Functional disorder Lack of progressive peristalsis, partial/incomplete relaxation of LES Issue is with circular layer of muscularis propria T Cell mediated destruction, or complete absence of myenteric ganglion cells in lower third of oesophagus Myenteric plexus inflammation/damage -> loss of inhibitory ganglion cells -> neurotransmitter inhibition is decreased (nitric oxide), imbalance of acetylcholine and nitric oxide -> Achalasia bird beak on barium swallow Risk of: Barrett's Candida infection GERD Lower Oesophageal diverticula Pepic ulceration Stricture

Gastro-oesophageal reflux disease Endoscopy: varies - normal to erythema/hyperemia to erosion/ulceration Micro: spongiosis, basal cell hyperplasia, elongation of vascular papilla, scattered inflammatory cells (eosinophils, lymphocytes, neutrophils Usually more prominent in distal aspect near GEJ

Oesophagus Flashcards by Hannah Barrow

What is the structure of the oesophagus?

Muscosa- non ketratinising stratified squamous epithelium
Submucosa - glands are connected to lumen by squamous lined ducts
Muscularis propria - inner circular muscle, outer longitudinal muscle (smooth), myenteric plexus
Adventitia
Squamocolumnar junction/Z-line
Gastrooesophageal junction - marked by rugal folds.

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Name some benign incidental findings of the oesophagus

Gastric inlet patch - heterotopic gastric mucosa (fundic/oxyntic type admixed with mucous glands) in upper 1/3 of oesophagus. Can resemble malignancy radiologically.
Pancreatic metaplasia/heterotopia- benign pancreatic acini and ducts
Heterotopic sebaceous gland.
Glycogenic acanthosis- epithelial hyperplasia, abundent glycogen accumulation in superficial squamous cells. endoscopic appearance: white plaques

extensive glycogenic acanthosis - could be linked to Cowden Syndrome.

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Describe Achalasia

Functional disorder
Lack of progressive peristalsis, partial/incomplete relaxation of LES
Issue is with circular layer of muscularis propria
T Cell mediated destruction, or complete absence of myenteric ganglion cells in lower third of oesophagus
Myenteric plexus inflammation/damage -> loss of inhibitory ganglion cells -> neurotransmitter inhibition is decreased (nitric oxide), imbalance of acetylcholine and nitric oxide -> Achalasia
bird beak on barium swallow

Risk of:
* Barrett’s
* Candida infection
* GERD
* Lower Oesophageal diverticula
* Pepic ulceration
* Stricture

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What are the causes of Achalasia?

Primary - idiopathic

Secondary
Diabetes
Malignancy
Chagas Disease
Amyloidosis
Sarcoidosis
Neurofibromatosis
Eosinophilic Gastroenteritis
MEN 2B
Anderson-Fabry Disease
Juvenile Sjogren’s syndrome

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What is the treatment of Achalasia?

Laparoscopic myotomy
Pneumatic balloon dilation
Botulinum neurotoxin (BOTOX) injection - inhibits contraction promotic cholinergic neurons

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Describe Oesophageal Rings

AKA Schatzki rings
Circumferential, thicker
Include mucosa, submucosa, occasionally hypertrophic muscularis propria

A RING: distal oesophagus - above GOJ, covered in squamous mucosa

B RING: at squamocolumnar junction of lower oesophagus, may have gastric cardia-type mucosa on under-surface

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Describe Oesophageal Webs

Semi-Circumferential lesions
Fibrovascular connective tissue and overlying epithelium

Seen in women >40
May be associated with GERD, graft vs host, blistering skin diseases

Forms part of Plummer-Vinson Syndrome
* Iron deficient anaemia
* Glossitis
* Cheilosis

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Plummer-Vinson Syndrome

AKA Paterson-Brown-Kelly syndrome

TRIAD:
* IDA
* Dysphagia
* Cervical oesophageal web

Premalignant disease

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Describe GERD

Gastro-oesophageal reflux disease
Endoscopy: varies - normal to erythema/hyperemia to erosion/ulceration
Micro: spongiosis, basal cell hyperplasia, elongation of vascular papilla, scattered inflammatory cells (eosinophils, lymphocytes, neutrophils
Usually more prominent in distal aspect near GEJ

