Pathology of the Esophagus,,,,,,,,,,,,,,,,,,,,,,,,by urs Dr N.D

1. Pathology of the
esoPhagus
Presented by:
Dr Barkam Nagaraju
MD(General Medicine)

2. 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

3. 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
•

4. 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

5. Esophageal-gastric junction
Normal smooth gray-white
squamous mucosa of esophagus
3 parts of mucosa?
1)
mucosa
submucosa
2)
muscularis propria
3)

6. Congenital & Acquired Malformations
Ectopias
Atresias
Stenoses
Duplications
Webs and Rings

7. 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

8. Ectopic gastric mucosa
Endoscopy: red patch within
otherwise gray mucosa
Biopsy: normal appearing
gastric-type mucosa

9. Atresia and tracheoesophageal fistula:
5 types
Which two cause
paroxysms of
coughing upon
baby’s first feeding?
B
A
________
Which one is the most
common type, and
causes immediate
regurgitation upon
baby’s first feeding?
_________
C
D
E
All need immediate
surgical correction

10. 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)

11. 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

12. WEB
Glossitis with angular stomatitis

13. Plummer-Vinson syndrome:
potential sequela
upper esophageal web
Endoscopic view of
esophagus: ulcerated and
nodular mass
What is the most likely
What is the most likely
diagnosis for this mass
diagnosis for this mass
lesion?
lesion?
Courtesy www.gastrointestinalatlas.com

14. Schatzki’s Ring
Circumferential ring in lower esophagus near EG junction; thicker than
webs (may contain hyperplastic muscularis propria)  dysphagia
barium swallow esophagram
endoscopic view

15. Lesions affecting motor function
Achalasia
Zenker
diverticulum
Sliding
hiatal
hernia
Epiphrenic
diverticulum
Rolling
hiatal
hernia
MalloryWeiss
tear

16. 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.
•

17. 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

18. Zenker’s Diverticulum (pulsion)
Barium swallow esophagram
Resection of upper esophagus

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

20. Epiphrenic diverticulum

21. 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

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

23. 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

24. Hiatal Hernia, sliding
type
Anatomy: 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)

25. 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.

26. 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

27. Esophagitis
Reflux Esophagitis
Infectious Esophagitis
Chemical/Physical Esophagitis
Eosinophilic Esophagitis
Eosinophilic Esophagitis

28. 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

29. Histopathology of Reflux Esophagitis
Evidence of mild acute injury:
• Reactive squamous
hyperplasia • Scattered
eosinophils or neutrophils within
mucosa
PBD 8th ed, Elsevier 2010
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)

30. • 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

31. 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

32. 
2) Herpes simplex, ground glass nuclei,
intranuclear inclusions in squamous cells,
multinucleated cells

33. 
3) CMV, large intranuclear basophilic inclusions in
endothelial or stromal cells; dot-like cytoplasmic
inclusions

34. Chemical/Physical Esophagitis
Causes:
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)

35. 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 8thth,2010
Fig. 17-5B, PBD 8 , 2010

36. 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!

37. Barrett gross pathology: red granular mucosa
Metaplasia = gray hatched areas
Long segment (>3cm)
Short segment
(< 3cm, near EG jct)
Long segment

38. 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

39. Barrett esophagus: histopathology 1
Diagnosis: intestinal
metaplasia, negative for
dysplasia
Diagnosis: intestinal metaplasia,
indefinite for dysplasia (reactive
inflammatory changes vs. lowgrade dysplasia

40. Barrett’s: histopathology 2
Diagnosis: intestinal
metaplasia with low grade
dysplasia
Diagnosis: intestinal
metaplasia with high grade
dysplasia

41. Proposed Treatment
Algorithm for Patients
with Barrett's
Esophagus
Sharma P. N Engl J Med
2009;361:2548-2556

42. 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
•
•
40% die during first bleeding episode
•
If survive first episode, 50% re-bleed in one year
•
•
No symptoms until varices rupture!!
Cause of death: hypovolemic shock ⇒ multi-organ failure
Rx: replace intravascular volume, give packed RBCs, stop bleeding

43. Esophageal varices: pathology
Dilated blue
varices
beneath intact
squamous
mucosa
Hemorrhage
secondary to
ruptured
varices
(KMC autopsy)
EG junction

44. Benign neoplasms & tumorlike lesions
•
Esophageal benign neoplasms are mostly of mesenchymal
origin (non-epithelial): leiomyomas, lipomas,
hemangiomas, neurofibromas.
•
Two distinctive lesions:
•
Fibrovascular polyp
•
Squamous papilloma

45. 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.

46. 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

47. 
A,Large ulcerated squamous cell carcinoma of the
esophagus. B,Low power view of cancer invasion of the
submucosa.
A
B

48. 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.

49. Fibrovascular polyp
Presentation: dysphagia; lesion usually in upper 1/3 esophagus
Histopathology:
abundant
vascularized
connective tissue
covered by
squamous mucosa
Is this a
neoplasm or
exuberant
hyperplasia?

50. Squamous papilloma
Low magnification: fronds of
thickened squamous epithelium
supported by connective tissue cores
Some have HPV-related cytologic
changes or evidence of HPV DNA
by in-situ hybridization methods
If squamous papilloma identified, respiratory tract should be
examined for HPV-related papillomatosis (especially children)

51. 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
•

52. Squamous Carcinoma
Descriptor
Adenocarcinoma
M:F = 4:1; high incidence Iran,
China, Puerto Rico
(environmental initiators)
Epidemiology M:F = 7:1; >95% from
Initiators: environmental
carcinogens; promoters:
nutritional deficiencies
(vitamins A, B1, B2, B6, trace
metals)
Pathogenesis Barrett dysplasia:
Ethanol, tobacco, achalasia,
chronic esophagitis, PlummerVinson 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
Barrett metaplasia; <5%
from submucosal glands
early mutation or
overexpression of p53;
amplfication cERB-B2,
cyclin D, cyclin E

53. Staging esophageal carcinoma

54. Squamous carcinoma: putative carcinogenesis
Fig. 1.21, Tumors of Digestive System, IARC Press, 2000.

55. Squamous CA: gross pathology
Exophytic polypoid (obstructing lesion)
Ulcerated stricture (dysphagia)
Early, superficial T1
lesion, good prognosis

56. Adenocarcinoma: gross pathology
Barrett associated
adenocarcinoma:
circumferential
papillary lesion
(left)
ulcerated polypoid
lesion (right)

57. Adenocarcinoma: early invasive lesions
developing in setting of high grade dysplasia
High-grade dysplasia with
single dysplastic cell invading
lamina propria (intramucosal
adenocarcinoma = T1)
Adenocarcinoma invading submucosa,
T1 lesion (circled), arising in Barrett
intestinal metaplasia with high-grade
dysplasia (right half)
left photo courtesy University of Washington department pathology;
right photo courtesy University of Pittsburgh

58. Invasive Adenocarcinoma arising in Barrett esophagus
Intestinal metaplasia
with dysplasia (red)
Malignant glands invading into
submucosa (black)
Fig. 17-11B, Pathologic Basis of Disease, 7th ed, Elsevier 2005