Pathology of the Esophagus

Presented by:

Dr Barkam NagaRaju

MD(General Medicine)

Outline of Content

• Normal anatomy and histology• Congenital and acquired malformations• Lesions associated with motor dysfunction• Esophagitis• Barrett esophagus • Esophageal varices• Benign neoplasms and tumor-like lesions• Malignant neoplasms and staging

Normal anatomy/physiology

• Muscular tube from pharynx (C6) to esophageal-gastric junction, about 25 cm long

• Endoscopy: defined as 15-40 cm from incisor teeth

• Two areas of increased intraluminal pressure that normally remain contracted at rest:• Upper esophageal sphincter: 3 cm segment at

cricopharyngeus muscle• Lower esophageal sphincter (LES): 3-5 cm

segment of thickened smooth muscle around diaphragmatic esophageal hiatus, just proximal to histologic EG junction

Normal Histology and Pathologic Correlations• Mucosa: nonkeratinized

squamous; basal zone is 10-15% of thickness

• Lymphocytes: CD8 T cells in epithelium; CD4 T cells and B cells in lamina propria

• Muscularis mucosa: smooth muscle between mucosa and submucosa

• Submucosal mucous glands: mainly proximal & distal esophagus

• Muscularis propria: skel. muscle upper 1/3 (voluntary swallow); sm. muscle lower 1/3; middle 1/3 mixed

• Myenteric nerve plexus: between circular inner and longitudinal outer layers of muscularis propria

• Serosa: mostly absent, facilitating spread of invasive tumors or infections into mediastinum

Normal smooth gray-white squamous mucosa of esophagus

3 parts of mucosa?

1)

2)

3)muscularis propria

submucosa

mucosa

Esophageal-gastric junction

Congenital & Acquired Malformations

Ectopias

Atresias

Stenoses

Duplications

Webs and Rings

Congenital Malformations

Ectopias; About 4% of persons by endoscopic exam

“inlet patch” of gastric-type epithelium replaces squamous, just below upper esophageal sphincter

• Atresias; atresia = segment reduced to thin cord, no lumen

• • 1/1000 live births

• • usually near tracheal bifurcation, usually with associated tracheal-esophageal fistula

• • mechanism: failed septation of foregut

• • symptoms: regurgitation, paroxysmal choking, aspiration of liquid into lungs

Ectopic gastric mucosa

Endoscopy: red patch within otherwise gray mucosa

Biopsy: normal appearing gastric-type mucosa

Atresia and tracheo-esophageal fistula: 5 types

Which two cause paroxysms of coughing upon

baby’s first feeding? ________ A B

C D E

Which one is the most common type, and causes immediate regurgitation upon baby’s first feeding? _________

All need immediate surgical correction

Congenital & Acquired Malformations Stenoses:(narrowing of a duct or

passage)Usually acquired due to chronic gastro-esophageal reflux, radiation, or ingested caustic substances; result in progressive dysphagia

Duplications: • congenital duplication cysts of 60% occur in lower esophagus

• Lined by epithelium (squamous, gastric, or respiratory type) with smooth muscle wall

• Imaging studies: differential diagnosis includes other thoracic cysts (bronchogenic, thymic, thyroidal)

Acquired Malformations• Webs: • usually women > 40 years old

• web: a mucosal fold (2-4 mm thick)

• which protrudes into the lumen, causing dysphagia with solid foods

• Plummer-Vinson syndrome

• dysphagia due to upper esophageal web + Fe deficiency anemia + glossitis

• • mucosal abnormalities: glossitis and angular stomatitis (mouth) secondary to mucosal atrophy associated with Fe lack • in P-V syndrome, chronic iron-deficiency anemia precedes development of web, but how or whether Fe deficiency causes the web to form is controversial • associated with increased risk for squamous carcinoma in oral cavity, hypopharynx, and esophagu

WEBGlossitis with angular stomatitis

Plummer-Vinson syndrome: potential sequela

upper esophageal web

Endoscopic view of esophagus: ulcerated and nodular mass

What is the most likely diagnosis for this mass lesion?

