Esophageal cancer is the 6th most common cause of cancer deaths worldwide. There are two main types: squamous cell carcinoma and adenocarcinoma. Risk factors for squamous cell carcinoma include smoking and alcohol consumption, while gastroesophageal reflux disease (GERD) is the main risk factor for adenocarcinoma. Survival rates depend on the stage - localized cancer has around a 47% 5-year survival rate while distant metastasis is only around 5%. Prognosis is generally better without lymph node involvement and for those who have a complete response to neoadjuvant chemoradiation therapy prior to surgery. Positron emission tomography (PET) scanning and presence of FDG-avid lymph nodes can

1. ESOPHAGEAL CANCER
Name:ELGHA PARAMBI Rollno:
INTRODUCTION
Esophageal cancerisa disease inepidemiologictransition.Until the 1970s, the most commontype
of esophageal cancerinthe UnitedStateswassquamous cell carcinoma,whichhassmokingand
alcohol consumptionasriskfactors.Since then,there hasbeenasteepincrease inthe incidence of
esophageal adenocarcinoma,forwhichthe mostcommonpredisposingfactorisgastroesophageal
reflux disease(GERD).See the image below:
Cascade of eventsthatleadfromgastroesophageal reflux diseasetoadenocarcinoma
BACKGROUND
Esophageal cancerisa devastatingdisease.Itisthe 6th most commoncause of cancer deaths
worldwide. Althoughsome patientscanbe cured, the treatmentforesophageal cancerisprotracted,
diminishesqualityof life,andislethal inasignificantnumberof cases.
The principal histologictypesof esophageal cancerare squamouscell carcinoma(SCC) and
adenocarcinoma.Bothare commonin men.Adenocarcinomaisdiagnosedpredominantlyinwhite
menand the incidence hasrisenmore steeplyinthatpopulation.However,adenocarcinomais
graduallyincreasinginmenof all ethnicbackgroundsandalsoinwomen.
Squamouscellsline the entire esophagus,soSCCcanoccur inany part of the esophagus,butitoften
arisesinthe upperhalf.Adenocarcinomatypicallydevelopsinspecializedintestinal metaplasia
(Barrettmetaplasia) thatdevelopsasaresultof gastroesophageal refluxdisease (GERD);thus,
Gastroesophageal
reflux
Metaplasia
Low Grade
Dysplasia
High Grade
Dysplasia
Adenocarcinoma

2. adenocarcinomatypicallyarisesinthe lowerhalf of the distal esophagusandofteninvolvesthe
esophagogastricjunction.
SIGNS AND SYMPTOMS
Presentingsignsandsymptomsof esophagealcancerinclude the following:
 Dysphagia(mostcommon);initiallyfor solids,eventuallyprogressingtoinclude liquids
(usuallyoccurswhenesophageal lumen<13 mm)
 Weightloss(secondmostcommon) due todysphagiaandtumor-relatedanorexia.
 Bleeding(leadingtoirondeficiencyanemia)
 Epigastricor retrosternal pain
 Bone painwithmetastaticdisease
 Hoarseness(due tothe involvementof the recurrentlaryngeal nerve)
 Persistentcough
 Intractable coughingorfrequentpneumonia(duetotracheobronchial fistulascausedby
directinvasionof tumorthroughthe esophageal wall andintothe mainstembronchus)
Physical findingsinclude the following:
 Typically,normal examinationresultsunlessthe cancerhasmetastasized
 Hepatomegaly(fromhepaticmetastases)
 Lymphadenopathyinthe laterocervical orsupraclavicularareas(reflectingmetastasis)
DIAGNOSIS
Laboratory studiessuchascomplete bloodcount(CBC) andcomprehensivemetabolicpanel (CMP)
focusprincipallyonpatientfactorsthatmayaffecttreatment(e.g.,nutritional status,renal
function).
Imagingstudiesusedfordiagnosisandstaginginclude the following:
 Esophagogastroduodenoscopy(EGD;allowsdirectvisualizationandbiopsiesof the tumor)
 Endoscopicultrasonography(EUS;mostsensitive testforTand N staging; usedwhenno
evidence of M1 disease)
 Computedtomography(CT) of the abdomenandchestwithcontrast(forassessinglungand
livermetastasisandinvasionof adjacentstructures)
 PelvicCTscan withcontrast if clinicallyindicated
 Positronemissiontomography(PET) scanning(forstaging)
 Bronchoscopy(if tumorisat or above the carina,to helpexclude invasionof the tracheaor
bronchi)
 Laparoscopyand thoracoscopy(forstagingregional nodes)
 Bariumswallow(verysensitive fordetectingstricturesandintraluminal masses,butnow
rarelyused)
MANAGEMENT
Treatmentof esophageal cancervariesbydisease stage,asfollows:
 Stage I-III(locoregional disease) - Available modalitiesare endoscopictherapies(e.g.,
mucosal resectionorablation),esophagectomy,preoperativechemoradiation,anddefinitive
chemoradiation.