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Describe Candida Oeophagitis

Endoscopy: white plaques, scraped off to reveal erythematous/ulcerated underlying mucosa
Micro: fungal pseudohyphae and budding yeast, squamous debris, active oesophagitis
Stains: GMS (Grocotts), PAS
Treat with Fluconazole

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Describe HSV Oesophagitis

Endoscopy: shallow, punched out ulcers, necrotic exudate

Biopsy taken from ulcer edge:
* Acantholysis
* Multinucleated squamous cells - steel blue nuclei, Cowdry type A inclusions (dense, eosinophillic, intranuclear).

viral cytopathic effects in epithelial cells - ground glass nuclei
*** the 3 Ms **- margination of chromatin, multinucleation, and nuclear molding

Tests:
HSV1 and HSV2 IHC stain
PCR for HSV DNA
ISH

Treatment:
Acyclovir in immunosuppressed
Self-limited in immunocompetent individuals

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Describe CMV Oesophagitis

Common in patients with AIDS
Endoscopy: erythema, erosions, ulceration - non specific ulcers
Viral cytopathic effects in mesenchymal cells - enlarged cells with nucleomegaly and inclusions
Owls -eye intranuclear inclusions and granular intracytoplasmic inclusions

Test:
CMV immunostain
ISH

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Describe pill/medicine-induced Oesophagitis

Endoscopy: ulceration
Inflammatory exudate (neutrophils), polarisable foreign material/pill filler
Microcrystalline cellulose - refractile, transparent
Crospovidone - pink/purple

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Describe eosinophilic oesophagitis

Endoscopy: concentric rings/linear furrows - trachealisation/felinization
white plaques/exudates
micro: intraepithelial eosimophils (>15 per hpf), eosinophilic microabscesses, superficial concentrations of eosinophils with degranulation and surface desquamation
basal cell hyperplasia, oedema. elongated papillae, lamina propria fibrosis.

immune/antigen driven - type 2 helper t-cell mediated (Th2)

clinicopathlogical diagnosis:
* clinical features - dysphagia, food impaction, feeding intolerance
* endoscopic appearance
* >15 intraepithelial cells per hpf
* exclusion of other causes of eosinophilia

Association with ectopic triad - allergies, asthma, eczema

Often worse proximally

Treat with PPI for symptoms and corticosteroids

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Describe Oesophagitis Dessicans Superficialis

Sloughing Oesophagitis
Endoscopy: white plaques of peeling and sloughing epithelium
two tone appearence - superficial hypereosinophilic/necrotic epithelium with parakeratosis and underlying viable uninflamed/minimally inflamed deeper layers

oedema and vacuolisation of interface will eventually cause splitting of squamous epithelium

associated with medications, autoimmune bullous dermatoses, thermal/chemical injury, heavy smoking, alcohol and having multiple comorbidities.

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Describe Lymphocytic Oesophagitis

Endoscopy: may mimic oesinophilic esophagitis - rings/furrows/white plaques
increased intraepithelial lymphocytes - concentrated around dermal papillae
intracellular oedema, dyskeratotic epithelial vells

associated with:
* GERD
* Crohn’s
* Coeliac
* achalasia and dysmotility
* lichen planus (of oesophagus)
* graft vs host
* common variable immunodeficiency

Describe Barrett’s Oesophagus

extension of salmon-coloured mucosa into the oesophagus extending >1cm prox to the GEJ.
Intestinal metaplasia (goblet cells, ACID MUCIN) - seen with Alcian-Blue/PAS
True goblet cells - rounded/ovoid, blue tinged cytoplasmic mucin, eccentric nucleus
Incomplete IM: only goblet cells with mucin are present
Complete IM: goblet cells and brush border present, paneth cells can be seen

British definition doesnt rely on IM, unlike American.
But needs both endoscopic and histological correlation

SHORT segment: <3cm
LONG segment: >3cm

SEATTLE protocol for biopsies:
* four quadrant biopsies
* taken every 2cm through Barrett’s segment

Dysplasia needs to be double reported

What are the risk factors for BE?

