clinical pathological conference: barrett’s esophagus and esophageal carcinoma ralph lee,...

Clinical Pathological Conference: Barrett’s Esophagus and Esophageal Carcinoma

Ralph Lee, MMEd(Dist), MD, FRCPC (Division of Gastroenterology)Celia Marginean, MD (Department of Pathology)

Thursday, September 10, 2015

Objectives (1)

At the end of this lecture, the student will be able to:

Define Barrett’s esophagus.

Illustrate the underlying pathogenesis and clinical relevance of Barrett’s esophagus.

Discuss the epidemiology and risk factors for Barrett’s esophagus.

Identify the morphological features of GERD and Barrett’s esophagus.

Identify the morphological features of Barrett’s dysplasia (low grade, high grade).

Summarize the diagnosis and management of Barrett’s esophagus.

Objectives (2)

Classify the different types of esophageal tumours.

Differentiate between the two primary types of esophageal carcinoma in terms of their epidemiology, etiology, clinical presentation, complications and prognosis.

Identify the morphological features of esophageal carcinoma (squamous and adenocarcinoma).

Outline the diagnosis, staging, management and prevention of the two primary types of esophageal carcinoma.

Describe the epidemiology, clinical presentation/diagnosis and management of eosinophilic esophagitis.

Identify the morphological features of eosinophilic esophagitis.

To Review…

GERD is a condition which develops when the reflux of stomach contents into the esophagus causes troublesome (i.e. adversely affecting a patient’s well-being) symptoms and/or complications.

Classic symptoms include heartburn and regurgitation

‘Alarm features’

Persistent vomiting, signs or symptoms of gastrointestinal blood loss, anemia, unintentional weight loss, dysphagia and a palpable epigastric mass.

Indicate when patients presenting with GERD-like symptoms should be further investigated vs. empiric treatment

Case 1 (1)

50y.o. Caucasian male

RFR: Endoscopy for GERD

HPI: Longstanding (>15 years) history of heartburn, 3-4x/week, controlled with ranitidine (H2RA) prn. Denies dysphagia, odynophagia, nausea, vomiting, early satiety or weight loss.

PMx: Hypertension, hypercholesterolemia. No previous surgeries or endoscopies.

Case 1 (2)

Meds: Ranitidine 150mg po prn, atorvastatin 10mg po OD, ASA 81mg po OD. All: NKDA

Habits: Smoking: 30 pack-years; Alcohol: 4 glasses wine/day.

Family Hx: Non-contributory

Physical Exam: Obese, but otherwise normal.

Labs: CBC, electrolytes, BUN, Cr, LFTs, Iron studies N.

Case 1 (3)

Does this patient need an upper endoscopy? Why or why not?

YES!Why (i.e. what indication)?

> 15 year history of GERD

Why does this matter?13 – 20% of patients undergoing endoscopy for chronic GERD will have Barrett’s esophagus

Why does Barrett’s esophagus matter?

Because this… …can turn into this.

Barrett’s Esophagus

Esophageal Adenocarcinoma

Barrett’s Esophagus (BE)Definition (1)

DefinitionChange in the distal esophageal epithelium of any length that:1. Can be recognized as columnar type mucosa during

endoscopy (i.e. looks orange, not pink).

2. Is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus.


Esophagus normally lined by stratified squamous epithelium which transitions to columnar mucosa at the squamocolumnar junction (SCJ; AKA Z-line)


In Barrett’s, columnar-appearing epithelium with intestinal metaplasia replaces the squamous epithelium

Why is this important?Clinical relevance

Barrett’s esophagus is a premalignant lesion for adenocarcinoma

0.5%/year develop esophageal adenocarcinoma

(+) low-grade dysplasia HGD/esophageal CA0.5 – 13.4%/patient/year

(+) high-grade dysplasia esophageal CA6%/patient/year

Barrett’s esophagus is associated with ↓ quality of life.

However, impact on life expectancy is low.

Barrett’s Esophagus (BE)

Epidemiology and Risk FactorsPrevalence 23 – 376/100,000

Another estimate: 1.6% of the population

Symptomatic (i.e. GERD): 2 – 18%

Risk Factors:Age ≥ 50

Male (2:1)

White raceUncommon in blacks, Asians

Chronic GERD (> 10 years)

Hiatus hernia

Elevated BMI

Intra-abdominal distribution of body fat


Clinical PresentationGERD

Heartburn, regurgitation

Chest pain, cough, sore throat, water brash

Esophagitis, esophageal ulcers, strictures

Asymptomatic*44% of with patients with BE have not had troublesome heartburn and/or acid regurgitation in the past 3 months


DiagnosisNot a clinical diagnosis

Upper endoscopy (EGD) must be performed.

