Upper GIT malignancies

Question 1

DEscribe the categorisation of UGIT neoplasms

Answer 1

HIERARCHICAL
* Benign
* (premalignant/preinvasive)
* Malignant
– Primary
– Secondary

LINEAGE-BASED
* Epithelial
* Mesenchymal
* Haematolymphoid
* Other
– Melanoma
– Germ cell tumour

Question 2

DESRIBE THE demographics of oesophageal carcinoma

Answer 2

• Common worldwide, less so in Western countries
• Marked geographic and ethnic variation (eg squamous cell carcinoma)
• Incidence rises with age
• Increasing in Australia

Question 3

List risk factors for oesophageal carcinoma

Answer 3

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

Question 4

Compare and contrast SCC and adenocarcinoma risk factors

Answer 4

• 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

Question 5

Correlate the hstology with the molecular biology of oesophageal cancer

Answer 5

• 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

Question 6

List some symptoms and investigations done in oesophageal cancer

Answer 6

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.

Question 7

Describe macoscopic appearance of oesophageal cancer

Answer 7

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

Question 8

Describe histology of oesophgeal cancer

Answer 8

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

Question 9

DEscribe adenocarcinoma of oesophagus

Answer 9

• 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

Question 10

Describe Barrett’s

Answer 10

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)

Question 11

Describe dyspalstic changes in Barrett’s

Answer 11

intracytoplasmic mucin droplets of varying sizes , nuclei are pleomorphic, darker, larger and disorganised with multiple layers indicating dysplastic change.

Diagnosis: endoscopy and histology appearance

Question 12

describe the architectural changes in adenocarcinoma

Answer 12

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

Question 13

describe poorly diffrentiated adenocarcinoma

Answer 13

• 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

Question 14

Describe stagign

Answer 14

T STAGING: degree of invasion of primary tumour through oesophageal wall
N STAGING: number of LN mets
M STAGING: presence/absence metastatic disease

Question 15

List some other types of oesophageal cancer

Answer 15

• Undifferentiated large cell
• Small cell; other neuroendocrine
• Basaloid
• Verrucous
• Spindle cell/sarcomatoid
• Salivary type (adenoid cystic, muco-
  epidermoid)
• Adenosquamous

Question 16

Describe treatment and behaviour of UGITs

Answer 16

• 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

Question 17

Braodly describe gastric carcinoma epidemiology

Answer 17

• 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

Question 18

List risk factors of GC

Answer 18

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

Question 19

Describe the histology of GC/developmenr

Answer 19

• 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

Question 20

describe diffuse type GC

Answer 20

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

Question 21

Describe GC treatment and behaviours

ie mets and survival

Answer 21

• 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%

Question 22

B

broadly describe SI carcinoam

Answer 22

• 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)

Question 23

Broadly describe GIST

Answer 23

• 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)

Question 24

Describe the moelcular gentics of GIST

Answer 24

• 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

Question 25

Describe GIST demographics

Answer 25

• Sporadic – commonest in 40-60 group; slight male preponderance
• Syndromic/special types:
  – Carney’s triad (GIST, pulmonary chondroma, paraganglioma)
  – Familial GIST
• rare, autosomal dominant; germline kit or PDGFR mutation
• multiple tumours, ICC hyperplasia
  – Paediatric GIST
• Median age 12, 75% female, 70% epithelioid
  – NF1-associated
• Usually spindled, CD117 negative
• Usually intestinal, often multiple
• Often Imatinib-resistant
  – Other associations: tuberous sclerosis, others

Question 26

Describe GIST histology

Answer 26

• macroscopy: dumbbell shape
• Spindled, elongated cells and nuclei
• Epithelioid
• Other variants (signet ring, oncocytic, rhabdoid, small cell, …)
• Majority express CD117, CD34, DOG-1 – pathognomic
• May express neural and/or myoid markers

Question 27

Describe GIST behaviour

Answer 27

• Histology is an imperfect predictor of behaviour: size, mitotic rate, necrosis
• Varies with site:
  – Oesophageal: rare, most are malignant
  – Gastric: commonest, fundic more often malignant than antral
  – Small bowel: less often malignant
  – Colorectal: less common but 50% malignant,
  often aggressive
• Mets to liver/peritoneum; other sites rare
• Molecular genetics relevant

Question 28

List some other primary GITs

Answer 28

• Lymphoma
  – Gastric – Mucosal associated lymphoid tissue (MALT) lymphomas, associated with H. pylori
  – Small bowel – Enteropathy associated T cell lymphoma (EATCL)
  – Other types, not site-specific
• Melanoma
• Mesenchymal
  – Benign (lipoma, neuroma, schwannoma, neurofibroma, leiomyoma etc)
  – Sarcoma
• Synovial Sarcoma (esophagus)
• Others e.g leiomyosarcoma

Question 29

List some secondary GITs

Answer 29

• Carcinoma
  – Primary elsewhere in GI tract
  – Direct spread from adjacent organs (lung, larynx, thyroid)
  – Other primary sites (breast, kidney, prostate, pancreas)
• Melanoma
• Other