Esophagus

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Esophagus connects the pharynx to the stomach. It is afflicted by tumours on occasion. Probably the most common affliction is gastroesophageal reflux disease (GERD). Most biopsies revolve around the questions: 1. intestinal metaplasia? 2. dysplasia? and 3. cancer?

Normal esophagus

General:

  • Stratified squamous non-keratinized epithelium.

Normal (esophageal) squamous epithelium:

  • Should "mature" to the surface like good stratified squamous epithelium does.
    • No nuclei at luminal surface.
    • Cells should become less hyperchromatic as you go toward the lumen.
    • Mitoses should be rare and should NOT be above the basal layer.
  • Inflammatory cells should be very rare.

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ESOPHAGUS, DISTAL, BIOPSY:
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC INFLAMMATION.
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Diagnoses

Common

  • Normal.
  • Metaplasia (Barrett's esophagus).
  • Dysplasia.
  • Adenocarcinoma.

Less common

  • Squamous cell carcinoma.
  • Eosinophilic esophagitis.
  • Candidiasis.
  • CMV esophagitis.

Tabular summary

Simplified overview

Entity Key feature Other features IHC/Special Clinical Image
Normal squamous epi. matures to surface no inflammation, no atypia - -
 
Normal esophagus. (WC)
GERD inflammation (eosinophils, lymphocytes) elongated (epithelial) papillae, basal cell hyperplasia incr. risk of Barrett's
Eosinophilic esophagitis abundant eosinophils elongated (epithelial) papillae, basal cell hyperplasia, lymphocytes unresponsive to PPIs
 
Eosinophilic esophagitis. (WC/Nephron)
Barrett's type change goblet cells no dysplasia Alcian blue +ve incr. risk of adenocarcinoma
 
Barrett's esophagus. Alcian blue. (WC)
Dysplasia, low grade nuclear crowding at surface hyperchromasia, mild arch. complexity, no necrosis incr. risk of carcinoma
Dysplasia, high grade cribriforming and/or necrosis nuclei often round & large, hyperchromasia marked incr. risk of carcinoma

Columnar dysplasia

Entity Surface maturation Architecture Cytology Other Clinical Image
Normal matures round glands no nuclear atypia - - Image
Barrett's esophagus matures round glands, normal gland density +/-scant nuclear atypia goblet cells clinical diagnosis Image
Indefinite for columnar dysplasia minimal maturation or cannot see surface round glands, normal gland density mild nuclear atypia, nuclear pseudostratification, no necrosis - follow-up Image
Low-grade columnar dysplasia minimal-to-scant maturation round glands, +/-rare budding, increased gland density mild-to-moderate nuclear atypia, nuclear pseudostratification, no necrosis - follow-up Image
High-grade columnar dysplasia no maturation incr. density of irregular glands with budding and/or rare cribriforming and/or gland dilation moderate-to-marked nuclear atypia (usu. plump round nuclei), hyperchromasia, +/-necrosis - EMR, surgery Image
Intramucosal adenocarcinoma no maturation single cells or back-to-back irregular glands with budding and/or cribriforming and/or gland dilation or glands with long axis along muscularis mucosae moderate-to-marked nuclear atypia - usu. round large nuclei, hyperchromasia, +/-necrosis - EMR, surgery Image

Columnar dysplasia - another table

Feature Indefinite for columnar dysplasia Low-grade columnar dysplasia High-grade columnar dysplasia Intramucosal carcinoma (IMCa) Utility
Depth of glands superficial only superficial only superficial/deep deep low vs. high
Gland density normal near normal increased back-to-back low vs. high vs. IMCa
Gland morphology round round irregular/rare cribriforming irregular/cribriform/sheeting low vs. high vs. IMCa
Necrosis none none may be present may be present low vs. high & IMCa
Hyperchromasia +/- present present present indef. vs. low
Palisaded/crowded nuclei present present absent/present uncommon low vs. high
Round nuclei + enlargement absent absent present/absent present low vs. high
Desmoplasia absent absent absent +/- (uncommon) high vs. IMCa
Surface involvement present (required) present (required) +/- +/- low vs. high

Indications

  • Pyrosis = heartburn.[1]

Infectious esophagitis

Is a relatively common problem, especially in those that live at the margins (EtOH abusers) and immunosuppressed individuals (HIV/AIDS).