What is the most likely diagnosis for this mass lesion?

Courtesy www.gastrointestinalatlas.com

Schatzki’s Ring

barium swallow esophagram endoscopic view

Circumferential ring in lower esophagus near EG junction; thicker than webs (may contain hyperplastic muscularis propria) dysphagia

Lesions affecting motor function

Achalasia Sliding hiatal hernia

Rolling hiatal hernia

Zenker diverticulum Epiphrenic

diverticulum

Mallory-Weiss tear

Diverticula• Definition: outpouching

comprised of all visceral layers (mucosa, submucosa, muscularis)

• Sites: hypopharynx, thoracic, epiphrenic

• Pathogenesis• Congenital: embryologic defect• Traction: fibrous scarring of soft

tissue adherent to serosa, pulling wall of esophagus outward

• Pulsion: unclear mechanism; potentially weak area at junction of pharyngeal constrictors (Killian’s triangle) allowing diverticulum to develop in response to increased intraluminal pressure.

Zenker’s Diverticulum• 27 cases described in 1877 by Zenker &

Ziemssen• Most common esophageal

diverticulum• Pathogenesis: pulsion explanation favored

(increased pressure in lumen forces tissue through weak spot in muscle layer)

• Location: hypopharynx of older persons (superior to upper esophageal sphincter)

• May become large and sequester food, with regurgitation or mass effect in the neck

• Treatment: surgical resection of larger lesions

Zenker’s Diverticulum (pulsion)

Barium swallow esophagram Resection of upper esophagus

Less common diverticula• Traction • Usually small, mid-esophagus• Few symptoms • Pathogenesis: uncertain; motor disorder or

post-inflammatory fibrosis• Epiphrenic

• Just above LES, may be wide-mouthed; 1-10 cm. diameter

• Pathogenesis: majority of patients have motility disorder (achalasia or diffuse esophageal spasm)

• Symptoms: nocturnal regurgitation of large volumes of fluid

• Treatment: resection large ones; address motor disorder

Epiphrenic diverticulum

Achalasia• Swallowing disorder defined by 3 major problems

• Aperistalsis

• Incomplete relaxation LES with swallowing

• Increased resting tone of LES (impaired relaxation)

• Pathogenesis: normally, distal inhibitory neurons and interruption of cholinergic signals allow relaxation of LES. Degenerative failure of inhibitory neurons impaired relaxation. Usually primary (idiopathic), but also secondary to malignancy, amyloidosis, sarcoidosis, Chagas disease

• Symptoms:

• progressive dysphagia; nocturnal regurgitation of food

• Treatment: surgical myotomy with balloon dilation of LES

• Sequelae:

• 5% develop squamous carcinoma

• epiphrenic diverticulum, aspiration pneumonitis

Achalasia

Pathology: progressive dilation of esophagus, proximal to an abnormal segment which is functionally denervated

Hiatal Hernia• Definition: pouch of proximal stomach extending

>2cm above diaphragmatic hiatus into thorax• Incidence: VERY COMMON, 15-50% adults

(depending on strictness of definition); incidence increases with age

• Types• Sliding: 95%; stomach and esophagus bulge through

hiatus together• Paraesophageal: 5%; stomach alone herniates

adjacent to esophagus• Complications

• Reflux esophagitis (to be discussed)• Incarceration: more likely in paraesophageal;

uncommon in sliding• Treatment: surgery for paraesophageal HH; degree of

morbidity determines medical vs. surgical therapy for sliding

Hiatal Hernia, sliding typeAnatomy: widened space between muscular crura of diaphragm and wall of esophagus

Pathogenesis: unknown; possible congenital weakness (some children have HH) combined with acquired defect

