande,MD

268 Colon/RectumTable

JoelK.Greenson,MDandAmitabhSrivastava,MD

270 Esophagus/Stomach/SmallBowelTable

Ying-HsiaChu,MDandVikramDeshpande,MD

SECTION6:GENITOURINARY

BLADDER

274 BladderUrothelialCarcinoma

GladellP.Paner,MD,(BS)MT

282 BladderTable

GladellP.Paner,MD,(BS)MT

KIDNEY

286 Angiomyolipoma

GladellP.Paner,MD,(BS)MT

290 ClearCellRenalCellCarcinoma

GladellP.Paner,MD,(BS)MT

294 CysticNephroma

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS) MT

296 HLRCCSyndrome-AssociatedRenalCellCarcinoma

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS) MT

300 PapillaryRenalCellCarcinoma

GladellP.Paner,MD,(BS)MT

304 RenalOncocytoma,Chromophobe,andHybrid Tumors

GladellP.Paner,MD,(BS)MT

308 SuccinateDehydrogenase-DeficientRenalCell Carcinoma

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS) MT

312 WilmsTumor

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS) MT

320 KidneyTable

GladellP.Paner,MD,(BS)MT

PROSTATE

326 ProstateCarcinoma

GladellP.Paner,MD,(BS)MT

338 ProstateTable

GladellP.Paner,MD,(BS)MT

RENAL

PELVIS

ANDURETER

344 RenalUrothelialCarcinoma

GladellP.Paner,MD,(BS)MT

348 UreterUrothelialCarcinoma

GladellP.Paner,MD,(BS)MT

350 RenalPelvisandUreterTable

GladellP.Paner,MD,(BS)MT

TESTICLE

352 GermCellTumor

GladellP.Paner,MD,(BS)MT

358 SertoliCellNeoplasms

GladellP.Paner,MD,(BS)MT

362 TesticleTable

GladellP.Paner,MD,(BS)MT

SECTION7:GYNECOLOGY

370 CervicalCarcinoma

FabiolaMedeiros,MD

372 FallopianTubeCarcinoma

FabiolaMedeiros,MD

374 OvarianTumors

FabiolaMedeiros,MD

380 EndometrialCarcinoma

FabiolaMedeiros,MD

384 GynecologicTumors

FabiolaMedeiros,MD

SECTION8:HEADANDNECK

390 EndolymphaticSacTumor

VaniaNosé,MD,PhD

394 HeadandNeckSquamousCellCarcinoma

VaniaNosé,MD,PhD

400 HeadandNeckTable

VaniaNosé,MD,PhD

404 SalivaryGlandsTable

VaniaNosé,MD,PhD

SECTION9:NERVOUSSYSTEM

412 CentralNervousSystem

FaustoJ.Rodríguez,MD

416 Eye

FaustoJ.Rodríguez,MD

TABLEOFCONTENTS

420 PeripheralNervousSystem

FaustoJ.Rodríguez,MD

SECTION10:PULMONARY

426 Adenocarcinoma,Lung

MariMino-Kenudson,MD

432 AdenocarcinomaWithLepidic(Bronchioloalveolar)

PredominantPattern

MariMino-Kenudson,MD

434 Lymphangioleiomyomatosis

MariMino-Kenudson,MD

438 NeuroendocrineTumor,Lung