Useful stains

Overview

  • Candida - worms.
  • HPV - koilocytes.
  • CMV - large nuclei.
  • HIV - non-specific.

Candida esophagitis

  • AKA esophageal candidiasis.

Gross (endoscopic)

Features:

  • White patches.

DDx (endoscopic):[2]

Microscopic

Features:

  • Worm-like micro-organisms - key feature.
    • Pseudohyphae (single cells).
    • Thickness ~ 1/3-1/2 of squamous cell nucleus.
    • Should be within (squamous) epithelium.
  • Superficial inflammation - esp. neutrophils - important.

Notes:

  • On top of epithelium does not count,[3] i.e. it is likely an artifact.
  • Bacilli and cocci may accompany the candida. They are typically ignored.

DDx:

Image

Sign out

ESOPHAGUS, BIOPSY:
- ESOPHAGITIS WITH FUNGAL ORGANISMS CONSISTENT WITH CANDIDA.
ESOPHAGUS, BIOPSY:
- ACUTE ESOPHAGITIS WITH FUNGAL ORGANISMS CONSISTENT WITH CANDIDA.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA.

Cytomegalovirus esophagitis

Microscopic

Features:

  • Classically at the base of the ulcer; within endothelial cells - key point.

Note:

  • Biopsying the the base of an ulcer usually just yields (non-diagnostic) necrotic debris; so, clinicians are told to biopsy the edge of the lesion. A suspected CMV infection is the exception to this rule!

Herpes esophagitis

General

Etiology:

Gross/endoscopic

Features:

  • Ulcers with a "punched-out" appearance with a brown/red edge.
Images

www:

Microscopic

Features (3 Ms):

  • Moulding.
  • Multinucleation.
  • Margination of chromatin.
Images

Human papillomavirus esophagitis

General:

Microscopic

Features:

  • Koilocytes:
    • Perinuclear clearing.
    • Nuclear changes.
      • Size similar (or larger) to those in the basal layer of the epithelium.
      • Nuclear enlargement should be evident on low power, i.e. 25x. [7]
      • Central location - nucleus should be smack in the middle of the cell.

Images:

Other

The group of conditions doesn't fit neatly with the others. It is a mixture of different non-neoplastic conditions.

Gastroesophageal reflux disease

  • Abbreviated GERD or GORD (gastro-oesophageal reflux disease).

General

Clinical:

  • Usually chest pain
  • +/-Abdominal pain.
  • +/-Vomiting.
  • +/-Blood loss.

Treatment:

  • Treated with proton pump inhibitors (PPIs).

DDx (clinical):

Gross

  • Erythema.
  • Erosions.
  • +/-Ulceration.

Note:

  • Many be graded using Savary-Miller classification.

Images:

Microscopic

Features:

  1. Basal cell hyperplasia;[4] > 3 cells thick or >15% of epithelial thickness.
  2. Papillae elongated; papillae reach into the top 1/3 of the epithelial layer.[5]
  3. Inflammation, esp. eosinophils, lymphocytes with convoluted nuclei ("squiggle cells").
  4. +/-Intraepithelial edema.
  5. +/-Apoptotic cells.[6]

Notes:

  • Intraepithelial cells with irregular nuclear contours, "squiggle cells" (T lymphocytes[7]), may mimic neutrophils.
  • Changes may be focal.

DDx:

Images:

Sign out

Poorly oriented

ESOPHAGUS, BIOPSY:
- SQUAMOUS MUCOSA WITH BASAL CELL HYPERPLASIA, INTRAEPITHELIAL EDEMA AND RARE INTRAEPITHELIAL 
EOSINOPHILS -- COMPATIBLE WITH GASTROESOPHAGEAL REFLUX.