3.  Stage IV – Systemicchemotherapywithpalliative/supportivecare forpatientswithECOG
performance score of 2 or lessandpalliative/supportive care onlyforpatientswithECOG
performance score of 3 or more.
Indicationsforsurgical treatmentof esophageal cancerincludethe following:
 Esophageal cancerina patientwhoisa candidate forsurgery(esophagectomy)
 High-grade dysplasiainapatientwithBarrettesophagusthatcannot be adequatelytreated
endoscopically
Contraindicationsforsurgical treatmentinclude the following:
 Metastasisto N2 (celiac,cervical,supraclavicular) nodesorsolidorgans(e.g.,liver,lungs)
 Invasionof adjacentstructures(e.g.,recurrentlaryngeal nerve,tracheobronchial tree,aorta,
pericardium)
 Severe associatedcomorbidconditions(e.g.,cardiovasculardisease,respiratorydisease)
Surgical optionsinclude the following:
 IvorLewisesophagogastrectomy(laparotomyplusrightthoracotomy)
 McKeownesophagogastrectomy(rightthoracotomypluslaparotomyplus cervical
anastomosis)
 Minimallyinvasive IvorLewisesophagogastrectomy(laparoscopicapproach)
 Minimallyinvasive McKeownesophagogastrectomy(laparoscopicapproach)
 Roboticminimallyinvasive esophagogastrectomy
 Transhiatal esophagectomy(THE)
 Transthoracic/transabdominal esophagectomywithanastomosisinchestorneck
Palliativecare optionsforpatientswhoare notcandidatesforsurgeryare as follows:
 Chemotherapy
 Radiotherapy
 Laser therapy
 Stents
ANATOMY
The esophagusisa musculartube that extends fromthe level of the 7thcervical vertebratothe 11th
thoracic vertebra.The esophaguscanbe dividedintothe followinganatomicparts:
 Cervical esophagus
 Thoracic esophagus
 Abdominal esophagus
The bloodsupplyof the cervical esophagusisderivedfrom the inferiorthyroidartery,while the
bloodsupplyforthe thoracicesophaguscomesfromthe bronchial arteriesandthe aorta.The
abdominal esophagusissuppliedbybranchesof the leftgastricarteryandinferiorphrenicartery.
Venousdrainage of the cervical esophagusisthroughthe inferiorthyroidvein,while the thoracic
esophagusdrainsviathe azygousvein,the hemiazygousvein,andthe bronchial veins.The
abdominal esophagusdrainsthroughthe coronaryvein.

4. The esophagusischaracterizedbya rich networkof lymphaticchannelsinthe submucosathatcan
facilitate the longitudinal spreadof neoplasticcellsalongthe esophagealwall.Lymphaticdrainage is
to the followingnode basins:
 Cervical
 Tracheobronchial
 Mediastinal
 Gastric
 Celiac
PATHOPHYSIOLOGY
Major riskfactors for SCCinclude alcohol consumptionandtobaccouse.Most studieshave shown
that alcohol isthe primaryriskfactor but smokingincombinationwithalcohol consumptioncan
have a synergisticeffect.
Alcohol damagesthe cellularDNA bydecreasingmetabolicactivitywithinthe cell andtherefore
inhibitsdetoxificationandpromotesoxidation. Alcohol isasolvent,specificallyof fat-soluble
compounds.Therefore,the carcinogenswithintobaccoare able topenetrate the esophageal
epitheliummore easily.
Some of the carcinogensintobaccoinclude the following:
 Aromaticamines
 Nitrosamines
 Polycyclicaromatichydrocarbons
 Aldehydes
 Phenols
Othercarcinogens,suchas nitrosaminesfoundincertainsaltedvegetablesandpreservedfish,have
alsobeenimplicatedinesophageal SCC.The pathogenesisappearstobe linkedtoinflammationof
the squamousepitheliumthatleadstodysplasiaandinsitumalignanttransformation
Adenocarcinomaof the esophagusmostcommonlyoccursinthe distal esophagusandhasa distinct
relationshiptoGERD. UntreatedGERD can progresstoBarrett esophagus(BE),inwhichthe stratified
squamousepitheliumthatnormallylinesthe esophagusisreplacedbya columnarepithelium.
The chronic reflux of gastricacidand bile atthe gastroesophageal junctionandthe subsequent
damage to the esophagushasbeenimplicatedinthe pathogenesisof Barrettmetaplasia.Diagnosis
of Barrettesophaguscanbe confirmedbybiopsiesof the columnarmucosaduringanupper
endoscopy.
The progressionof Barrettmetaplasiatoadenocarcinomaisassociatedwithseveral changesingene
structure,gene expression,and proteinstructure. The oncosuppressorgene TP53and various
oncogenes,particularlyerb-b2,have beenstudiedaspotential markers.Cassonandcolleagues
identifiedmutationsinthe TP53gene inpatientswithBarrettepitheliumassociatedwith
adenocarcinoma. Inaddition,alterationsinp16 genesandcell cycle abnormalitiesoraneuploidy
appearto be some of the most importantandwell-characterizedmolecularchanges.
Obesityisanotherriskfactorfor esophageal adenocarcinoma,specificallyinindividualswithcentral
fat distribution.Hypertrophiedadipocytesandinflammatorycellswithinfatdepositscreate an
environmentof low-grade inflammationandpromote tumordevelopmentthroughthe releaseof

5. adipokinesandcytokines. Adipocytesinthe tumormicroenvironmentsupplyenergyproductionand
supporttumorgrowth andprogression.
ETIOLOGY
The etiologyof esophagealcarcinomaisthoughttobe relatedtoexposure of the esophageal
mucosato noxiousortoxicstimuli,resultinginasequence of dysplasiatocarcinomainsituto
carcinoma.In Westerncultures,retrospective evidence hasimplicatedcigarette smokingand
chronicalcohol exposure asthe mostcommonetiologicfactorsforsquamouscell carcinoma.High
bodymass index,GERD,andresultantBarrettesophagusare oftenthe associatedfactorsfor
esophageal adenocarcinoma.
Riskfactors foresophageal squamouscellcarcinoma
 Smokingandalcohol use
 Diet
 Certaininfections
 Tylosis
Tylosis ofbalms andsoles
A varietyof otherfactorsmay promote esophageal SCC.These includethe following:
 Causative stricture
 Achalasiacardia
 Priorgastrectomy
 Use of oral bisphosphonates
 Drinkingscalding-hotliquids(hotterthan65° C [149° F])
 Poororal hygiene
 Plummer-Vinsonsyndrome
Riskfactors foradenocarcinoma
The principal riskfactorsand etiologicassociationsforesophagusadenocarcinomainclude the
following:
 GERD: isthe most commonpredisposingfactorforadenocarcinomaof the esophagus.
Adenocarcinomamayrepresentthe lasteventof asequence thatstartswithirritation
causedby the reflux of acidandbile andprogressestospecializedintestinal (Barrett)
metaplasia,low-grade dysplasia,high-grade dysplasia,andfinallyadenocarcinomasee the
image above).Approximately10%-15% of patientswhoundergoendoscopyforevaluationof
GERD symptomsare foundtohave Barrett epithelium.