MariMino-Kenudson,MDandYinRexHung,MD,PhD

442 PleuropulmonaryBlastoma

MariMino-Kenudson,MDandYinRexHung,MD,PhD

444 LungTable

MariMino-Kenudson,MD

SECTION11:SKIN

448 % $ 3 -InactivatedMelanocyticTumor

MaiP.Hoang,MD

450 BasalCellCarcinoma

MaiP.Hoang,MD

456 CutaneousMelanoma

MaiP.Hoang,MD

460 CutaneousSquamousCellCarcinoma

MaiP.Hoang,MD

466 SebaceousCarcinoma

MaiP.Hoang,MD

472 SkinTable

MaiP.Hoang,MD

PartII:OverviewofSyndromes

SECTION1:INTRODUCTION

476 PathologyofFamilialTumorSyndromes

VaniaNosé,MD,PhD

484 ClinicalDiagnosisandManagementof Familial/HereditaryTumorSyndromes

VaniaNosé,MD,PhDandDanielC.Chung,MD

494 MolecularAspectsofFamilial/HereditaryTumor Syndromes

AlexanderCraigMackinnon,MD,PhD

SECTION2:SYNDROMES

502 AtaxiaTelangiectasia

FaustoJ.Rodríguez,MD

504 % $ 3 TumorPredispositionSyndrome

MaiP.Hoang,MD

506 BasalCellNevusSyndrome/GorlinSyndrome

MaiP.Hoang,MD

510 Beckwith-WiedemannSyndrome

VaniaNosé,MD,PhDandPatriciaNogueiradeSa,MD

518 Birt-Hogg-DubéSyndrome

MaiP.Hoang,MD

522 BloomSyndrome

ValentinaNardi,MD

524 Brooke-SpieglerSyndrome

MaiP.Hoang,MD

528 CarneyComplex

VaniaNosé,MD,PhD

536 ColonicCarcinomaSyndromes

JoelK.Greenson,MDandAmitabhSrivastava,MD

540 CostelloSyndrome

MaiP.Hoang,MD

542 Denys-DrashSyndrome

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS)

MT

546 Diamond-BlackfanAnemia

ValentinaNardi,MD

548 DICER1Syndrome

VaniaNosé,MD,PhDandMichelleMenonMiyake,MD

556 DownSyndrome

ValentinaNardi,MD

560 DyskeratosisCongenita

MaiP.Hoang,MD

564 FamilialAcuteMyeloidLeukemiaand MyelodysplasticSyndrome

ValentinaNardi,MD

568 FamilialAdenomatousPolyposis

AlexandrosD.Polydorides,MD,PhDandVaniaNosé,MD, PhD

576 FamilialChordoma

G.PeturNielsen,MDandYinRexHung,MD,PhD

578 FamilialGastrointestinalStromalTumor

VaniaNosé,MD,PhDandDanielC.Chung,MD

584 FamilialInfantileMyofibromatosis

G.PeturNielsen,MDandYinRexHung,MD,PhD

586 FamilialIsolatedHyperparathyroidism

VaniaNosé,MD,PhD

590 FamilialNonmedullaryThyroidCarcinoma

VaniaNosé,MD,PhD

596 FamilialParagangliomaPheochromocytoma Syndrome

VaniaNosé,MD,PhDandArthurS.Tischler,MD

600 FamilialTesticularTumor

GladellP.Paner,MD,(BS)MT

602 FamilialUvealMelanoma

FaustoJ.Rodríguez,MD

604 FamilialWilmsTumor

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS)