Columnar epithelium present

ESOPHAGUS, BIOPSY:
- SQUAMOUS MUCOSA WITH BASAL CELL HYPERPLASIA, INTRAEPITHELIAL EDEMA AND RARE INTRAEPITHELIAL 
EOSINOPHILS -- COMPATIBLE WITH GASTROESOPHAGEAL REFLUX.
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC INACTIVE INFLAMMATION.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Ulceration present

ESOPHAGUS, DISTAL, BIOPSY:
- SQUAMOUS MUCOSA WITH BASAL CELL HYPERPLASIA, INTRAEPITHELIAL EDEMA, RARE
  INTRAEPITHELIAL EOSINOPHILS AND EVIDENCE OF ULCERATION -- COMPATIBLE WITH
  GASTROESOPHAGEAL REFLUX.
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC INACTIVE INFLAMMATION.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

COMMENT:
PAS-D staining is negative for microorganisms.

BE and GERD present

ESOPHAGUS (DISTAL), BIOPSY:
- COLUMNAR EPITHELIUM WITH INTESTINAL METAPLASIA AND MODERATE CHRONIC INFLAMMATION,
  SEE COMMENT.
- SQUAMOUS MUCOSA WITH BASAL CELL HYPERPLASIA, INTRAEPITHELIAL EDEMA AND RARE
  INTRAEPITHELIAL EOSINOPHILS -- COMPATIBLE WITH GASTROESOPHAGEAL REFLUX.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

COMMENT:
The findings are consistent with Barrett's esophagus in the appropriate endoscopic setting.

Eosinophilic esophagitis

  • Abbreviated EE.

General

  • The current thinking is that it is a clinico-pathologic diagnosis.[8]

Clinical:

Treatment:

  • Avoid exacerbating antigens.
  • Topical corticosteroids, e.g. fluticasone.
  • Do not respond to proton pump inhibitors.

Biopsies:

  • Should be taken from: upper, mid, lower and submitted in separate containers (eosinophilia present through-out-- to differentiate from GERD).

Associations:

Gross/endoscopic

  • Trachealization; eosphagus looks like trachea.[14]
  • White.

DDx (endoscopic):

Image

Microscopic

Features:[11]

  • Mucosa with "abundant eosinophils".
  • Basal cell hyperplasia.
    • Three cells thick or >15% of epithelial thickness.
  • Papillae elongated.
    • Papillae that reach into the top 1/3 of the epithelial layer - definition for GERD.[5]

Notes "abundant eosinophils":

  • Criteria for number of eosinophils/area is highly variable; there is a 23X fold variation in published values and only 11% of studies actually define an area (most studies, embarassing for pathologists that understand this issue, only give the number of eosinophils per "HPF")![16]
    • Interrater variability is low, i.e. good, if the procedure is standardized.[17]
  • The most commonly reported cut points are 15, 20 and 24 eosinophils/HPF, without defining HPF.[16]
    • The Foundation Series book[11] says: "> 20/HPF"; onlinepathology sees this definition as garbage, as "HPF" is not defined (see HPFitis).
    • There is a consensus paper[18] that makes note of HPFitis... and then goes on to ignore to whole issue by defining EE as 15/HPF. It blows my mind that the people could be so will fully blind and that the idiotic reviewers didn't understand this.
    • Most resident microscopes at the Toronto teaching hospitals have 22 mm eye pieces and have for their highest magnification objective a 40X. De facto, this means most people in Toronto are using the Liacouras et al. definition.[19]
  • Eosinophils may be patchy.[20]

DDx:[2]

Images

Sign out

ESOPHAGUS, DISTAL, BIOPSY:
- SQUAMOUS MUCOSA WITH BASAL CELL HYPERPLASIA, ABUNDANT INTRAEPITHELIAL EOSINOPHILS, 
  EDEMA, AND PAPILLARY ELONGATION, SEE COMMENT.
- STAINS (PAS-D, GMS) NEGATIVE FOR MICROORGANISMS.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
There are approximately 65 eosinophils per 0.2376 mm*mm (1 HPF). 