Symptoms: Only 10-20% of adults with anatomically demonstrable sliding HH have “heartburn” (substernal pain caused by regurgitation of gastric juices into esophagus)

Lacerations (Mallory-Weiss syndrome)

• Def: linear lacerations in mucosa near EG junction

• Pathogenesis: presumably mechanical trauma due to prolonged retching; failure of E-G muscular relaxation

• Risk factors: EtOH binges; prolonged vomiting

• Pathology: mucosal defect of variable depth

• Complications: mild to massive hemorrhage, ulceration or perforation, mediastinitis, rarely rupture of esophagus (Boerhaave syndrome)

• Therapy: usually supportive because bleeding often stops spontaneously. May need endoscopic coagulation, balloon tamponade, or rarely surgery.

Mallory-Weiss laceration

Endoscopy: laceration straddling the squamo-columnar junction

Surgical resection of distal esophagus and proximal stomach for uncontrolled hemorrhage caused by Mallory-Weiss laceration

Esophagitis

Reflux Esophagitis

Infectious Esophagitis

Chemical/Physical Esophagitis

Eosinophilic EsophagitisEosinophilic Esophagitis

Reflux esophagitis• Def: mucosal injury secondary to reflux of acidic

gastric contents into lower esophagus; clinical term is GERD (gastroesophageal reflux disease)

• Incidence: 5% U.S. adults (millions of people!)• Clinical features: “heartburn”, chest pain mimicking

MI, regurgitation, dysphagia• Complications: ulceration, stricture, Barrett’s

metaplasia• Pathogenesis: decreased LES tone or increased

abdominal pressure• Risk factors

• sliding hiatal hernia• delayed gastric emptying increased gastric

volume• obesity• CNS depressant drugs; EtOH abuse, smoking

Histopathology of Reflux EsophagitisEvidence of mild acute injury: • Reactive squamous hyperplasia • Scattered eosinophils or neutrophils within mucosa

More severe acute reflux injury: mucosal ulceration

Evidence chronic reflux injury: • basal zone hyperplasia (early) • Barrett intestinal metaplasia (later)

Chronic Reflux: hyperplastic basal layer comprises > 20% of mucosal thickness (normal basal layer is < 20% of mucosal thickness)

PBD 8th ed, Elsevier 2010

• most commonly seen in immunocompromised patients • three organisms comprise >90% esophageal infections

1) Candida: Endoscopy shows white patches

Silver stain: pseudohyphae in squamous mucosa

2) Herpes simplex, ground glass nuclei, intranuclear inclusions in squamous cells, multinucleated cells

3) CMV, large intranuclear basophilic inclusions in endothelial or stromal cells; dot-like cytoplasmic inclusions

Infectious Esophagitis

• most commonly seen in immunocompromised patients

• three organisms comprise >90% esophageal infections

1) Candida: Endoscopy shows white patches

Silver stain: pseudohyphae in squamous mucosa

2) Herpes simplex, ground glass nuclei, intranuclear inclusions in squamous cells, multinucleated cells

3) CMV, large intranuclear basophilic inclusions in endothelial or stromal cells; dot-like cytoplasmic inclusions

Chemical/Physical EsophagitisCauses:

Ethanol abuse, heavy smoking

Acid or alkali (accidental or suicide attempt)

Very hot tea

Chronic uremia

Chemotherapy

Post-radiation therapy for tumors

Post-arsenic ingestion Post-radiation Therapy (stricture)

Eosinophilic Esophagitis

Path: abundant intraepithelial eosinophils

Symptoms: dysphagia (adults); reflux-like (children)

Associations: hypersensitivity (atopic dermatitis, allergic rhinitis, asthma)

Peripheral blood eosinophilia

Must prove absence of reflux to make this diagnosis

Fig. 17-5B, PBD 8th, 2010Fig. 17-5B, PBD 8th, 2010

Barrett esophagus (BE)• Definition (2 criteria):

• (1) endoscopic evidence of abnormal mucosa above EG junction (clinical criterion)

• (2) intestinal metaplasia of squamous mucosa in biopsies of esophagus (pathologic criterion)

• Pathogenesis

• Precise molecular mechanisms unclear

• Acid reflux inflammation chronic mucosal injury metaplasia into more acid-resistant epithelium

• Clinical: BE develops in 10-20% those with symptomatic chronic reflux esophagitis; usually presents ages 40-60 after years of chronic GERD.