Chronic GERD
Male
Caucasian
Central obesity
Smoking
Age >50
Lack of nonsteroidal anti inflammatory agent use
Lack of PPI use
Lack of statin use

Describe the pathgenesis of BE

Chronic GERD induces tissue damage
Upregulation of columnar transcription factors (SOX9)
Induces columnar differentiation
Upregulation of intestinal differentiation factors (CDX2)
Intestinal metplasia
Molecular alterations
Low-grade dysplasia
TP53, DNA aneuploidy
High-grade dysplasia and carcinoma

Negative for dysplasia

Polarity seen in 4 lines:
* apical neutral mucin cap
* base of mucin cap
* eosinophilic cytoplasm below the mucin
* row of nuclei

Endoscopic surveillance interval:** 3-5 years**

Indefinite for dysplasia

Used if unsure if reactive vs neoplastic
ie - inflammation/ulceration/technical artifacts/diathermy

Treat for GERD and repeat biopsy in 3-6 months

Low grade dysplasia

Adenoma-like or intestinal type
Cytological abnormality, little/no architectural complexity
Nuclear enlargement
Hyperchromasia
Retained nuclear polarity
Both strong or absent (null phenotype) p53 staining considered significant
AMACR and **IMP3 **sometimes useful

Findings extend to surface and often show abrupt transition point from non-dyplastic to dysplastic area

Manage with endoscopic mucosal ablation
endoscopic surveillance every 12 months an acceptable alternative

High grade dysplasia

greater degree of cytological atypia
Often with architectural abnormalities
No surface maturation
Crowded crypts with variable size and shape

What are endoscopy timelines in Barretts?

Just Squamous epithelium - ?sampling error - Repeat

Barretts
* <3cm, gastric metaplasia –> repeat –> if same, consider discharge
* <3cm, IM –> repeat OGD every 3 to 5 years
* >3cm –> repeat OGD every 2 to 3 years

Dysplasia
* Indefinite –> repeat OGD in 6 months with max acide suppression
* Low grade –> OGD every 6 months until 2 consecutive non-dysplastic –> follow Barratts flowchart
* High grade –> MDT discussion –> Therapeutic intervention

What underlying conditions can lead to oesophageal Ca?

1) **Barrett's Oesophagus ** Effects 1-6% people 10% go on to develop ADENOCARCINOMA Familial Barretts Oesophagus - gene MSR1 2) **Achalasia** 1 in 100,000 people x50 higher risk of SCC and ADENOCARCINOMA 3) **Tylosis** 'Howel-Evans Syndrome' Rare hereditary disease - autosomal dominant Gene RHBDF2 High risk (25-95%) of SCC 4) **Fanconi anaemia** gene FANCA 5) **Bloom Syndrome** gene BLM

Adenocarcinoma patterns

* TUBULAR: most common, irregular single or anastomosing glandular structures * PAPILLARY: form papillae or micropapillae * MUCINOUS: tumour cells float in abundant extracellular mucin * SIGNET-RING: worse prognosis

What are adverse features of Oesophageal AdenoCa?

* Submucosal invasion (pT1b) over 500 microns * Poor differentiation * LVI * Positive margins

What is the treatment of Oesophageal AdenoCa?

* **pT1 adenos with NO adverse features** - endoscopic resection +/- radiofrequency ablation * **Advanced Ca** - oesophagectomy +/- chemoradiation HER2 testing is done routinely - if amplified, **Trastuzumab** **Pembrolizumab** - promising early results.