Literature valves show a large variation when defining eosinophilic esophagitis 
and frequently use "HPF" as a measure of area, which is not a standardized measure. 
[Am. J. Gastroenterol. 102 (10): 2300–13.] 

Common cut-points are 15 eosinophils/HPF and 20 eosinophils/HPF, where HPF is 
often undefined.

The above findings are suggestive of eosinophilic esophagitis in the proper
clinical context.

Patchy eosinophils

ESOPHAGUS (DISTAL), BIOPSY:
- SQUAMOUS MUCOSA WITH BASAL CELL HYPERPLASIA, INTRAEPITHELIAL EDEMA AND ONLY
  FOCALLY ABUNDANT INTRAEPITHELIAL EOSINOPHILS, SEE COMMENT.
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC INFLAMMATION, AND PANCREATIC
  ACINAR METAPLASIA.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

COMMENT - PART B:
One high power field (field diameter 0.55 mm) has 25 eosinophils. The findings are
compatible with gastroesophageal reflux; however, eosinophilic esophagitis is also a
consideration. Clinical correlation is required.

Literature valves show a large variation when defining eosinophilic esophagitis
and frequently use "HPF" as a measure of area, which is not a standardized measure.
[Am. J. Gastroenterol. 102 (10): 2300 13.]

Common cut-points are 15 eosinophils/HPF and 20 eosinophils/HPF, where HPF is
often undefined.

Erosive esophagitis

DDx

Work-up

Pill esophagitis

Classic causes:

Esophageal varices

General

Gross

  • Prominent blood vessels in the distal eosphagus.

Note:

  • At autopsy its best demonstrated by inversion of the esophagus.[22]

Image:

Microscopic

Features:

  • Large dilated submucosal veins - key feature.
  • +/-Blood.

Image:

Acute esophagitis

Preneoplastic

Barrett esophagus

Neoplastic

Columnar dysplasia of the esophagus

  • AKA esophageal columnar dysplasia, abbreviated ECD.[24]
  • AKA dysplasia in the columnar-lined esophagus.[25]
  • AKA columnar epithelial dysplasia.[26]

General

Classification

  1. Indefinite for dysplasia.
    • Diagnosis used in the context of uncertainty (like ASCUS and ASAP); the classic reason for its use is: the surface (epithelium) cannot be seen (which precludes assessment of maturation); may be used in the context of inflammation.
  2. Low grade dysplasia.
  3. High grade dysplasia.

Management

Low grade dysplasia & indefinite for dysplasia:

  • Follow-up.

High grade dysplasia:

  • Endoscopic mucosal resection.[27]
  • Surgical resection (esophagectomy).

Microscopic

Features to assess:[28]

  1. Lack of surface maturation - very common, occasionally absent.[29]
    • Lack of lighter staining at surface.
    • Nuclear crowding at surface.
    • Nuclei at the surface not smaller.
  2. Architecture - esp. at low power.
    • Glands not round.
      • Low-grade feature: gland budding.
      • High-grade features: cribriforming, cystic dilation, necrotic debris.
    • Gland density:
      • Increased & round - think low-grade dysplasia.
      • Increased & irregular - think high-grade dysplasia.
  3. Cytology, esp. at high magnification.
    • Nuclear abnormalities in: size, staining, shape.
    • Loss of "nuclear polarity" = high-grade feature
      • Loss of palisaded appearance, rounding-up of nuclei.
  4. Inflammation, erosions & ulceration.
    • Marked inflammation should prompt consideration of knocking down the diagnosis one step, i.e. low-grade becomes indefinite or high-grade becomes low-grade.

