L5 - Gastrointestinal pathology: how Helicobacter pylori defined gastric pathology (Dr Francesca Maggiani)y Flashcards
- Understanding how HP interacts with the host - Recognising the features of HP induced gastritis - Appreciating how the chronic damage induced by HP leads to precancerous lesions - Assessing the different forms of cancers assiciated with HP exposure. (141 cards)
1
Q
What are the major conditions linked to gastric pathology?
A
Abnormal motility, inflammation, infection, and severe conditions like gastric cancer ( becoming more frequent)
2
Q
How has the understanding of gastric cancer improved in recent years?
A
The use of endoscopy allows earlier detection, leading to less aggressive and more successful treatments.
3
Q
What type of carcinoma are gastric and oesophageal
A
adenocarcinomas (formed from glandular structures in epithelial tissue)
4
Q
why are we starting to see more and more gastric and oesophageal carcinomas?
A
Because they are being understood better (this is good because it means that they are being identified earlier which results in less aggressive and more successful treatment)
5
Q
What is the most common pathogen associated with inflammatory gastric disease?
A
Helicobacter pylori (H. pylori).
6
Q
What is the estimated prevalence of Helicobacter pylori in the general population?
A
Approximately 50%, with higher levels (up to 90%) in developing countries.
7
Q
because of H.pyloris being found in at a high abundance in the general population what is the assumption
A
that it forms part of the normal gut microflora
8
Q
is there any overlap in the prevealence of H.pylori and the prevalence of gastric cancer?
A
Yes (there is some ethnic and geographic associations)
9
Q
what is the global burden of gastric cancer
A
- 4th most common malignant disease (~930,000)
- 2nd most common cause of cancer related death worldwide (~700,000)
- Falling incidence of distal gastric cancer
- Increasing incidence of proximal gastric cancer
- Wide geographical variation
- ethnic and geographic association (not always clear when one ends and the other starts)
10
Q
what are example countries where the incidence of gastric cancer is high and how does immigration affect trends?
A
some parts of Japan and China (but then studies done on immigrants coming from this area, especially in the Japanese American population, found that incidence started to decline in the second generation of immigrants (this shows how it is multifactorial and more than just genetics / ethnicity playing a role in gastric cancer cases)
11
Q
Helicobacter pylori general info
A
gram-negative microaerobic bacterium with a worldwide prevalence.
12
Q
What are the forms and key features of Helicobacter pylori?
A
Spiral or coccoid form, with flagella that allow mobility along the gastric mucosa.
13
Q
When was the link between the bacterium and the clinical symptoms associated with gastritis confirmed
A
in the early 80s
14
Q
How was the link between H. pylori and gastritis established?
A
Warren and Marshall drank H. pylori, developed gastritis, and confirmed its presence (+ inflammation) via biopsies / endoscopy earning them the Nobel Prize ( a bit extreme but it worked) …. Marshall and Warren demonstrated that treating H. pylori infections with antibiotics could cure ulcers, which was a major shift in medical thinking and practice.
15
Q
What was believed to cause gastritis before Barry MArshall and Robin Warren proved that it was H.pylori which caused it?
A
At the time, the prevailing medical opinion was that ulcers were caused by excessive stomach acid, stress, or lifestyle factors, not an infection
16
Q
What are the common conditions caused by H. pylori infection?
A
Gastritis, gastric ulcers, and duodenal ulcers (peptic ulcers).
17
Q
How is H. pylori-associated gastritis treated?
A
With antibiotics and proton pump inhibitors to reduce stomach acidity and protect the mucosa ( once you identify the cause of disease and have a valid treatment option, the patient can be cured)
18
Q
What are the protective mechanisms of the stomach against infection?
A
mucus coating, acidic environment, and specialised cells (e.g., parietal and chief cells).
19
Q
What is the Cardia
A
the first part of the stomach, which is connected to the esophagus. It contains the cardiac sphincter, which is a thin ring of muscle that helps to prevent stomach contents from going back up into the esophagus.
20
Q
What type of cells line the esophagus
A
squamous epithelial cells because it has to sustain mechanical trauma (with chunks of food going down)
21
Q
What type of cells line the cardia
A
monostratified glandular epithelium which produce mucus that protect the stomach lining from the corrsive effects of gastric acid
22
Q
What does H. pylori do to survive in the acidic stomach environment?
A
Uses flagella to penetrate mucus and get ontop of the cell membrane. Here the environment is less acidic.
Releases urease to convert urea into ammonia, neutralising stomach acid.
Adheres closely to the mucosa and disrupts cell junctions.
23
Q
What are the functions of different stomach regions?
A
Fundus: Produces mucus via foveolar cells.
Body: Releases acid (parietal cells) and pepsinogen (chief cells).
Antrum: Produces mucus and gastrin, which regulates acid secretion.
24
Q
What role does gastrin play in the stomach?
A
It stimulates acid release, which activates pepsinogen into pepsin for digestion.