IHC for Oesophageal Adeno vs Squamous

* Can be difficult to distinguish poorly diff adeno from poorly diff squamous **CK7**: positive in adeno, negative in SCC **CK5/6, p63, p40**: negative in adeno, positive in SCC **PAS, Mucin**: positive in adeno, negative in SCC

Describe HER2 IHC

* **IHC 3+**: strong, complete lateral or basolateral membranous reactivity in >10% tumour cells * **IHC 2+/Equivocal**: weak to moderate complete lateral or basolateral membranous reactivity in >10% tumour cells - **perform ISH testing** * **IHC 1+**: faint membranous reactivity in >10% tumour cells * **IHC 0**: no reactivity, or membranous reactivity in <10% tumour cells

Describe Squamous Papilloma

* Small polypoid lesions, warty surface * Benign papillary proliferation of squamous epithelium * Fibrovascular core of lamina propria * Vacuolated cells can be seen (look like koilocytes, without atypical nuclear features * Usually exophytic, but can be flat/endophytic Caused by mucosal irritation- hyper-regenterative response: * GERD * Trauma * HPV infection US populations - distal oesophagus Asian populations - mid oesophagus

Describe Squamous Dysplasia

* Flat lesions are better highlighted by Lugol iodine solution * needs BOTH cytological and architectural atypia * LOW GRADE: involves lower half of the epithelium only, with mild atypia * HIGH GRADE: involves more than half of the epithelium OR severe cytological atypia is present regardless of the extent of epithelial involvement. Risk factors are similar to those of SCC Accumulting genetic abnormalities result in normal -> low grade dysplasia -> high grade dysplasia -> invasive carcinoma **TP53** mutation is key early driver mutation

What are the genetic mutations in Oesophageal SCC?

* **TP53** mutation found in 59 - 93% of all cases * **NOTCH1** and **NOTCH3 **mutations detected in up to 28% of cases * **EGFR **overexpression reported in 59.6 - 76% of cases * Mutations or amplification in **RAS** and **AKT **family seen in at least 75% of cases

SCC Subtypes

VERRUCOUS: * well-differentiated, minimal cytological atypia, minimal mitotic activity * invasive front - broad bulbous pushing projections SPINDLE CELL: * polypoid growth pattern * biphasic pattern - squamous epithelium and spindle cells * squamous - well to moderately differentiated or carcinoma in situ alone * spindle - high grade malignancy, may have osseus, cartilaginous or skeletal muscle diff BASALOID: * Solid or nested growth pattern of basaloid cells - sometimes comedo necrosis, pseudoglandular/cribriform formations. * Unlike in oropharynx... NO association with HPV infection

What are the risk factors for Oesophageal SCC?

* Tobacco * Alcohol * Hot Beverages * Plummer-Vinson syndrome * Achalasia * Tylosis * Radiotherapy * Caustic Ingestion

What is Tylosis?

* Autosomal dominant keratosis disorder * Missense mutation in **RHBDF2**, **17q25.3** * Associated with familial early onset oesophgeal SCC

Describe Granular Cell Tumour

* Second most common benign mesenchymal tumour behind leiomyomas * Soft tissue tumour * Neuroectodermal differentiation (schwannian origin) * Common 30-50 year olds * Mostly asymptomatic with slow, indolent growth * Associated with **Noonan (Leopard) syndrome** macro: yellow, finely granular micro: poorly defined mass - sheets or nests separated by thin collagenous bands Round/polygonal to slightly spindled cells Mild to mod nuclear atypia Abundant eosinophillic cytoplasm Overlying squamous epithelium - pseudoepitheliomatous hyperplasia

How do you diagnosis granular cell tumour?

** Fanburg-Smith Criteria** - 6 features * Necrosis * Spindling * Vesicular nuclei with large nucleoli * >2 mitoses/10 high-power fields * High NC ratio * Pleomorphism 3 or more: malignant 1-2: Atypical 0/focal pleomorphism: Benign IHC: S100+ SOX10+ CD68+ NSE+ EMA+ Treatment: Benign - surgical excision, excellent prognosis Malignant - Wider surgical resection