MT

606 FanconiAnemia

ValentinaNardi,MD

608 GlucagonCellHyperplasiaandNeoplasia

VaniaNosé,MD,PhD

610 Breast/OvarianCancerSyndrome:BRCA1

616

SusanC.Lester,MD,PhDandDavidG.Hicks,MD

Breast/OvarianCancerSyndrome:BRCA2

DavidG.Hicks,MDandSusanC.Lester,MD,PhD

620 HereditaryDiffuseGastricCancer

JoelK.Greenson,MDandDanielC.Chung,MD

TABLEOFCONTENTS

624 HereditaryLeiomyomatosisandRenalCell CarcinomaSyndrome

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS) MT

628 HereditaryMixedPolyposisSyndrome

JoelK.Greenson,MD

630 MultipleOsteochondromas

G.PeturNielsen,MDandYinRexHung,MD,PhD

632 HereditaryNeuroblastoma

VaniaNosé,MD,PhD

636 HereditaryPancreaticCancerSyndrome

DanielC.Chung,MDandVaniaNosé,MD,PhD

640 HereditaryPapillaryRenalCellCarcinoma

GladellP.Paner,MD,(BS)MT

642 HereditaryParaganglioma/Pheochromocytoma Syndromes

VaniaNosé,MD,PhD

650 HereditaryProstateCancer

GladellP.Paner,MD,(BS)MT

652 HereditaryRenalEpithelialTumors,Others

GladellP.Paner,MD,(BS)MT

656 HereditaryRetinoblastoma

FaustoJ.Rodríguez,MD

658 HereditarySWI/SNFComplexDeficiencySyndromes

FaustoJ.Rodríguez,MD

660 Howel-EvansSyndrome/KeratosisPalmaresand PlantaresWithEsophagealCancer

MaiP.Hoang,MD

662 Hyperparathyroidism-JawTumorSyndrome

VaniaNosé,MD,PhD

668 JuvenilePolyposisSyndrome

DanielC.Chung,MD,GregoryY.Lauwers,MD,and AmitabhSrivastava,MD

674 Li-FraumeniSyndrome

DavidG.Hicks,MDandSusanC.Lester,MD,PhD

680 LynchSyndrome

JoelK.Greenson,MD,DanielC.Chung,MD,andVania Nosé,MD,PhD

686 McCune-AlbrightSyndrome

VaniaNosé,MD,PhD

692 Melanoma/PancreaticCarcinomaSyndrome

MaiP.Hoang,MD

696 MultipleEndocrineNeoplasiaType1(MEN1)

VaniaNosé,MD,PhD

704 MultipleEndocrineNeoplasiaType2(MEN2)

VaniaNosé,MD,PhDandMichelleMenonMiyake,MD

712 MultipleEndocrineNeoplasiaType4(MEN4)

VaniaNosé,MD,PhDandMichelleMenonMiyake,MD

718 MUTYH-AssociatedPolyposis

VaniaNosé,MD,PhD

720 NeurofibromatosisType1

VaniaNosé,MD,PhDandMichelleMenonMiyake,MD

728 NeurofibromatosisType2

FaustoJ.Rodríguez,MD

734 NijmegenBreakageSyndrome

ValentinaNardi,MD

736 PancreaticNeuroendocrineTumorSyndromes

VaniaNosé,MD,PhD

744 HamartomatousPolyps,Peutz-Jeghers

GregoryY.Lauwers,MDandAmitabhSrivastava,MD

750 PTEN-HamartomaTumorSyndromes

VaniaNosé,MD,PhD

758 RASopathies:NoonanSyndrome

ValentinaNardi,MD

762 RhabdoidPredispositionSyndrome

FaustoJ.Rodríguez,MD

766 Schwannomatosis

FaustoJ.Rodríguez,MD

770 Shwachman-DiamondSyndrome

ValentinaNardi,MD

772 SteatocystomaMultiplex

MaiP.Hoang,MD

774 TuberousSclerosisComplex

FaustoJ.Rodríguez,MD

780 TumorSyndromesPredisposingtoOsteosarcoma

G.PeturNielsen,MDandYinRexHung,MD,PhD

782 vonHippel-LindauSyndrome

VaniaNosé,MD,PhDandCarlaMartinsAlberti,MD

790 WernerSyndrome/Progeria

MaiP.Hoang,MD

794 WilmsTumor-AssociatedSyndromes

AlexanderJ.Gallan,MDandGladellP.Paner,MD,(BS)

MT

796 Wiskott-AldrichSyndrome

ValentinaNardi,MD

798 XerodermaPigmentosum

MaiP.Hoang,MD

PartIII:Reference

SECTION1:MOLECULARFACTORS

804 MolecularFactorsIndex

VaniaNosé,MD,PhD

AcuteLymphoblasticLeukemiaandNon-HodgkinLymphoma

CLINICALISSUES

•Acutelymphoblasticleukemia(ALL)

○Notexclusivelysporadicdisease

KEYFACTS

○RiskofdevelopingB-acutelymphoblasticleukemia(BALL)is2-4xincreasedamongsiblingsofaffectedchildren

•Numberofgeneticalterationsthatpredisposeindividuals todevelopmentofALLisgrowing

•ChildrenwithALLshouldhavethoroughhistoryand focusedphysicalexamorbereferredtoscreenfor potentialfamilialsyndrome

•Implicationsforpreimplantationgeneticdiagnosis, managementofpatientandrelatives,screeningofrelated stemcelldonors

DIAGNOSTICCHECKLIST

•FamilialB-ALLdueto

○Germline PAX5 mutations

○Germline ETV6 mutationsordeletions

○Germline SH2B3 mutations

(Left)Bonemarrowis100% cellular.Hematopoietic marrowisreplacedbyblasts withhighnuclear:cytoplasmic ratioconferringtheblue appearanceatlowpower. (Right)Lymphoidblastscan haveirregularnuclear contoursmimickingmyeloid blasts.Thechromatinis vesicular,anddistinctnucleoli canbeseen.

