DEscribe the categorisation of UGIT neoplasms
HIERARCHICAL
* Benign
* (premalignant/preinvasive)
* Malignant
– Primary
– Secondary
LINEAGE-BASED
* Epithelial
* Mesenchymal
* Haematolymphoid
* Other
– Melanoma
– Germ cell tumour
DESRIBE THE demographics of oesophageal carcinoma
- Common worldwide, less so in Western countries
- Marked geographic and ethnic variation (eg squamous cell carcinoma)
- Incidence rises with age
- Increasing in Australia
List risk factors for oesophageal carcinoma
ENVIRONMENTAL:
– Low SES
– Alcohol, smoking
– Thermal/radiation injury
– Toxins:
* mycotoxins, asbestos,
– Dietary deficiencies
* trace elements, Vit A, C, riboflavin, retinol (fruit & veg!)
– Viruses (HPV, mainly for larynx)
– Obesity, reflux disease and Barrett’s metaplasia
GENETICS
– eg. aldehyde dehydrogenase, EGFR polymorphisms
- genetics not well explored
Compare and contrast SCC and adenocarcinoma risk factors
- Shared: bisphosphonates and smoking
- SCC: ETOH, and to a lesser extent diet, caustic or thermal injury, achalasia, strictures, gastrectomy, HPV…
- Ade: GORD, factors pre-disposing to GORD e.g. obesity or drugs
Correlate the hstology with the molecular biology of oesophageal cancer
- repeated inflammation of gastrointestinal tract
- acquired stem cell mutations with repeated inflammation e.g. p53
- low grade dysplasia
- high grade dysplasia – amplification and loss of genes
- invasive carcinoma
List some symptoms and investigations done in oesophageal cancer
Symptoms of oesophageal cancer may include pain or difficulty when swallowing, heartburn, vomiting blood, unexplained fatigue or weight loss. In early stages it may not cause any symptoms. Investigations include endoscopy. The image below shows an oesophageal tumour presenting as a mass at the lower end of the oesophagus. There is bleeding on the muscosal surface of the tumour.
Describe macoscopic appearance of oesophageal cancer
A. Shows a large fungating/cauliflower tumour presenting as an exophytic mass on the luminal surface of the oesophagus
B. The tumour is invading into the wall of the oesophagus near the gastro-oesophageal junction and causing a stricture or narrowing of the lumen.
C. Tumour ** in the wall of the oesophagus/plaque like
D. Ulcerated tumour causing luminal stenosis or narrowing
Describe histology of oesophgeal cancer
SQUAMOUS CELL CARCINOMAS
* MAKE KERATIN
* KERATIN PEARLS
* INDIVIDUAL CELL KERATIN PRODUCTION (BRIGHT PINK DENSE CYTOPLASM)
* HAVE CENTRAL NUCLEI
* HAVE SQUMAOUS INTERCELLULAR BRIDGES/PRICKLES
Oesophageal carcinoma
- high NC ratio
- prominent nucleolus
- desmoplastic stroma
- keratin pearl
DEscribe adenocarcinoma of oesophagus
- Typically arise at gastro-oesphageal junction, may be difficult to distinguish from proximal gastric cancer
- But usually arises in Barrett’s mucosa
- Follows dysplasia-carcinoma sequence
– therefore suitable for surveillance
– anticipated decline in population treated with PPI’s
Describe Barrett’s
Barrett’s esophagus - stratified squamous epithelium is replaced by metaplastic columnar epithelium which in turn predisposes to the development of adenocarcinoma of the oesophagus.
**Endoscopically it appears as salmon pink tongues of mucosa extending above the gastro-oesophageal junction (GOJ) and into the tubular oesophagus, replacing the stratified squamous epithelium that normally lines the distal oesophagus.
**Barrett’s oesophagus – squamous mucosa is
replaced by glands with intestinal metaplasia,
(numerous goblet cells)
Describe dyspalstic changes in Barrett’s
intracytoplasmic mucin droplets of varying sizes , nuclei are pleomorphic, darker, larger and disorganised with multiple layers indicating dysplastic change.
Diagnosis: endoscopy and histology appearance
describe the architectural changes in adenocarcinoma
Architectural changes – invasive glandular pattern, very poorly formed and disorderly glands with a cribriform pattern. In a background of desmoplastic stroma. + Cytological features of malignancy
describe poorly diffrentiated adenocarcinoma
- Marked nuclear and cytoplasmic pleomorphism,
- very/no recognizable glandular structures.