6.  Obesityandmetabolicsyndromes:Obesityhasbeenlinkedtoahigherriskfor Barrett
esophagus andesophageal adenocarcinoma.
Obesityincreasesthe riskof GERD and subsequentlyof esophageal adenocarcinomabya
"mechanical"processthatconsistsof an amplificationof intragastricpressure,disruptionof
normal esophageal sphincterfunction,andincreasedriskof ahiatal hernia. Obesityalsohas
an inflammatoryeffectmediatedbythe release of variousproinflammatorycytokines,which
can leadto metabolicsyndrome,aconstellationof metabolicdisordersthatincludesobesity,
impairedfastingglucose,highbloodpressure,anddyslipidemia.Like obesity,metabolic
syndrome isalsolinkedwiththe riskof esophageal adenocarcinoma.
EPIDEMIOLOGY
International statistics
Esophageal canceristhe ninthmostcommoncancer and the sixthmostcommoncause of cancer
deathsworldwide. Itisendemicinmanyparts of the world,particularlyinthe thirdworldcountries,
where itisthe fourthmostcommoncause of cancer deaths. Incidence ratesare variable worldwide,
withthe highestratesfoundinsouthernandeasternAfricaandeasternAsiaandthe lowestratesin
westernandcentral AfricaandCentral Americainbothmenand women.
In some regions,suchasareas of northernIran,some areas of southernRussia,andnorthernChina
(sometimescalledan"esophageal cancerbelt"),the incidence of esophagealcarcinomamaybe as
highas 800 casesper100,000 population.Majorriskfactorsin these areasare not well knownbut
are probablyrelatedtothe poornutritional status,includinglow intake of fruitsandvegetablesand
drinkingveryhotbeverages.Unlike inthe UnitedStates,squamouscell carcinomaisresponsible for
95% of all esophageal cancersworldwide.
Age and sex relateddemographics:
Esophageal cancerismore commoninmenthan inwomen.The male-to-femaleratiois3-4:1.
Esophageal canceroccurs mostcommonlyduringthe sixthandseventhdecadesof life.The disease
becomesmore commonwithadvancingage;itisabout 20 times more commoninpersonsolder
than 65 yearsthan itis inindividualsbelow thatage.Medianage at diagnosisis68 years.
PROGNOSIS
Survival inpatientswithesophagealcancerdependsonthe stage of the disease.Squamouscell
carcinomaand adenocarcinoma, stage-by-stage,appeartohave equivalentsurvivalrates.
Lymphnode or solidorganmetastasesare associatedwithlow survivalrates.In2009-2015, the
overall 5-yearsurvival rate foresophageal cancerwas19.9%. Patientswithoutlymphnode

7. involvementhave asignificantlybetterprognosisand5-yearsurvival rate thanpatientswith
involvedlymphnodes.Stage IV lesionswithdistantmetastasisare associatedwitha5-yearsurvival
rate of around 5%. See the table below
Stage Survival rate(%)
Localised 46.7
Regional 25.1
Distant 4.8
all stages 19.9
The 5-year survival rate in2015 was21.5% in whitesand13.5% inblacks. A reportof 1085 patients
whounderwenttranshiatal esophagectomyforcancershowedthatthe operationwasassociated
witha 4% operative mortalityrate anda 23% 5-year survival rate.A better5-yearsurvival rate (48%)
was identifiedinasubgroupof patientswhohada complete response (i.e.,disappearanceof the
tumor) followingpreoperative radiationandchemotherapy(i.e.,neoadjuvanttherapy).
Transhiatal andtransthoracicesophagectomieshave equivalentlong-termsurvival rates.
Imagingandprognosis
Suzuki etal foundthata higherinitial standardizeduptakevalue onpositronemissiontomography
(PET) scanningisassociatedwithpooreroverall survival inpatientswithesophagealor
gastroesophageal carcinomareceivingchemoradiation.The authorssuggestedthatPETscanning
may become useful forindividualizingtherapy.
A studyby Gilliesetal alsofoundthatPET–computed tomography(CT) scanningcanbe usedto
predictsurvival;inthisstudy,the presence of fluorodeoxyglucose(FDG)-avidlymphnodeswasan
independentadverse prognosticfactor.
HER-2 andprognosis
A studyby Prinsetal of humanepidermal growthfactor2 (HER-2) proteinoverexpressionandHER-2
gene amplificationinesophagealcarcinomasfoundthatHER-2 positivityandgene amplificationare
independentlyassociatedwithpoorsurvival.Intheirstudy,whichinvolved154patientswith
esophageal adenocarcinoma,HER-2positivitywasseenin12% of these patientsandoverexpression
was seenin14% of them.
CLINICAL PRESENTATION
HISTORY
Dysphagia,the mostcommonpresentingsymptomof esophagealcancer,isinitiallyexperiencedfor
solidsbuteventually progressestoincludeliquids.Itusuallyoccurswhenesophageal lumen
diameterisunder13 mm and indicateslocallyadvanceddisease.A complaintof dysphagiainan
adultshouldalwayspromptanendoscopytohelprule outthe presence of esophageal cancer.A
bariumswallowstudyisalsoindicatedinthesecases.
Othersymptomsinclude:

8.  Weightloss - This isthe secondmostcommon symptom, occurringinmore than50% of
people withesophagealcarcinoma.Itiscausedby dysphagiaandtumor-relatedanorexia.
 Bleeding- Patientsmayexperiencebleedingfromthe tumorleadingtoirondeficiency
anemia.
 Pain- Painmay be feltinthe epigastricorretrosternal area;painoverbonystructures
indicatesmetastaticdisease.
 Hoarseness - Thisiscausedby invasionof the recurrentlaryngeal nerve;itisa signthat the
cancer has progressedbeyondthe pointatwhichsurgical resectionremainspossible.
 Persistentcough
 Respiratorysymptoms(persistentcoughandrecurrentpneumonia) - These canbe causedby
aspirationof undigestedfoodorbydirectinvasionof the tracheobronchial tree bythe tumor
(tracheobronchial fistula);the latterisalsoasignof unresectabiliy.
PHYSICAL EXAMINATION
Physical examinationfindingsinpatientswithesophageal cancerare typicallynormal,unlessthe
cancer has metastasizedtonecknodesorthe liver.Lymphadenopathyinthe laterocervical or
supraclavicularareaor the presence of hepatomegalyoftenindicatesunresectable disease.
DIFFERENTIAL DIAGNOSIS
Diagnosticconsiderations:
Esophageal lesionsotherthancancerthat can cause dysphagiainclude the following:
 Achalasia
 Esophageal stricture fromgatroesophageal reflux
 Benignesophagealtumors(principallyesophageal leiomyoma)
Achalasiamaybe clinicallyindistinguishablefromesophageal cancer.Patientspresentwithalong
historyof regurgitationandslowlyprogressive dysphagia.Uppergastrointestinal imaging(e.g.,
bariumstudy) showsa typical "bird'sbeak"fillingdefect.
Cautionisrequiredtodifferentiate achalasiafromso-calledpseudoachalasia,whichcanmimicthis
benigncondition;itiscrucial therefore tofollow upwithendoscopyformucosal assessmentand
biopsytorule out anymalignantpathology.Esophagogastroduodenoscopy(EGD) haslow sensitivity
for the diagnosis of achalasia;resultsare oftenreportedasnormal inearlyachalasia.Esophageal
manometryconfirmsthe diagnosisbyshowingincomplete relaxation(increasedresting
pressure/tone) of the loweresophageal sphincter(LES)
Esophageal stricture ischaracterizedbyslowlyprogressive dysphagiaandheartburn.EGD confirms
the diagnosis.
DIAGNOSIS AND STAGING
APPROACH CONSID ERATIONS
In 2013, the Societyof ThoracicSurgeonsreleasedclinical practice guidelinestoassistinthe
diagnosisandtreatmentof localizedesophageal cancer.Theirrecommendationsfor diagnosis
include the following:
 Flexible endoscopywithbiopsyisthe primarymethodfordiagnosisof esophageal cancer.

9.  Computedtomography(CT) of the chestandabdomenisan optional testforstagingof
early-stage esophagealcancer,anda recommendedtestforstagingof locoregionalized
esophageal cancer.
 Positronemisisontomography(PET) isanoptional testforstagingof early-stage esophageal
cancer, anda recommendedtestforstagingof locoregionalizedesophageal cancer.
 In patientswithoutmetastaticdisease,endoscopicultrasonographyisrecommendedto
improve the accuracy of staging
 In patientswithsmall,discrete nodulesorareasof dysplasiainwhomdisease appears
limitedtothe mucosaor submucosaas assessedbyendoscopicultrasonography,endoscopic
mucosal resectionshouldbe consideredasa diagnostic/stagingtool.
 In patientswithlocallyadvanced(T3/T4) adenocarcinomaof the esophagogastricjunction
infiltratingthe anatomiccardiaor Siewarttype IIIesophagogastrictumors,laparoscopyis
recommendedtoimprove the accuracyof staging.
IMAGING STUDIES
Imagingstudiesusedinthe diagnosisandstagingof esophageal cancerincludethe following:
 CT scanning
 PET scanning
 Endoscopicultrasound(EUS)
 Bronchoscopy
 Bariumswallow
Computedtomography
Abdominal andchestcomputedtomography(CT) scansare useful forhelpingtoexclude the
presence of metastases(Mstaging) tothe lungsandliverandmay be useful forhelpingto
determine whetheradjacentstructureshave beeninvaded.
Chest CT showing invasion ofthe tracheabyesophageal cancer
Positronemissiontomography
PET scanningisalso a useful baselineimagingtechnique andisincreasinglybecomingstandardinthe
stagingof esophageal cancer.Itmay be particularlyuseful indetectingoccultdistantlymphnode
metastasesandbone spread.Inaddition,the intensityof radiopharmaceutical uptakeonPETscans
may reflectthe biologyof the cancerandthus mayhave prognosticsignificance.
Endoscopicultrasound