Two criteria must be met to diagnose BE:1. Endoscopic evidence of columnar-

appearing epithelium lining the distal esophagus above the GEJ

2. Histological biopsies from this area must show specialized intestinal metaplasia (goblet cells)

4 quadrant biopsies every 1-2cm

What is an EGD?(Esophagastroduodenoscopy)

Patient administered topical anesthetic and/or conscious sedation

Flexible, fiber optic camera inserted into the oral cavity and guided down into the esophagus, stomach and duodenum

Instrument maneuvered by torqueing tube or using directional dials

Other features:

Air insufflation

Lens flush

Suction

Working channel

biopsies, snares, injections, cautery

Digital pictures, zoom, narrow band imaging


Endoscopy (1)

Normal Barrett’s

Barrett’s

Barrett’s Esophagus (BE)Pathology

ESOPHAGUS

Squamous

epithelium

Submucosa

with mucus secreting glands

Muscularis propria (inner circular and outer longitudinal layers )

GEJ

Gastroesophageal junctionSquamous epithelium Gastric cardia columnar epithelium

ESOPHAGITIS

Epithelial damage due to inflammation

Most common cause is gastroesophageal reflux -GERD- (reflux of gastric contents into lower esophagus)

Infectious causes are much less common - Candida, herpes virus, CMV, bacteria (immunocompromised)

Chemical (erosive) esophagitis - acids, alkali

Eosinophilic esophagitis

GERD - Reflux esophagitis

Most common; due to reflux of gastric contents into lower esophagus

Physiology: chronic exposure to gastric juices (acid) impairs reparative capacity of esophageal mucosa

Gross: severe cases exhibit hyperemic mucosa with focal hemorrhage

hyperemia

GERD

elongated vascular papillae

basal cell hyperplasia intraepithelial eosinophils

normal

Barrett’s esophagus

Distal squamous mucosa is replaced by columnar epithelium with goblet cells (small intestinal type) as a response to prolonged injury = intestinal metaplasia

Columnar epithelium may be more resistant to acid, pepsin and bile

Metaplasia = replacement of one type of normal epithelium by another type of normal epithelium usually not found at that location

Barrett’s esophagus

Goblet cells

Columnar epithelium with glands

BE Dysplasia

Dysplasia in BE is defined as unequivocal neoplastic epithelium confined to the basement membrane (intraepithelial neoplasia)

Invasion of basement membrane = invasive adenocarcinoma

Risk factors for dysplasia include increasing length of BE and increasing patient age

Pathologically, BE dysplasia is classified as:negative

indefinite

positive for low dysplasia

positive for high-grade dysplasia

adenocarcinoma

BE dysplasia Pathologic Features

Invasive adenocarcinoma

Malignant glands invading the muscularis mucosae


ManagementThree main aspects1. Screening

2. Surveillance

3. InterventionPharmacological

Endoscopic

Surgical


Screening (1)Screening the general population with GERD

NOT recommended

Not enough evidence of benefit40% with esophageal adenocarcinoma have no preceding history of chronic GERD symptoms

Cost-ineffective, given the:

1. High prevalence of GERD (10 - 20% of US pop = GERD weekly)

2. Low incidence of esophageal adenocarcinoma


Screening (2)Targeted screening

Screening populations with high-risk factors

What’s recommended:AGA (2011): Chronic GERD + ≥ 1 risk factor:

age ≥ 50 y.o.

male sex

white race

hiatal hernia

elevated body mass index

intra-abdominal distribution of body fat


SurveillanceRegularly monitoring those with an established diagnosis of BE to detect progression and complications

Evidence does suggest endoscopic surveillance, with proper biopsy protocols, decreases mortality through earlier detection of treatable cancers

Biopsies taken every 1-2cm in 4-quadrant distribution

The more advanced the histology (i.e. low, high grade dysplasia), the more frequently surveillance is performed


Barrett’s Surveillance Guidelines


Intervention (1)Pharmacological Chemoprevention

Proton pump inhibitors (PPIs)Mostly indirect evidence

Acid damages DNA, ↑ proliferation, ↓ apoptosis

Some evidence of inverse relationship between long-term PPI therapy and incidence of dysplasia and adenocarcinoma in BE