○GermlineIKZF1mutations

•ALLasmanifestationsofgeneticsyndromes

○Li-Fraumenisyndrome

○Downsyndrome

○Wiskott-Aldrichsyndrome

○Bloomsyndrome

○Ataxiatelangiectasiasyndrome

○Constitutionalmismatchrepairsyndrome

○Nijmegenbreakagesyndrome

○FamilialplateletdisorderduetoRUNX1mutations

○Fanconianemia

○Neurofibromatosistype1

○Noonansyndrome

•Geneticpredispositiontolymphoma

○Noknownsyndromespredisposingexclusivelyto lymphomas

○Syndromesleadingtoimmunodeficiencycanpredispose toNHL

(Left)High-powerviewshows bonemarrowinvolvedbyBALL.Thecellularityconsistsof sheetsofsmall-tomediumsizedblasts,withscant cytoplasm,slightlyindented, irregularnuclei,fine chromatin,andoccasional distinctnucleoli.(Right)Sheets ofimmaturecellswithopen chromatinanddistinctnucleoli consistentwithblastsare fillingthesinusesand replacingtheparenchyma.

B-ALL/LymphomainBoneMarrow
B-ALL/LymphomaMorphology
B-ALL/LymphomainBoneMarrowAspirate
B-ALL/LymphomainLymphNode

AcuteLymphoblasticLeukemiaandNon-HodgkinLymphoma

TERMINOLOGY

Abbreviations

•Acutelymphoblasticleukemia(ALL)

•Non-Hodgkinlymphoma(NHL)

ETIOLOGY/PATHOGENESIS

ALLasManifestationofGeneticSyndromes

•Li-Fraumeni(pediatrichypodiploidB-ALL)

•Downsyndrome(oftencharacterizedbysomaticCRLF2 rearrangements)

•Wiskott-Aldrichsyndrome

•Bloomsyndrome

•Ataxiatelangiectasia:T-ALL>B-ALL

•Constitutionalmismatchrepairsyndrome

•Nijmegenbreakagesyndrome:T-ALL>B-ALL

•Familialplateletdisorderwithpredispositiontomyeloid malignancyduetoRUNX1mutations(T-ALL)

•Fanconianemia

•NeurofibromatosistypeI

•Noonansyndrome

FamilialB-ALLSecondarytoGermlineMutationsin

GenesSomaticallyMutatedinALL

• PAX5

• ETV6

• SH2B3

• IKZF1

GeneticPredispositiontoLymphoma

•Currentlynoknownsyndromespredisposingexclusivelyto lymphomas(mostlyNHL)

•Syndromesleadingtoimmunodeficiencycanpredisposeto NHL

○Ataxiatelangiectasia(alsoatriskforHodgkinlymphoma)

○Bloomsyndrome

○Nijmegenbreakagesyndrome

○WiskottAldrichsyndrome

○Constitutionalmismatchrepairsyndrome

CLINICALISSUES

FamilialB-ALLDuetoGermline 3 $ ; ˘Mutations

•B-celltranscriptionfactorpairedboxproteinPAX5 is essentialfornormalB-celldevelopment

• PAX5 issomaticallydeleted,rearranged,orotherwise mutatedin~30%ofsporadicB-ALL

•Heterozygoushypomorphgermlinemutations(i.e., p.Gly183Ser)needsomaticlossofwild-typePAX5alleleto beleukemogenic

FamilialB-ALLDuetoGermline ( 7 9 ˇMutationsor Deletions

• ETV6isETSfamilytranscriptionalrepressoressentialfor bonemarrowhaematopoiesis

•Manygermline ETV6 variants havedominantnegative effectontranscriptionalrepressionmediatedbywild-type protein

•Heterozygousgermlinemutationsin ETV6 areassociated withthrombocytopeniaandpredispositiontoB-ALLwith hyperdiploidkaryotype

•25-30%ofpatientswithgermlineETV6mutationswill developB-ALL;inadditionsomemaydevelopsolidtumors &/ormyeloidmalignancies