10. EUS isthe most sensitivetestfordeterminingthe depthof tumorpenetration(Tstaging) andthe
presence of enlargedperiesophageal lymphnodes(N staging)
Characteristicfeaturesof malignantorinflammatorylymphnodesdetectedonEUS:
 Enlargedinsize
 Hypoechoic(dark)
 Homogeneous
 Well circumscribedandrounded
The accuracy of diagnosingnodal diseaseissignificantlyincreasedwiththe combinationof above-
mentionedfeatures,butalsoisconfirmedwiththe use of fine needle aspiration(FNA) biopsyfor
cytologyassessment. The combineduse of EUSand FNA (EUS-FNA) hasa greateraccuracy than EUS
alone inthe evaluationof lymphnode metastasis. Ina studythatcomparedthe role of CT, EUS, and
EUS-FNA forpreoperative nodal stagingin125 patientswithesophageal cancer,EUS-FNA wasmore
sensitivethanCT(83% vs. 29%) and more accurate thanCT (87% vs.51%) or EUS (87% vs. 74%) for
nodal staging. The reviewof CTand PET scans priorto EUS isrecommendedtoevaluate the nodal
distributionforapossible FNA biopsy.
Bronchoscopy
Bronchoscopyisindicatedforcancersof the middle andupperthirdof the thoracicesophagus
(tumorat or above carina) to helpexclude invasionof the tracheaorbronchi.It shouldbe performed
onlyif the patientshowsnoevidence of M1 disease.Laparoscopyandthoracoscopyhave agreater
than 92% accuracy instagingregional nodes.
Bariumswallow
Bariumswallowisverysensitive fordetectingstrictures(seethe firstimage below) andintraluminal
masses(see the secondimage below) butdoesnotallow stagingandbiopsy.Itisnow rarelyused,
but itmay be helpful forstudyingthe distal anatomyinobstructive tumorsthatare inaccessible by
endoscopy.
STAGING
1.Bariumswallow
demonstrating stricture
due to cancer
2.Bariumswallowdemonstrating
an endoluminal massinthe mid
esophagus

11. Esophageal cancerstagingfollowsthe tumor-node-metastasis(TNM) classificationof the American
JointCancerCommittee/UnionforInternational CancerControl/(AJCC/UICC)
No completelysatisfactorymethodisavailabletoclinicallystage esophageal cancer.The difficultyof
clinicallyassessingthe diseaseisreflectedbychangesovertime inthe AJCCstagingsystem.
The revised2010 AJCCstagingclassificationwasbasedonthe risk-adjustedrandomforestanalysisof
the data generatedbythe Worldwide Esophageal CancerCollaboration(WECC) for4627 patients
whowere treatedwithprimaryesophagectomywithoutpreoperative orpostoperative therapy. In
the data reportedbythe WECC, survival decreasedwithincreasingdepthof tumorinvasion(T),
presence of regional lymphnodemetastases(N),andthe presence of distantmetastases(M).
The 2017 TNMclassificationforesophagealcancerisshownbelow:
Primary tumor (T)
TX Primarytumorcannot be assessed
T0 No evidenceof primarytumor
Tis High-grade dysplasia,definedasmalignantcellsconfinedbythe basementmembrane
T1 Tumor invadeslaminapropria,muscularis,mucosae,orsubmucosa
T1a Tumor invadeslaminapropriaormuscularismucosa
T1b Tumor invadessubmucosa
T2 Tumor invadesmuscularispropria
T3 Tumor invadesadventitia
T4 Tumor invadesadjacentstructures
T4a Resectable tumorinvadingpleura,pericardium, azygousvein,diaphragm, orperitoneum
T4b Unresectable tumorinvadingotheradjacentstructures,suchasthe aorta, vertebral body,and
trachea
* High-grade dysplasiaincludesall noninvasive neoplastic epithelial lesionsformerlycalled
carcinomain situ;that termisno longerusedforcolumnarmucosae anywhere inthe
gastrointestinal tract.
Regional lymph nodes (N)
NX Regional lymphnode(s)cannotbe assessed
N0 No regional lymphnode metastasis
N1 Metastasisin1-2 regional lymphnodes (N1issite dependent)
N2 Metastasisin3-6 regional lymphnodes
N3 Metastasisin7 or more regional lymphnodes

12. Distant metastasis (M)
M0 No distantmetastasis
M1 Distantmetastasis
Diagram showingT1,T2, T3 stagesof esophageal cancer.
Clinical stagingclassification:Squamouscell carcinoma
Stage 0 Tis N0 M0
Stage I T1 N0-1 M0
Stage II T2 N0 M0
T3 NO M0
Stage III T3 N1 M0
T1-3 N2 M0
Stage IVA T4 N0-2 M0
Any T N3 M0
Stage IVB AnyT AnyN M1
Clinical stagingclassification: Adenocarcinoma
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T1 N1 M0
Stage IIB T2 N0 M0
Stage III T2 N1 M0
T3 N0-1 M0
T4a N0-1 M0
Stage IV A T1-4a N2 M0
T4b N0-2 M0
AnyT N3 M0
Stage IVB AnyT AnyN M1

13. All esophageal tumors,aswell astumorswithepicenterswithin5cm of the esophagogastric
junctionthatalsoextendintothe esophagus,are classifiedandstagedaccordingtothe AJCC/UICC
esophageal scheme.Tumorswithanepicenterinthe stomachthat are more than5 cm from the
esophagogastricjunctionorthose within5cm of the esophagogastricjunctionwithoutextension
intothe esophagusare stagedusingthe gastriccarcinoma scheme.
However,thisclassificationmaynotworkwell forpatientswhohave receivedpreoperative therapy.
Some othershortcomingsassociatedwiththe currentstagingclassificationare asfollows:
 Inclusionof proximal 5cm of the stomach
 Lack of guidance forregional resectable andunresectablecancer
 Emphasisonthe numberof nodesratherthantheirsize andanatomiclocations/significance.
Otherclassifications—suchasthatof the Japanese SocietyforEsophagealDiseases,whichiswidely
usedinAsia—differfromthatof the AJCC/UICC,especiallyregardinglymphnode distribution and
nomenclature.
LABORATORY STUDIES
Laboratory studiesinpatientswithesophageal cancerfocusprincipallyonpatientfactorsthatmay
affecttreatment.These include completebloodcount(CBC) andcomprehensive metabolicpanel
(CMP).Nutritional status shouldbe evaluatedinpatientswithdysphagia;liverfunctionstudies
shouldbe performedinpatientswhoabuse alcohol.
PROCEDURES
Upper GI endoscopy
Upper GI endoscopyallowsdirectvisualisationandbiopsiesof the tumor.
Endoscopydemonstratingintraluminal esophagealcancer
Endoscopyisa veryimportanttool inthe diagnosis,staging,andsurveillanceof patientswith
esophageal cancer.Mostendoscopyproceduresare performedunderconscioussedation.Patients
whoare at riskof aspirationduringendoscopymayrequiregeneralanesthesia.
Diagnosticendoscopiesare performedtodetermine the following:
 Detectionof esophagealtumor
 Biopsyof any suspiciouslesions
 Locationof the tumorrelative tothe teethandesophagogastricjunction
 Tumor length