Negatives:

  1. No desmoplasia.
    • Stromal fibrotic reaction to the tumour.
      • Desmoplasia is rare in the superficial esophagus.[30]
  2. No single cells.
  3. No extensive back-to-back glands.

Notes:

  • Changes similar to those see in colorectal tubular adenomas; however, what would be low-grade dysplasia in the rectum is high-grade dysplasia in the esophagus.
  • Presence of goblet cells suggests it is not dysplasia.[31]
  • Desmoplasia present = invasive adenocarcinoma.[32]
  • Some literature suggests community pathologists should not make this call, i.e. it should be diagnosed by an expert.[33]

DDx:

Images

Indefinite for columnar dysplasia:

Low-grade columnar dysplasia:

High-grade columnar dysplasia:

Sign out

ESOPHAGUS, DISTAL, BIOPSY:
- LOW-GRADE COLUMNAR EPITHELIAL DYSPLASIA, SEE COMMENT.
- COLUMNAR EPITHELIUM WITH GOBLET CELL METAPLASIA.
- REACTIVE SQUAMOUS EPITHELIUM.

COMMENT:
This was reviewed with Dr. X and they agree with the diagnosis.

Alternate

ESOPHAGUS, 30 CM, BIOPSY:
- LOW-GRADE COLUMNAR DYSPLASIA WITH INTESTINAL METAPLASIA AND MILD CHRONIC
  INFLAMMATION.
- NEGATIVE FOR MALIGNANCY.

Squamous dysplasia of the esophagus

  • AKA eosphageal squamous dysplasia.

General

Microscopic

Features:

  • Squamous cell nuclear atypia.
  • Lack of maturation to the surface.

Note:

  • Grading differences between Western pathologists and those of the east.[36]

DDx:

Images

A set of cases from Japan:[37]

IHC

  • Ki-67 may be useful:[38]
    • Reactive changes/normal: ~98% negative, ~2% intermediate.
    • Low-grade esophageal squamous intraepithelial neoplasia (LGESIN): ~80% intermediate, ~20% negative.
    • High-grade esophageal squamous intraepithelial neoplasia (HGESIN): ~37% intermediate, ~63% strong.

Definitions:[38]

  • Negative defined as: < 25% of epithelium +ve and staining only in lower quarter of epithelium.
  • Intermediate defined: >=25% and <=50% of epithelium +ve and only in the lower half of the epithelium.
  • Strong defined: >50% of epithelium +ve or upper half of epithelium.

Leiomyoma of the esophagus

General

  • Benign.
  • Uncommon.
    • Before the time of GISTs - this was a relatively common diagnosis.
  • Like leiomyomas elswhere.

Microscopic

See: Leiomyoma.

DDx:

Gastrointestinal stromal tumour

Cancer

General

Risks:

Squamous cell carcinoma of the esophagus

  • AKA esophageal squamous cell carcinoma, abbreviated esophageal SCC.

General

  • Like squamous cell carcinoma elsewhere.

Risk factors:[39]

Note:

  • Reflux is not a risk factor for esophageal SCC.

Microscopic

See Squamous carcinoma.

Note:

  • Just to make things confusing, the Staging of early SCC differs from that of early adenocarcinoma!

DDx:

Images

Esophageal adenocarcinoma

  • AKA adenocarcinoma of the esophagus.

General

  • Often a prognosis poor - as diagnosed in a late stage.
  • May be difficult to distinguish from adenocarcinoma of the stomach.
    • By convention (in the CAP checklist) gastroesophageal junction carcinomas are staged as esophageal carcinomas.[40]

Tx

  • Adenocarcinoma in situ (AIS) - may be treated with endoscopic mucosal resection & follow-up.[27]
  • Surgery - esophagectomy.