FamilialB-ALLDuetoGermline 6 + % Mutations

•SH2Badaptorprotein3(SH2B3)gene(a.k.a. LNK) encodes negativeregulatorofcytokinesignalingandtyrosine kinases

• SH2B3playscriticalroleindevelopmentandfunctionof hematopoieticstemcellsandlymphoidprogenitors

•Biallelicgermlinelossoffunctionmutationsin SH2B3are associatedwithfamilialdevelopmentaldelay, autoimmunity,andB-ALL

•ALLwithsporadicorgermline SH2B3mutations,maybe sensitivetokinaseinhibitorsoragentsinhibitingactivated JAK-STATpathway

FamilialB-ALLDuetoGermline , . = ) Mutations

• IKZF1encodeszincfingertranscriptionfactorIKAROS, criticalregulatoroflymphoiddevelopment

•~0.9%ofpresumedsporadicpediatricB-ALLwillhave germlineIKZF1variants

•Germline IKZF1 variantstendtoclusteroutsideknown annotatedfunctionaldomains

•GermlineIKZF1alterationspredisposetoALL,withvariable penetrance,andpotentiallyreduceresponseto chemotherapyandkinaseinhibitors

•SomepatientswithgermlineIKZF1variantshaveB lymphopenia

MICROSCOPIC

HistologicFeatures

•Histologicallyindistinguishablefrompediatricsporadic acutelymphoblasticleukemia/lymphomaandfrom sporadicHodgkinandnon-Hodgkinlymphomas

ANCILLARYTESTS

GeneticTesting

•Targetedgenesequencingtodetectpointmutations, insertionsanddeletions

•Microarrays,multiplexligation-dependentprobe amplification-based(MLPA),ornext-generationsequencing assays todetectlarge-scalegenomic rearrangements &/or deletions

•Preferredtissueforgermlinegenetictestinginpatients withhematologicmalignancyareculturedskinfibroblasts

SELECTEDREFERENCES

1. PuiCHetal:Somaticandgermlinegenomicsinpaediatricacute lymphoblasticleukaemia.NatRevClinOncol.16(4):227-40,2019

2. RampersaudEetal:GermlinedeletionofETV6infamilialacute lymphoblasticleukemia.BloodAdv.3(7):1039-46,2019

3. ChurchmanMLetal:GermlinegeneticIKZF1variationandpredispositionto childhoodacutelymphoblasticleukemia.CancerCell.33(5):937-48.e8,2018

4. AuerFetal:InheritedsusceptibilitytopreB-ALLcausedbygermline transmissionofPAX5c.547G>A.Leukemia.28(5):1136-8,2014

5. Perez-GarciaAetal:GeneticlossofSH2B3inacutelymphoblasticleukemia. Blood.122(14):2425-32,2013

BloodandBoneMarrowTable

GermlineMutationsandConditionsAssociatedWithIncreasedRiskofHematological Malignancies

Disorder

Fanconianemia

Diamond-Blackfananemia

FANCA,FANCB*, FANCC,FANCD1 (BRCA2),FANCD2, FANCE,FANCF, FANCG,FANCI,FANCJ (BRIP1/BACH1), FANCL,FANCM, FANCN(PALB2), FANCO(RAD51C), FANCP(SLX4),FANCQ (ERCC4),FANCR (RAD51)**,FANCS (BRCA1),FANCT (UBE2T),FANCU (XRCC2),FANCV (MAD2L2/REV7)

RPL5,RPL11,RPL15, RPL23,RPL26,RPL27, RPL31,RPL35A, RPL36,RPS7,RPS10, RPS15,RPS17,RPS19, RPS24,RPS26,RPS27, RPS27A,RPS28, RPS29, GATA1   TSR2

Dyskeratosiscongenita DKC1

TERC

TERT

NOLA3/NOP10

NOLA2/NHP2

TINF2

WRAP53/TCAB1

CTC1

RTEL1

ACD/TPP1

PARN

NAF1

STN1

AR *X-linked **AD

MDS,AML,[ALL withFANCD1 (BRCA2)]

Squamouscell carcinomasofheadand neck,vulva,GItract;liver tumors;braintumors andWilmstumor [FANCD1(BRCA2)]