14.  Degree of obstruction
Endoscopicresection
Endoscopicresection(ER) of focal nodulesshouldbe performedinthe settingof early-stage disease
(T1a or T1b) to provide accurate assessmentof depthof invasion,degree of differentiation,andthe
presence of lymphovascularinvasion. Thus,ERisan essential procedure forthe accurate stagingof
early-stage cancerespeciallyinpatientswithsmall nodularlesions(≤2cm). ER can become a
therapeuticprocedure if asmall lesion(under2cm) is fullyremovedandhistopathologyrevealsthat
the lesioniswell differentiated,withpenetrationlimitedtosubmucosa,absence of lymphovascular
invasion,andclearmargins.
HISTOLOGIC FINDINGS
Histologically,esophageal squamouscell carcinomaischaracterizedmicroscopicallybykeratinocyte-
like cellswithintercellularbridgesorkeratinization.Adenocarcinomasthatarise fromBarrett
esophagusmucosaare typicallywell- ormoderatelydifferentiatedandhave well-formedtubularor
papillarystructures.Inpoorlydifferentiatedadenocarcinomas,glandularstructuresare onlysloightly
formed;inundifferentiatedadenocarcinomas,glandularstructuresare absent.See the images
below.
TREATMENT
National ComprehensiveCancerNetwork(NCCN) treatmentrecommendationsforesophageal
cancer include the following:
 Endoscopictherapy(endoscopicmucosal resection, endoscopicsubmucosaldissection
and/orablation) ispreferredforhigh-grade dysplasia(HGD) orT1a tumors ≤2 cm; ablation
alone isa primarytreatmentoptionforpatientswithHGD.
 SelectpT1a or pT1b tumors can be treatedwithendoscopicresection(ER); ablationof
residual Barrettesophagusshouldfollow ER.
 Additional ablationmaybe neededafterERif multifocal HGDispresentelsewhereinthe
esophagusbutmaynot be neededfortumorsthatare completelyresected.
 EsophagectomyisindicatedforpatientswithextensiveHGDor pT1a adenocarcinomawith
nodulardisease thatisnotadequatelycontrolledbyERwithor withoutablation;a
Micrograph of squamouscell carcinomaof
the esophagus(H&Estain)
Low magnificationmicrographof anintramucosal
esophageal adenocarcinoma(H&E).

15. transhiatal ortransthoracic,or minimallyinvasive approachmaybe used;gastric
reconstructionpreferred;forpostoperativenutritional support,feedingjejunostomyis
preferredtogastrostomy.
 PrimarytreatmentoptionsforpatientswithSCCT1b,N+ tumorsand locallyadvanced
resectable tumors(T2-T4a,anyregional N) include preoperative chemoradiation(fornon-
cervical esophagustumors),definitivechemoradiation(recommendedforcervical
esophagustumors) oresophagectomy(fornon-cervical esophagustumors).
 For patientswithadenocarcinomaT1b,N+ tumorsand locallyadvancedresectable tumors
(T2-T4a, any regional N) preoperativechemoradiationispreferred;definitive
chemoradiationisindicatedonlyfornon-surgical patients;esophagectomyisanoptionfor
patientswithlow-risk,<2 cm, well-differentiatedlesions.
 Tumorsin the submucosa(T1b) or deepermaybe treatedwithesophagectomy.
 For patientswithSCC,nopostoperativetreatmentisindicatedif noresidualdisease is
presentatsurgical margins(R0 resection).
 For patientswithadenocarcinomawhohave notreceivedpreoperativetherapy,
postoperative fluoropyrimidine-basedchemoradiation(followingR0resection) isindicated
for all patientswithTis,T3-T4 tumors,node-positive T1-T2tumors,andselectedpatients
withT2, N0 tumorswithhigh-riskfeatures.
 ChemotherapyfollowingR0resectionisindicatedforall patientswithadenocarcinoma,
irrespectiveof the nodal status.
 Chemoradiationmaybe offeredtoall patientswithresidual disease atsurgical margins(R1
and R2 resections).
 Definitive chemoradiationispreferredforall T4b(unresectable) tumors.
 Fluoropyrimidine- ortaxane-basedregimensare indicatedforpreoperative anddefinitive
chemoradiation.
 Two-drugcytotoxicregimensare preferredforpatientswithadvanceddiseasebecause of
lowertoxicity.
 Trastuzumabshouldbe addedtofirst-linechemotherapy(category1for combinationwith
cisplatinandfluoropyrimidine;category2Bforcombinationwithotherchemotherapy
agents) forpatientswithHER2-overexpressingadvancedormetastaticadenocarcinoma(a
tumor immunohistochemistry[IHC] score of 3+ or 2+ withthe evidence of HER2
amplificationbyfluorescentinsituhybridization[FISH]).
 Ramucirumab,eitherasa single agentorincombinationwithpaclitaxel,wasapprovedin
2014 by the US Food andDrug Administration(FDA) forthe treatmentof patientswith
advancedesophagogastricjunction(EGJ) adenocarcinomarefractorytoor progressive
followingfirst-line therapywithplatinum- orfluoropyrimidine-basedchemotherapy.
SURGICAL INDICATIONS AND CONTRAINDICATIONS
Surgeryremainsthe cornerstone of treatmentforesophageal cancer.Indicationsforsurgeryinclude
the following:
 Esophageal cancerina patientwhoisa candidate forsurgery
 High-grade dysplasiainapatientwithBarrettesophagusthatcannot be adequatelytreated
endoscopically
Contraindicationstosurgery includingthe following:

16.  Metastasisto N2 nodes(i.e.,cervical orsupraclavicularlymphnodes) orsolidorgans(e.g.,
liver,lungs);the treatmentof patientswithceliaclymphnode involvementremains
controversial
 Invasionof adjacent structures(e.g.,the recurrentlaryngeal nerve,tracheobronchial tree,
aorta, pericardium)
In addition,the presence of severe,associatedcomorbidconditions(e.g.,cardiovasculardisease,
respiratorydisease) candecrease apatient'schancesof survivinganesophagealresection.
Consequently,cardiacandrespiratoryfunctionmustbe carefullyevaluatedpreoperatively.A forced
expiratoryvolumein1 secondof lessthan1.2 L and a leftventricularejectionfractionof lessthan
0.4 are relative contraindicationstothe operation.
ESOPHAGECTOMY
Esophageal resection(esophagectomy) remainsacritical componentof multimodalitytherapyfor
patientswithtumorsof anystage.Endoscopicmucosal resectionisanexperimentalapproachto
patientswithT1a disease orhigh-grade dysplasiathatislimitedtocertain centresandperformed
onlyunderprotocol.Esophagectomyisnolongerisusedforpalliationof symptomsbecause other
treatmentmodalitieshave become availableforrelievingdysphagia.
An esophagectomycanbe performedbyusinganabdominal anda cervical incisionwithblunt
mediastinal dissectionthroughthe esophageal hiatus(i.e.,transhiatal esophagectomy[THE]) orby
usingan abdominal anda rightthoracic incision(i.e.,transthoracicesophagectomy[TTE]).
THE offersthe advantage of avoidingachestincision,whichcancause prolongeddiscomfortandcan
furtheraggravate the conditionof patientswithcompromisedrespiratoryfunction.Afterremovalof
the esophagus,continuityof the gastrointestinaltractisusuallyre-establishedusingthe stomach.
Some authorshave questionedthe validityof THEas a cancer operationbecause partof the
operationisnotperformedunderdirectvisionandfewerlymphnodesare removedthanwithTTE.
However,many retrospective studiesand2prospective oneshave shownnodifference insurvival
betweenthe operations,suggestingthatthe factorinfluencingsurvival isnotthe type of operation
but,rather,the stage of the cancer at the time the operationisperformed.
Morbidity and mortality
Complicationsfromesophagectomyoccurinapproximately40% of patients.The morbidity
associatedwiththe surgeryconsistsmostlyof respiratory,cardiac,andsepticcomplications,
includingthe following:
 Respiratorycomplications(15-20%) - Include atelectasis,pleural effusion,andpneumonia
 Cardiac complications(15-20%) - Include cardiacarrhythmiasandmyocardial infarction
 Septiccomplications(10%) - Include woundinfection,anastomoticleak(breakdownof the
newconnectionbetweenthe stomachandesophagus),andpneumonia
Transthoracic esophagectomy
There are twotypesof TTE, as follows:
 IvorLewisesophagectomy(rightthoracotomyandlaparotomy)
 McKeownesophagectomy(rightthoracotomyfollowedbylaparotomyand cervical
anastomosis)

17. For TTE, the patientisplacedsupine onthe operatingroomtable.Anarterial line,acentral venous
catheter,a Foleycatheter,anda dual-lumenendotrachealtube are placed.Preoperative antibiotics
are administered.Anuppermidline incisionismade.
Afterexploringthe peritoneal cavityformetastaticdisease(if metastasesare found,the operationis
not continued),the stomachismobilized.The rightgastricandthe rightgastroepiploicarteriesare
preserved,whilethe shortgastricvesselsandthe leftgastricarteryare divided.
Next,the gastroesophageal junctionismobilized,andthe esophageal hiatusisenlarged.A
pyloromyotomyisperformed,andafeedingjejunostomyisplacedforpostoperativenutritional
support.
Afterclosure of the abdominal incision,the patientisrepositionedinthe leftlateral decubitus
positionanda rightposterolateral thoracotomyisperformedinthe fifthintercostal space.
The azygos veinisdividedtoallowfull mobilizationof the esophagus. The stomachisdeliveredinto
the chestthrough the hiatusandis thendividedapproximately5cm below the gastroesophageal
junction.
An anastomosis(hand-sewnorstapled) isperformedbetweenthe esophagusandthe stomachat
the apex of the rightchest cavity.Then,the chestincisionisclosed.
McKeownesophagectomy,withananastomosisinthe cervical region,issimilarinconduct,butwith
the advantage of beingapplicable fortumorsinthe upper,middle,andlowerthoracicesophagus.
Transhiatal esophagectomy
For THE, the preoperativedetailsare similartothose of TTE, exceptthata single-lumen,ratherthan
a double-lumen,endotracheal tube isused.The neckispreparedinthe operative field.
The abdominal partof the operationisidentical to the TTE; however,dissectionof the esophagusis
performedthroughthe enlargedesophageal hiatuswithoutopeningthe rightchest.The esophagus
ismobilizedinthisfashionall the waytothe thoracic inlet.
The abdominal partof the operationisidentical tothe TTE; however,dissectionof the esophagusis
performedthroughthe enlargedesophageal hiatuswithoutopeningthe rightchest.The esophagus
ismobilizedinthisfashionall the waytothe thoracic inlet.
Then,a 6-cm incisionismade inthe left side of the neck.The internal jugularveinandcarotidartery
are retractedlaterally,andthe esophagusisidentifiedandisolatedposteriortothe airway.To
preventinjurytothe leftrecurrentlaryngeal nerve,nomechanical retractorsare usedtoretract the
trachea.
Next,afterresectionof the proximalstomachandthoracicesophagus,the remainingstomachis
pulledupthroughthe posteriormediastinumuntil itreachesthe remainingesophagusatthe
cervical level.Then,ahand-sewnanastomosisisperformed,andasmall drainis placedinthe neck