Esophagus vs. stomach

The convention is it's esophageal if both of the following are true:[41]

  1. Epicenter of tumour is in the esophagus.
  2. Barrett's mucosa is present.

Microscopic

Features:

  • Adenocarcinoma:
    • Cell clusters that form glands.
    • Nuclear atypia of malignancy:
      • Size variation.
      • Shape variation.
      • Staining variation.
    • Mitoses common.
Images

Grading

Graded like other adenocarcinoma:[41]

  • >95 % of tumour in glandular arrangement = well-differentiated.
  • 95-50% of tumour in glandular arrangement= moderately-differentiated.
  • <50% of tumour in glandular arrangment = poorly-differentiated.

Staging

Early esophageal adenocarcinoma has its own staging system:[42][43]

  • M1 = lamina propria.
  • M2 = superficial muscularis mucosae.
  • M3 = submucosa.
  • M4 = muscularis propria.

IHC

  • CK7 +ve.
  • CK20 +ve.

To rule-out SCC:

  • p63 -ve.
  • HWMK -ve.

Weird stuff

  • Inflammatory polyp - assoc. trauma/previous intervention.
  • Giant fibrovascular polyp - loose connective tissue covered with squamous epithelium.
  • Granular cell tumour.
  • Squamous papilloma - koilocytes.
  • Heterotopic gastric mucosa ("inlet patch") - benign appearing gastric mucosa.

Granular cell tumour

Microscopic

Features:

  • Abundant eosinophilic granular cytoplasm key feature.
    • Granules:
      • Size: 1-3 micrometers.
      • Poorly demarcated.
  • Usu. bland (cytologically non-malignant) nuclei.

Images

Esophagitis dissecans superficials

General

  • Rare & benign condition that resolves without lasting pathology.[44]
    • Case report - chronic with strictures.[45]
  • Sloughing of large fragments of the esophageal mucosa - seen on endoscopy.

Microscopic

Features:[44]

  • Flaking of superficial squamous epithelium.
  • Focal bullous separation of the layers.
  • Parakeratosis.
  • Variable acute or chronic inflammation.

Glycogenic acanthosis of the esophagus

General

  • Uncommon.
  • Benign.
  • Possible association with ingestion of hot liquids.[46]

Gross/endoscopic

  • Distinctive endoscopic appearance - grey/white raised lesion.[46]

Image:

Microscopic

Features:[46]

  • Squamous epithelium with:
    • Superficial clearing of the cytoplasm.
    • Thickening.

Images:

Achalasia

General

Microscopic

Features:[48]

  • Mucosa typically normal - even in long-standing achalasia.

Note:[48]

  • Achalasia seen in the context of a resection usually has inflammation.
  • Post-Heller myotomy often has inflammation.

Sign out

ESOPHAGUS, BIOPSY:
- SQUAMOUS EPITHELIUM WITH A MILD DEEP LYMPHOCYTIC INFILTRATE, EDEMA, AND
  REACTIVE CHANGES, NO EOSINOPHILS APPARENT.
- SCANT COLUMNAR EPITHELIUM WITH MINIMAL STROMA, NO APPARENT SIGNIFICANT PATHOLOGY.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Alternate

GASTROESOPHAGEAL JUNCTION, BIOPSY:
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC INFLAMMATION.
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Esophageal inlet patch

  • AKA inlet patch, AKA cervical inlet patch.

General

  • Benign and likely not of any significance.[49]

Gross

  • Proximal esophagus - salmon coloured lesion.[49]

Microscopic

Features:

Image:

Squamous papilloma of the eosphagus

  • AKA esophageal squamous papilloma.

General

  • Uncommon.

Microscopic

Features:

  • Papillomaous projections - low power.

Image

See also

References

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  3. ALS. 4 October 2010.
  4. Steiner, SJ.; Kernek, KM.; Fitzgerald, JF. (May 2006). "Severity of basal cell hyperplasia differs in reflux versus eosinophilic esophagitis.". J Pediatr Gastroenterol Nutr 42 (5): 506-9. doi:10.1097/01.mpg.0000221906.06899.1b. PMID 16707971.
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