Indirect evidence, only, that acid suppression prevents, causes regression of, or prevents progression of BE into esophageal adenocarcinoma

At least a daily PPI is administered

Therapeutic goal: minimum effective dose to achieve control of GERD symptoms and heal reflux esophagitis


Intervention (2)Non-steroidal anti-inflammatory drugs (including aspirin)

↓ proliferation, ↑ apoptosis, ↓ angiogenesis

Some epidemiological studies have shown ↓ risk of adenoCA

However, ↑ risk of bleeding and cardiovascular side effects

Recommend using ASA in patients with cardiovascular risk factors, but not for BE alone

Anti-reflux surgery? (i.e. laparoscopic fundoplication)No evidence it is more effective at preventing CA than medical therapy


Intervention (3)Endoscopic/Surgical

Indication: BE with high grade dysplasia

Choice of intervention dependent on local expertise, patient age, co-morbidities and patient preference


Intervention (4)Surgery - Esophagectomy

Historically, gold standard treatment of BE with high grade dysplasia

Advantage - curative

Disadvantages:

2.5 – 20% mortality rate (depending on volume of center)

High morbidity (32% complication rate)

Dysphagia, early satiety, loss of appetite, fatigue

Most cancers detected in presence of high grade dysplasia are early stage with low risk of metastases (4%)

Less invasive endoscopic treatments are also now available

Bennett et al. (2012) – Consensus statement for HGD in BE

“Endoscopic treatment should be preferred over surgical treatment for management of most patients with HGD in BE”


Intervention (5)


Intervention (6)Advanced Endoscopic techniques

Performed through EGD to:Eliminate dysplasia

Eliminate Barrett’s mucosa

Prevent development of esophageal adenocarcinoma

Achieve reversion to normal squamous epithelium

i.e. Endoscopic Mucosal Resection (EMR)*, Radiofrequency Ablation (RFA)*, Cryotherapy, Photodynamic Therapy (PDT), Thermal Ablation, Endoscopic Submucosal Dissection (ESD)

Some have shown incredible promiseShaheen et al. (2009): RFA eradicated dysplasia in 90.5% with low grade dysplasia, 81% with high grade dysplasia and 77.4% had complete BE eradication


Intervention (7)

Radiofrequency Ablation

Endoscopic Mucosal Resection


Intervention (8)

Case 1 (cont’d)

EGD is performed and reveals columnar-appearing epithelium above the GEJ. Biopsies confirm BE with low grade dysplasia.

Repeat endoscopy 6 months later confirms the same.

He is placed on a PPI daily and is advised to return yearly for EGD surveillance.

Case 2 (1)

Patient, unfortunately, does not return for follow-up.

10 years later he is re-referred for progressive, new onset solid food dysphagia, weight loss and anorexia.

Bloodwork reveals a microcytic anemia with low ferritin.

Case 2 (2)EGD reveals…

Esophageal Cancer

Two main types:Adenocarcinoma

Squamous cell carcinoma

1960’s90% of esophageal CA = squamous cell carcinoma

1986 – 2006 (Canada)Incidence of esophageal adenocarcinoma

↑ 4%/year

Incidence of squamous cell carcinoma↓ 3%/year

Esophageal CancerEpidemiology

Squamous Cell Carcinoma

Highest incidence: Asia, Africa, Iran

1.4 – 140/100,000

Incidence in US: 3/100,000Highest among african-americans (28.6/100,000)

Low incidence areasMore common in males

High incidence areasMales = females

Adenocarcinoma

Incidence in US: 5.31/100,000

Males > females (8:1)

Whites > blacks (5:1)

Esophageal CancerMajor Risk Factors

Squamous Cell Carcinoma

Smoking (OR 9.3)

Alcohol (> 170g/week)

Diet↓ fruits, vegetables

↑ n-nitrosamines – pickled vegetables, betel nut

hot foods/beverages

Pre-existing esophageal disorders

Achalasia, caustic injury, HPV, tylosis, previous aerodigestive squamous cell cancer

Adenocarcinoma

GERD (OR 7.7)Long-standing (OR 43.5)

> 50% have no history of symptomatic reflux

Smoking (OR 1.96)

Obesity (OR 2.78; BMI ≥ 30)

90%

Esophageal CancerClinical Manifestations

Age > 50

Progressive solid food dysphagia

Unintentional weight loss

Anorexia

Retrosternal discomfort

Iron deficiency anemia

Advanced stages:

Sialorrhea, hoarseness, aspiration pneumonia, UGI hemorrhage

40% - NO history of chronic GERD symptoms

Malignancy until proven otherwise

Diagnosis

Upper Endoscopy + multiple biopsies

Sensitivity: 96%

Radiological studies Only adjunctive and mostly for staging

Barium Swallow

CT scan

DiagnosisEGD

EarlySuperficial plaques, nodules, ulcerations

AdvancedStrictures, ulcerations, circumferential mass

DiagnosisStaging by Imaging (1)

Staging

Classifying severity/extent of disease, in terms of depth of invasion and spread to lymph nodes and distant sites

Determines prognosis and options for treatment

Investigations:

Computed Tomography (chest and abdomen)

Rule out metastases + (evaluate primary tumour)

Less useful for regional (T, N) staging

DiagnosisStaging by Imaging (2)

Endoscopic ultrasound (EUS)

Ultrasound transducer built into modified endoscope

Most accurate (90%) for:

Depth of invasion (T)

Lymph node involvement (N)

Allows tissue sampling via fine needle aspiration

Limited by availability and expertise

Positron Emission Tomography

More sensitive for detection of distant metastases than CT

Limited by availability

Endoscopic Mucosal Resection

Accurate for depth of invasion

Limited by availability and expertise

Esophageal CancerPathology

Adenocarcinoma of the Gastroesophageal Junction

SQUAMOUS CELL CARCINOMA

SQUAMOUS CELL CARCINOMA

Islands/nests of malignant squamous cells

NO gland formation

DiagnosisStaging by Pathology

TNM Staging SystemT = depth of invasion of primary tumour

N = regional lymph node metastases

M = distant metastases

Treatment (1)

Dependent on age, disease stage, co-morbidities, patient preference and local expertise

Curative or palliative

CurativeStage 0, I, IIA (Early)

Surgical esophagectomy

Treatment of choice in otherwise healthy patients

Mortality: 2%

Morbidity: 39%

Dysphagia, cough, reflux

Treatment (2)

Endoscopic TechniquesEndoscopic Mucosal Resection (EMR)

Cancer limited to mucosa (T1a)91 – 98% eradication

Preferred in elderly, multiple comorbidities, high surgical risk, patient preference

Endoscopic Submucosal Dissection (ESD) (T1b)

80% curative

Chemotherapy/RadiationThose ineligible for surgery or endoscopic techniques

Stage IIB, III (regionally advanced)Chemotherapy, radiation and surgery or palliation

Treatment (3)

PalliativeNon-curative

Stage IV (distant metastases)

Radiation+/-Chemotherapy

Esophageal dilation/stentingRelieve dysphagia

Close tracheoesophageal fistulas

Tumour ablation for debulkingEtOH injection, photodynamic therapy, argon plasma coagulation, cryotherapy

Enteral feeding (i.e. gastrostomy tubes)

Prognosis

Five-year survivalStage I – 60%

Stage II – 31%

Stage III – 20%

Stage IV – 4%

50 – 60% of patients present with incurable disease

Case 3

20 y.o. male presents with 5-year history of intermittent solid food dysphagia.

Denies heartburn, regurgitation, weight loss.

Past medical history:Asthma, multiple food allergies.

Started on a PPI by his family MD with little improvement.

Case 3EGD

Eosinophilic Esophagitis (EE)

Definition:Chronic immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.

Common cause of dysphagia and heartburn unresponsive to antireflux therapy.

Clinical and pathologic parameters must be considered together (not independently)

Eosinophilic EsophagitisPathophysiology

Esophagus normally devoid of eosinophils

Esophagus is immunologically active:Exposure to stimulus (i.e. food allergen) induces recruitment of eosinophils in genetically predisposed individual

Leads to esophageal inflammation, fibrosis and subsequent dysphagia

Eosinophilic EsophagitisEpidemiology

Incidence:Pediatric - 1.28/10,000/yr

Adult (Swiss) - 1.438 cases/100,000/yr

Prevalence:Pediatric - 4.296/10,000

Adult (US) - 55/100,000

Studies show ↑‘ing incidence and prevalence:↑’d occurrence vs. ↑’d recognition?

Most agree that ↑ incidence cannot be fully accounted by only ↑ recognition.