18. alongside the anastomosis.The abdominal andneckincisionsare closed.(Seethe image below.)
Minimally invasive esophagectomy
The use of laparoscopicandthoracoscopictechniqueshasrevolutionizedthe treatmentof benign
esophageal disorderssuchasachalasiaandgastroesophageal reflux disease (GERD).Advantagesof
minimallyinvasive surgeryincludeashorterhospital stay,lesspostoperative discomfort,andmuch
fasterrecoverytime thanwithopensurgery.Minimallyinvasiveesophagectomy(MIE) isfindinga
place inthe treatmentof esophagealcancer.
Video-assistedthoracoscopy(VATS) isbeingusedinmanycentersforthe thoracicmobilizationof
the esophagus,reducingthe size of the chestincision.Inaddition,laparoscopycanbe usedto
mobilize the gastricconduitinthe abdomen,reducingabdominal incisionsize aswell.
A studyby Uenosonoetal foundthat sentinelnode mappingcanbe appliedtopatientswithclinical
T1 and N0 esophageal cancer.Use of thistechnique mayfacilitatelessinvasive surgery,with
reductionof lymphadenectomy.
Endoscopicmucosal resection(EMR) isa modern,attractive optionforthe treatmentof superficial
esophageal cancers.High-gradedysplasiaandmucosa-limitedneoplasmsare candidatesforEMR,
because of the lowriskof node metastasisinthese cases.
Salvage endoscopic resection
In patientswithlocal failureafterdefinitive chemoradiotherapy(CRT) foresophageal squamouscell
carcinoma(SCC),salvage endoscopictreatment(SET) maybe a viable option.
CHEMOTHERAPY AND RADIATION
Chemotherapyandradiotherapyforesophagealcancerare deliveredpreoperatively.Nosurvival
benefitisobtainedwhenradiationandchemotherapyare administeredpostoperatively;however,
postoperative continuanceof chemotherapystartedpreoperativelymaybe beneficial. The aimsof
preoperative (neoadjuvant) chemotherapyandradiotherapyare toreduce the bulkof the primary
tumor before surgerytofacilitate highercurative resectionratesandtoeliminate ordelaythe
appearance of distantmetastases.
 Pembrolizumab:the FDA approvedpembrolizumab(Keytruda) forpatientswithrecurrent,
locallyadvancedormetastatic,squamouscell carcinomaof the esophagus(ESCC) whose

19. tumorsexpressPD-L1(CombinedPositive Score [CPS] ≥10),asdeterminedbyanFDA-
approvedtest,withdiseaseprogressionafter≥1priorlinesof systemictherapy.
 Tipiracil /trifluridine :The FDA approvedtipiracil/trifluridine formetastaticgastricor
gastroesophageal junction(GEJ) adenocarcinomapreviouslytreatedwithatleast2 prior
linesof chemotherapythatincludedafluoropyrimidine,aplatinum,eitherataxane or
irinotecan,andif appropriate,HER2/neu-targetedtherapy.
PALLIATIVE CARE
In patientswhoare not candidatesforsurgery,because of theirclinical conditionoradvanced
disease,treatmentfocusesoncontrol of dysphagia.The goal of palliative care istopreventand
relieve sufferingandimprovequalityof life forpatientsandtheircaregiversregardlessof the disease
stage.In patientswithunresectableorlocallyadvancedcancer,palliative interventionsprovide
symptomaticrelief andmayresultinsignificantprolongationof life,improvementinnutritional
status,the sensationof well-being,and overall qualityof life.
Dysphagiaisthe most commonsymptominpatientswithesophageal cancer.Assessingthe severity
of the conditionandswallowingimpairmentisessentialtoinitiate appropriate interventionsfor
long-termpalliationof dysphagiain patientswithesophageal cancer.
Available palliative methodsforthe managementof dysphagiainclude the following:
 Endoscopiclumenrestorationorenhancement
 Temporaryself-expandingmetal stents(SEMS)
 Brachytherapy
 Chemotherapy
 Laser
 Surgery
PREVENTION OF ESOPHAGEAL CANCER
For squamouscell carcinoma,preventionconsistsof
 Smokingcessation
 Effortsto reduce alcohol abuse
 Consumptionof adietcontaininganadequate amountof fruits,vegetables,andvitamins.
For esophageal adenocarcinoma,preventioninvolves
 Stoppingthe sequence of eventsleadingfromgastroesophageal refluxdisease (GERD) to
Barrett esophagustoadenocarcinoma.Bettercontrol of gastroesophagealreflux can
preventthe developmentof Barrett metaplasiainpatientswithGERDandcan discourage
the developmentof high-grade dysplasiainpatientswithmetaplasia.Endoscopicfollow-up
evaluationsshouldbe performedat1- to 2-year interval todetectthe presence of dysplasia,
allowinginterventionbeforecancerdevelops.