- Adenocarcinoma is diagnosable due to the **presence of
intracytoplasmic mucin vacuoles which have a clear appearance, often appearing as signet rings with a squashed, indented nucleus pushed to one side
Adenocarcinomas in summary
* MAKE GLANDULAR STRUCTURES WITH LUMINA
* +/OR PRODUCE MUCIN
* INTRACYTOPLASMIC
* EXTRACELLULAR
Describe stagign
T STAGING: degree of invasion of primary tumour through oesophageal wall
N STAGING: number of LN mets
M STAGING: presence/absence metastatic disease
List some other types of oesophageal cancer
- Undifferentiated large cell
- Small cell; other neuroendocrine
- Basaloid
- Verrucous
- Spindle cell/sarcomatoid
- Salivary type (adenoid cystic, muco-
epidermoid) - Adenosquamous
Describe treatment and behaviour of UGITs
- Surgery
- SCC is generally radiosensitive
- Chemo for adenocarcinoma (NAC)
- Mets to liver, lung, adrenal, kidney, bone
- 5-year survival Stage I = 95%;
Stage IV median survival <1 year
Braodly describe gastric carcinoma epidemiology
- Second most common tumour worldwide
- Predominantly disease of developing
countries + Japan; less common in Aus - Highly lethal
– tends to present late (except in Japan!)
– limited treatment options
List risk factors of GC
ENVIRONMENT:
* (atrophic gatsritis with intestinal metaplasia)
– Helicobacter pylori infection
– Autoimmune gastritis
* Diet: nitrosamines, salty foods, low consumption of fresh fruit and vegetables/fibre
* Tobacco, smoking
* Radiation
* Gastroenterostomy, ?bariatric surgery
* Obesity
* Low SES
* Viruses, e.g. EBV?
GENETICS:
– Susceptibility to H pylori
– Familial gastric cancer: e-cadherin (CDH1) mutation (herieditary Diffuse Gastric Cancer)
– HNPCC/Lynch. Peutz-Jeghers, BRCA, AD Fundic Gland Polyposis, Cowden’s Syndrome
Describe the histology of GC/developmenr
- Adenocarcinoma: “intestinal” or “diffuse”
– Many shared genetic aberrations eg p53
– Diffuse type: e-cadherin mutation
– Intestinal type: genes implicated in
colorectal cancer eg. APC, TGFB - Gastritis -> intestinal metaplasia -> dysplasia -> intramucosal carcinoma -> invasive cancer
The intestinal-type of Gastric Carcinoma is related to many of the risk factors previously alluded to: often occurs on the background of chronic gastritis → atrophy → intestinal metaplasia → dysplasia → adenocarcinoma
describe diffuse type GC
The diffuse-type of gastric carcinoma is NOT related to many of the risk factors
previously alluded to except hereditary diffuse gastric carcinoma
Diffuse type:
Diffusely infiltrating small groups and single cells (often signet-ring cells). E- Cadherin loss or mutation means that cells cannot adhere/stick to each other → diffuse pattern, no glands
Describe GC treatment and behaviours
ie mets and survival
- Surgery is mainstay for curative intent
- Chemo
- Herceptin for cases with HER2 overexpression
- Pattern of metastases:
– Intestinal type (distal stomach, men) -> liver
– Diffuse type (premenopausal women) -> ovaries (“Krukenberg tumour”)
– Both -> peritoneal spread - 5-year survival Stage I = 95%; Stage IV = 7%
B
broadly describe SI carcinoam
- Uncommon (most small bowel carcinomata are metastases from elsewhere)
- Most are adenocarcinoma
- Commonest 1o site is ampulla – arising in adenoma
- Adenoma/carcinoma elsewhere in small bowel - ?polyposis syndrome eg. FAP, Lynch syndrome
- Other – arising in Meckel’s diverticulum or heterotopic pancreas
- Usually poor prognosis as typically present late (better in ampulla)
Broadly describe GIST
- Commonest mesenchymal tumour of GI tract
- Extraintestinal examples eg. mesentery
- Recapitulate Interstitial Cells of Cajal (ICC) – “pacemaker” cells of gut, neural and myoid features – can have neural and myoid appearance
- Cause célèbre of targeted therapy
- Most (85%) GISTS in kids lack C-KIT or PDGFR muts , and more commonly have succinate dehydrogenase muts (adults will almost always have these)
- Sporadic vs. Inherited
– NF1 (SI), Carney Triad (Paraganglioma, GIST, pulmonary chondroma), Carney Stratakis syndrome (Paraganglioma, GIST, SDH muts), Familial GIST Syndrome (KIT muts)
Describe the moelcular gentics of GIST
- Majority of GIST (80-85%) have KIT mutations
– Usually gain-of-function; exon 11, also 9, 13, 17
– Results in abnormal activation of gene, “switches on” cell proliferation and survival pathways - Most others are wild type (10-12%) or have PDGFRα mutations (5-7%)
– PDGFR mutations are associated with myxoid and epithelioid phenotype and gastric location
– Exons 12, 18 - Kit and PDGFR mutations apparently mutually exclusive
- BUT those with PDGFR mutations often still express CD117 protein