• MAJOR CONCERN: a minority of patients with BE develop epithelial dysplasia which may progress into adenocarcinoma. Life-long risk of adenocarcinoma is 10-15% in patients with BE, but this risk is 40x that of general population!

Barrett gross pathology: red granular mucosa

Long segment (>3cm) Short segment (< 3cm, near EG jct)

Long segment

Metaplasia = gray hatched areas

Natural History of Barrett Esophagus• Not completely predictable, but well-studied

• Four histopathologic categories predict risk for future development of adenocarcinoma• Negative for dysplasia (intestinal metaplasia only)• Indefinite for dysplasia (unclear: inflammation or

dysplasia)• Low-grade dysplasia• High-grade dysplasia

• Some things are known• Low-grade dysplasia progresses to high-grade within 5

years in 10-30% patients. ** • Many low-grade dysplasias are not present on

subsequent endoscopic biopsies (regression or sampling error?) *

• High-grade dysplasia progresses to invasive adenocarcinoma in 30-60% patients within 5 years. **

* Sharma, Barrett’s Esophagus, NEJM 361:2548, 2009 ** Spechler, Barrett’s Esophagus, NEJM 346:836-842, 2002

Barrett esophagus: histopathology 1

Diagnosis: intestinal metaplasia, negative for dysplasia

Diagnosis: intestinal metaplasia, indefinite for dysplasia (reactive inflammatory changes vs. low-grade dysplasia

Barrett’s: histopathology 2

Diagnosis: intestinal metaplasia with low grade dysplasia

Diagnosis: intestinal metaplasia with high grade dysplasia

Sharma P. N Engl J Med 2009;361:2548-2556

Proposed Treatment Algorithm for Patients

with Barrett's Esophagus

Esophageal Varices

• Definition: permanently dilated submucosal veins

• Pathogenesis

• Normal venous circulation: GI tract to liver to inferior vena cava

• Chronic portal venous hypertension development of collateral bypass channels (portal venous blood diverted into esophageal plexus, then azygos veins, then superior vena cava)

• Clinical setting: cirrhosis with portal venous hypertension

• Clinical presentation

• No symptoms until varices rupture!!

• 40% die during first bleeding episode

• If survive first episode, 50% re-bleed in one year

• Cause of death: hypovolemic shock multi-organ failure

• Rx: replace intravascular volume, give packed RBCs, stop bleeding

Esophageal varices: pathologyDilated blue varices beneath intact squamous mucosa

Hemorrhage secondary to ruptured varices (KMC autopsy)

EG junction

Benign neoplasms & tumor-like lesions

• Esophageal benign neoplasms are mostly of mesenchymal origin (non-epithelial): leiomyomas, lipomas, hemangiomas, neurofibromas.

• Two distinctive lesions:

• Fibrovascular polyp

• Squamous papilloma

Esophageal Carcinoma

•Squamouscell carcinomas •Adenocarcinomas •Worldwide, squamouscell carcinomas constitute 90% of esophageal cancers, but in the United States there has been a very large increase (three-to fivefold in the last 40 years) in the incidence of adenocarcinomas associated with Barrett esophagus.

SquamousCell Carcinoma

•Mucosal epithelial dysplasia •Carcinoma in situ •Invasive cancer •Polypoidexophyticmasses that protrude into the lumen; •Necrotizing cancerous ulcerations that extend deeply and sometimes erode into the respiratory tree, aorta, or elsewhere; •Diffuse infiltrative neoplasms

A,Large ulcerated squamous cell carcinoma of the esophagus. B,Low power view of cancer invasion of the submucosa.