Eosinophilic EsophagitisClinical Features

Demographics (adult):

Age: 3rd or 4th decade

Sex: Male:Female = 3:1

Mostly caucasian

Symptoms (adults):Dysphagia (63 - 93%)

Food impaction (31 - 62%)

Heartburn (17 - 24%)

Other:

Non-cardiac chest pain (4%)

Odynophagia

Vomiting

Upper abdominal pain (3%)

Demographics (children):

Age: 10.5 ± 5.4 yrs

Sex: Male:Female = 3:1

Mostly caucasian

Symptoms (children)

Vary according to age:

Dysphagia (27%)

Vomiting (26%)

Abdominal pain (26%)

Feeding disorder (14%)

Food impaction (7%)

Eosinophilic EsophagitisClinical Features - Associations

AdultsAllergic history (46 - 52%)

Atopic dermatitis, allergic rhinitis, allergic conjunctivitis

Asthma - 15%

Food allergy - 25%

Family Hx:

EE (5%)

ChildrenRhinoconjunctivitis (57%)

Wheezing (37%)

Food allergy (46%)

Family Hx:

Atopy (74%)

EE (7%)

Esoph. dilatation (10%)

Eosinophilic EsophagitisEndoscopy

Normal (8.8%)

Mucosal fragility/edema (59.3%)

Ringed esophagus (49.2%)Trachealization

Strictures (39.7%)

White pinpoint exudates/plaques (15.7%)

Linear furrows

‘Too small esophagus’Diffuse esophageal narrowing

Eosinophilic EsophagitisDiagnosis (1)

Dependent on clinical AND pathologic criteria

Criteria:Symptoms related to esophageal dysfunction.

Eosinophil-predominant inflammation on esophageal biopsy (≥ 15 eos/hpf).

Mucosal eosinophilia isolated to esophagus and persists after PPI trial (at least 8 weeks).

Secondary causes of esophageal eosinophilia excluded.(See next slide)

2-4 biopsies taken from upper (proximal) and lower (distal) esophagus.

Eosinophilic EsophagitisDiagnosis (2)

Eosinophilic Esophagitis

Pathology

Eosinophilic EsophagitisPathological Features

1. Intraepithelial eosinophils :• > 15 eosinophils in > 2 high power fields (HPF =

400x) or, • > 25 eosinophils in any HPF

2. Eosinophilic microabscesses (42%), often with large clusters near surface

3. Elongated fibrovascular papillae4. Basal cell hyperplasia5. These changes are present at lower as well as

upper esophagus!!!

Eosinophilic Esophagitis

Eosinophilic EsophagitisOverview of Treatment

Topical Corticosteroids

Dietary elimination/restriction

Acid suppression

(Esophageal dilatation)

Others:Systemic corticosteroids, leukotriene inhibitors, anti-Interleukin-5 antibody therapy

Eosinophilic EsophagitisTopical Steroids

i.e. fluticasone, budesonide.

Steroids that are swallowed not inhaled.

Decreases eosinophilia and inflammation.

8-week course

Efficacy: @ 4 months: complete resolution solid food dysphagia = 100%

@ 1 year: symptom recurrence = 14%

Maintenance therapyCould be considered for severe dysphagia, food impaction, high-grade stricture, rapid symptomatic relapse following initial therapy.

Eosinophilic EsophagitisAcid Suppression

Superimposed acid reflux may irritate EEMay improve symptoms up to 70% of patients.

May improve histology in 30 – 50% of patients.

Mechanism (possible):Acid may dilate intracellular spaces → allergen permeation → eosinophilia

PPIs may have anti-inflammatory effects

Empiric PPI therapy should be tried if not done already

Eosinophilic EsophagitisDietary Elimination/Restriction

Food and environmental allergen avoidance

Children – routinely first-line therapy

77% - Responders (<5 eos/hpf)

10% - Non-responders

13% - Improvement (↓ eos/hpf)

Adults – not as effective

However, some improvement in symptoms and esophageal eosinophilia

Determining which foods to avoid?

Allergist referral or,

6-food elimination diet

Milk, soy, eggs, nuts/tree nuts, fish/shellfish, wheat

Eosinophilic EsophagitisPrognosis

Straumann et al. followed 30 adults for mean 7.5 years

Stable or increasing dysphagia - 60%

No impact on survival, nutritional status or development of systemic disorders including malignancy

Case 3 (cont’d)

Patient is placed on a 6 week course of fluticasone with complete resolution of his symptoms.

Repeat EGD shows persistent rings, but given absence of dysphagia and risk of perforation, these are not dilated.

Currently being followed.

Questions?

clinical pathological conference: barrett’s esophagus and esophageal carcinoma ralph lee,...

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