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.

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.[10]

Image:

Microscopic

Features:

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

Image:

Acute esophagitis

Benign esophageal stricture

Preneoplastic

Barrett esophagus

Neoplastic

Columnar dysplasia of the esophagus

  • AKA esophageal columnar dysplasia, abbreviated ECD.[12]
  • AKA dysplasia in the columnar-lined esophagus.[13]
  • AKA columnar epithelial dysplasia.[14]

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.[15]
  • Surgical resection (esophagectomy).

Microscopic

Features to assess:[16]

  1. Lack of surface maturation - very common, occasionally absent.[17]
    • 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.[18]
  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.[19]
  • Desmoplasia present = invasive adenocarcinoma.[20]
  • Some literature suggests community pathologists should not make this call, i.e. it should be diagnosed by an expert.[21]

DDx:

Images

Indefinite for columnar dysplasia:

Low-grade columnar dysplasia:

High-grade columnar dysplasia:

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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.[24]

DDx:

Images

A set of cases from Japan:[25]

IHC

  • Ki-67 may be useful:[26]
    • 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:[26]

  • 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:[27]

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

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ESOPHGAUS, BIOPSY:
- INVASIVE SQUAMOUS CELL CARCINOMA, KERATINIZING, MODERATELY DIFFERENTIATED.

COMMENT:
Benign squamous epithelium at least partially overlies the invasive squamous 
cell carcinoma; this may mask the true extent of the lesion on endoscopy.

Micro

The sections show a squamous mucosa with focal moderate atypia of the squamous cells, keratinization and easily identified mitotic figures. The atypical cells are partially covered by benign squamous cells, and there is a very sharp transition between the cells with atypia and those without. The atypical squamous cells extend into the subepithelial tissue in irregularly shaped nests and cords. A small amount of benign muscle is present.

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.[28]

Tx

  • Adenocarcinoma in situ (AIS) - may be treated with endoscopic mucosal resection & follow-up.[15]
  • Surgery - esophagectomy.

Esophagus vs. stomach

The convention is it's esophageal if both of the following are true:[29]

  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:[29]

  • >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:[30][31]

  • 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.[32]
    • Case report - chronic with strictures.[33]
  • Sloughing of large fragments of the esophageal mucosa - seen on endoscopy.

Microscopic

Features:[32]

  • 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.[34]

Gross/endoscopic

  • Distinctive endoscopic appearance - grey/white raised lesion.[34]

Image:

Microscopic

Features:[34]

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

Images:

Achalasia

General

Microscopic

Features:[36]

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

Note:[36]

  • 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.[37]

Gross

  • Proximal esophagus - salmon coloured lesion.[37]

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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