A B

Adenocarcinoma

•Barrett esophagus is the only recognized precursor of esophageal adenocarcinoma. •Large nodular masses •Deeply ulcerative •Diffusely infiltrative features •Mucin-producing glandular tumors

Clinical Features •Esophageal carcinoma is insidious in onset and

produces dysphagiaand obstruction gradually and late. •Weight loss, anorexia, fatigue, and weakness appear, followed by pain, usually related to swallowing. •Diagnosis is usually made by imaging techniques and endoscopic biopsy. •Surgical excision is rarely curative. •Esophageal cancer confined to the mucosa or submucosais amenable to surgical treatment.

Fibrovascular polyp

Is this a neoplasm or exuberant hyperplasia?

Presentation: dysphagia; lesion usually in upper 1/3 esophagus

Histopathology: abundant vascularized connective tissue covered by squamous mucosa

Squamous papilloma

Some have HPV-related cytologic changes or evidence of HPV DNA by in-situ hybridization methods

Low magnification: fronds of thickened squamous epithelium supported by connective tissue cores

If squamous papilloma identified, respiratory tract should be examined for HPV-related papillomatosis (especially children)

Malignant neoplasms of esophagus: overview

• Malignant tumors of esophagus comprise 6% of all gastrointestinal cancers, but account for 10% GI cancer mortality

• Problem: often asymptomatic until late, when they are deeply invasive or already metastatic

• Worldwide: 90% squamous / 10% adenocarcinoma

• U.S.: 50% squamous / 50% adenocarcinoma; incidence of adenocarcinoma rising steadily since 1970, almost always arising in Barrett esophagus

Squamous Carcinoma Descriptor AdenocarcinomaM:F = 4:1; high incidence Iran, China, Puerto Rico (environmental initiators)

Epidemiology M:F = 7:1; >95% from Barrett metaplasia; <5% from submucosal glands

Initiators: environmental carcinogens; promoters: nutritional deficiencies (vitamins A, B1, B2, B6, trace metals)

Pathogenesis Barrett dysplasia: early mutation or overexpression of p53; amplfication cERB-B2, cyclin D, cyclin E

Ethanol, tobacco, achalasia, chronic esophagitis, Plummer-Vinson syndrome

Clinical Risk Factors

chronic reflux esophagitis tobacco, obesity

20% upper third 50% middle third

30% lower third

Anatomic Distribution

>95% lower third

5 yr. survival: 5-10%

--75% 5 yr. survival if T1 lesion

--25% 5 yr. survival for all cases subjected to surgery

Prognosis 5 yr. survival: 25%

>80% 5 yr. survival with esophagectomy for T1 lesion

Staging esophageal carcinoma

Squamous carcinoma: putative carcinogenesis

Fig. 1.21, Tumors of Digestive System, IARC Press, 2000.

Squamous CA: gross pathology

Exophytic polypoid (obstructing lesion)

Ulcerated stricture (dysphagia)

Early, superficial T1 lesion, good prognosis

Adenocarcinoma: gross pathology

Barrett associated adenocarcinoma:

circumferential papillary lesion (left)

ulcerated polypoid lesion (right)

Adenocarcinoma: early invasive lesions developing in setting of high grade dysplasia

Adenocarcinoma invading submucosa, T1 lesion (circled), arising in Barrett intestinal metaplasia with high-grade dysplasia (right half)

High-grade dysplasia with single dysplastic cell invading lamina propria (intramucosal adenocarcinoma = T1)

left photo courtesy University of Washington department pathology; right photo courtesy University of Pittsburgh department pathology

Invasive Adenocarcinoma arising in Barrett esophagus

Fig. 17-11B, Pathologic Basis of Disease, 7th ed, Elsevier 2005

Intestinal metaplasia with dysplasia (red)

Malignant glands invading into submucosa (black)