Shortstature,skin pigmentation,skeletaland thumbabnormalities, facialdysmorphisms, renal,gonadal,cardiac,GI, andCNSabnormalities

AD

MDS,AML Osteosarcoma,soft tissuesarcomas

Macrocyticanemia,short stature,thumb abnormalities,facial dysmorphisms,cleft lip/palate,PierreRobin syndrome,cardiacand genitourinary abnormalities

X-linked

X-linked

X-linked AD AD,AR AR AR AD AR AR AD,AR AD,AR AD,AR AD AD

MDS,AML,AA Squamouscell carcinomasofheadand neck,GItract

Naildystrophy,rash, leukoplakia,shortstature, pulmonaryfibrosis, vascularanomalies,early grayingofhair,hairloss; dental,CNS,GIandGU abnormalities

Shwachman-Diamondsyndrome SBDS AR MDS,AML - Shortstature,steatorrhea, metaphysealdysostosis

Severecongenitalneutropenia ELANE HAX1 AD AR MDS,AML - Neurological abnormalities

FamilialMDS/AMLwithmutated GATA2 GATA2 AD MDS,AML, CMML -

Warts,atypical mycobacteria, lymphedema,deafness, pulmonaryalveolar proteinosis,arteriovenous malformations

MIRAGEsyndrome SAMD9 AD MDS,AML - Shortstature,adrenal hypoplasia,infections; CNS,GI,GU,andskeletal abnormalities

Ataxia-pancytopeniasyndrome SAMD9L AD MDS,AML - Ataxia(variable)

Myeloidneoplasmwithmutated SRP72 AD MDS - Sensorineuralhearingloss

BloodandBoneMarrowTable

GermlineMutationsandConditionsAssociatedWithIncreasedRiskofHematological Malignancies(Continued)

Disorder Genes

SRP72

FamilialMDS/AMLwithmutated DDX41 DDX41 AD MDS,AML - -

Familialplateletdisorder withpropensityto myeloidmalignancy RUNX1 AD MDS,AML,ALL - Thrombocytopeniaand abnormalplatelet function

Thrombocytopenia2 ANKRD26 AD MDS,AML - Thrombocytopeniaand abnormalplatelet function

Thrombocytopenia5 ETV6 AD ALL,MDS,AML - Thrombocytopeniaand abnormalplatelet function

FamilialAMLwithCEBPA mutation CEBPA AD AML - -

Li-Fraumeni TP53 AD ALL,MDS,AML Breast,softtissue sarcomas,brain, adrenocortical carcinoma,lung,colon, pancreas,Wilms, prostate -

SusceptibilitytoALL3 PAX5 AD ALL - -

Constitutionalmismatch repairdeficiency syndrome

MLH1

PMS2

MSH2

MSH6 AR AR AR AR Lymphoma, ALL,AML CNS,GItract,other Caféaulaitspots,axillary freckling,Lischnodules, neurofibromas,intestinal adenomas

WiskottAldrich WAS X-linked Lymphoma, leukemia Thrombocytopenia, neutropenia,eczema, infections,autoimmune disorders

Nijmegenbreakagesyndrome NBN AR Lymphoma Gliomas, rhabdomyosarcoma, medulloblastoma

Bloomsyndrome BLM AR Lymphoma, MDS,ALL

Colon,skincancer, squamouscell carcinomasofheadand neck,Wilmstumor, and others,atearlyage

Ataxiatelangiectasia ATM AR Lymphoma, leukemia Solidtumors -

Noonansyndrome

Severemicrocephaly, abnormalfacies,other malformations

Facialrashwithbutterfly distribution,other dermatologic manifestations,chronic obstructivelungdisease, endocrineabnormalities

PTPN11,SOS1,RAF1, KRAS,NRAS,BRAF, MAP2K1 AD JMML Rhabdomyosarcoma, neuroblastoma Shortstature, macrocephaly,feeding difficulty,cardiacdefects, other

AD=autosomaldominant;AR=autosomalrecessive; A<L=acutemyeloidleukemia:ALL=acutelymphoblasticleukemia;JMML=juvenile myelomonocyticleukemia;MDS=myelodysplasicsyndrome.

GodleyLAetal:Geneticpredispositiontohematologicmalignancies:managementandsurveillance.Blood, 130(4):424-432),2017.

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