25
What is the role of pepsin
enzyme which starts the digestive process and allows the digested molecules to be absorbed in the small bowel later on
26
What is the feedback loop in the stomach
Stimulus: Food enters the stomach.
G cells: Release Gastrin in the antrum
→ Parietal cells (Body) : Release HCl
→ Chief cells (Body): Release Pepsinogen (pro-enzyme)
HCl: Activates Pepsinogen → Pepsin (enzyme)
Pepsin: Breaks down proteins → Stimulates G cells (positive feedback)
Negative Feedback:
↑ HCl → Stimulates D cells: Release Somatostatin
Somatostatin: Inhibits Gastrin release
27
why are parietal cells and chief cells in the Body of the stomach required
to secrete acid and pepsinogen (acid enhances the pepsin activity) to protect from pathogens
28
why are mucus secreting cells in the Fundus / cardia needed
to create mucus to coat and protect the epithelial cells from the acid content
29
How does H. pylori disrupt the gastric mucosa?
It creates a niche by neutralising acid and adhering to cells, damaging junctions and altering the local pH.
30
What happens to most pathogens in the stmach
They die (although H.Pylori has evolved coping strategies)
31
How does H.pylorWhat is H.pylori's survival strategy
It migrates to regions of less acidic pHs, releases urease to turn urea into ammonia (neutralising the gastric acid and allow colonisation) and adheres to gastric mucosa linking to lipoprotein A-B (making A blood group more susceptible)
32
Where in the gastric region does H.pylori get into (less acidic environment)
using its flagella, it gets into the mucus and deposits itself onto the membrane of the cells
33
Can you recognise Helicobacter pylori when taking a biopsy of the stomach.
yes - this allows for immediate diagnosis which isn't very common in histology (diagnose with almost 100% certainty)
34
How can anti-acid treatment affect detection of H. pylori?
It can make it harder to identify the bacterium and alter results of other tests, like the breath test.
35
What does a positive breath test for H. pylori indicate?
Increased ammonia due to changes in stomach acidity caused by H. pylori.
36
What test is most reliable for confirming H. pylori?
Genetic testing on gastric samples.
37
Name the exotoxin associated with H. pylori.
Vacuolating cytotoxin A (vacA).
38
What is the effect of VacA?
affects the cell structures causing ballooning, degeneration, and immediate cell death, leading to acute gastritis and ulcers.
39
What cytotoxin is associated with chronic inflammation caused by H. pylori?
Cytotoxin-associated gene A (c agA).
40
How does CagA contribute to disease?
It affects cell attachment, induces chronic inflammation, and is linked to adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
41
What are the main pathogenic features of H.pylori
1. Flagella ( bacterial mobility and chemotaxis to clonise under mucosa)
2. Urease (neutralises gastric acid and is responsible for gastric mucosal injury through ammonia)
3. Lipopolysaccharides (Adhere to host cells and cause inflammation)
4. Outer proteins (which adhere to host cells)
5. Type IV secretion system (pilli-like structure for injection of effectors)
6. Effectors e.g. cagA which lead to actin remodelling, IL-8 induction, host cell growth and apoptosis inhibition
7. secretory enzymes e.g. mucinase, protease and lipase which causes gastric mucosal injury
8. Exotoxin(s) e.g. vacA which causes gastric mucosal injury
42
What is the CagA T4SS
The CagA T4SS is a multi-protein machine in H.pylori that spans the bacterial inner and outer membrane acting as a molecular syringe to inject proteins e.g. CagA into the gastric epithelial cells
43
how does CagA T4SS work?
It forms a pilus-like structure that binds to host cell integrin receptors (α5β1), facilitating the translocation of CagA into the host cell where CagA undergoes tyrosine phosphorylation, mimicking host proteins and disrupting intracellular signaling pathways.
44
How does the Cag T4SS contribute to disease
It induces cellular alterations e.g. actin cytoskeleton rearrangements, membrane dynamic changes and disruption of cell-cell junctions.
45
How does gastritis progress if untreated?
Acute gastritis → Chronic gastritis → Atrophic gastritis → Intestinal metaplasia → Dysplasia → gastric Adenocarcinoma.
46
What happens if a patient is treated at the acute gastritis stage
the gut will go back to normal functionality and morphology
47
At which point does antimicrobial eradication of H.pylori interrupt the cascade
up until intestinal metasplasia and SPEM ( acute and chronic gastritis, atrophic gastritis and intestinal metaplasia / spem)
48
What is functional dyspepsia?
a chronic digestive condition that causes stomach pain, bloating, and other symptoms without an obvious cause
49
What is GERD?
Gastroesophageal reflux disease is a digestive condition that occurs when stomach acid flows back up into the esophagus - linked to non effective digestion
50
What is the link between functional dyspepsia / GERD and HP
not entirely clear of the role of HP but symptoms improve with eradication HP (valid connection)
51
What is the first stage of Helicobacter pylori infection in the stomach?
The initial stage is superficial gastritis ( inflammation of the stomach lining that can be treated and reversed to normal morphology if addressed early). This can develop into chronic gastritis though ( characterised by persistent inflammation and recruitment of inflammatory cells e.g. lymphocytes, plasma cells and myeloid-derived suppressor cells).
52
how does chronic gastritis contibute to tissue damage?
chronic inflammation releases interleukins that cause mucosal damage, leading to atrophic gastritis with high gastric pH, bacterial overgrowth and nitrosamine formation
53
How does HP lead to peptic ulcers
virulent factors e.g. VacA m1 is possibly associated with an increased risk of peptic ulcer disease
54
What dietary factors increase susceptibility to H. pylori-related gastritis?
High salt, low iron, and high fat diets.
55
What dietary factors may protect against gastric cancer?
Diets rich in fruits, vegetables, and fibre.
56
What is atrophic gastritis?
Loss of gastric glands and reduction of gland-to-stroma ratio, often considered a precancerous lesion
57
What is intestinal metaplasia?
Replacement of gastric epithelium with intestinal-type epithelium.
58
what can replace the gastric glands lost in atrophy
intestinal metaplasia or spasmolytic metaplasia (SBM) which increases the risk of neoplastic progression
59
What are the histological differences between normal gastric mucosa, intestinal metaplasia, and dysplasia?
- Normal mucosa: Organized glands with pink-staining cells.
- Intestinal metaplasia: Presence of goblet cells and loss of normal glandular architecture.
- Dysplasia: Loss of cell organization, multiple layers of nuclei, increased mitotic activity, and absence of goblet cells.
60
What does dysplasia indicate in the stomach?
Precancerous changes in the mucosa, characterised by disorganised nuclei and loss of maturation.
61
What is the hallmark of adenocarcinoma in gastric pathology?
Invasion of glandular-structured tumours into the stroma and mucosa.
62
What do blue inflammatory dots in gastric tissue indicate?
Presence of inflammatory cells in gastritis.
63
How can acute and chronic gastritis be differentiated histologically?
Acute shows neutrophils; chronic shows lymphocytes and plasma cells ( which release cytokines which can cause more damage to the mucosa)
64
What histological finding is characteristic of intestinal metaplasia?
Goblet cells which should be found in the stomach, not in the intestine
65
What histological change defines dysplasia?
Increased nuclear size, disorganisation, and loss of mucin production.
66
how does gastrirtis distribution help determine the cause of gastritis?
Bacterial gastritis (e.g., H. pylori): Affects the lower stomach (antrum).
Autoimmune gastritis: More common in the upper stomach (fundus and corpus).
Reflux gastritis: Affects the lower stomach due to acid exposure.
67
What is reactive gastritis often caused by?
Bile reflux or chemical exposure.
68
What is looked at when assessing gastric biopsies
the extent, quantity and type of inflammation (e.g. mild, focal, predominantly lymphocytic, chronic .... ) and extent and quantity of atrophy (glandular density) and possible metaplasia is looked at
69
how is the extent of atrophy assessed
looking at the glandular to stroma ratio (see if there is a reduction at all)
70
Name significant risk factors for gastric cancer.
H. pylori infection,
ethnicity,
smoking,
family history,
obesity (don't know the link but this is increasingly being seen as a risk factor for many diseases)
previous radiation therapy or chemotherapy for other malignancy
more common in people of lower socio-economic status
71
What regions have higher incidences of gastric cancer?
Japan, China, Chile, Northern Italy, Portugal, and Russia.
72
Incidence of gastric cancer in Japanese who move to America
Incidence of gastric carcinoma in Japanese Americans was 3-6 times higher than those of US born whites, but the incidence started to decline in second generation immigrants (more than just the ethnic aspect +/- other aspects - multifactorial system)
73
How does socioeconomic status affect gastric cancer risk?
Lower socioeconomic status often correlates with delayed diagnosis and treatment - if people don't have access or the ability to refer to a healthcare centre for early diagnosis / endoscopy
74
What is being found about the age range for onset of gastric cancer
It is being found more and more frequently in younger patients
75
What is the role of obesity in gastric cancer?
It is associated with increased risk, though mechanisms are unclear.
76
How are gastric biopsies typically taken?
Samples are collected from different stomach regions (fundus, corpus, antrum) to assess damage distribution.
77
What is being looked for when assessing gastric biopsies
The extent, quantity and type of inflammation e.g. mild, focal, predominantly lymphocytic and the amount of atrophy with glandular density and possible metaplasia
78
what is atrophy in the gastrointestinal tract
atrophy occurs when there is a significant decline in the number of glands in the stomach or intestine leading to tissue thinning, functional impairment, (decrease in number of gastric glands) and the normal structure may be replaced by metaplastic glands or fibrotic tissue
79
What type of glands are found in an atrophic stomach?
Instead of normal gastric glands, metaplastic glands e.g. intestinal-type glands (intestinal metaplasia) mat develop which occurs when normal gastric glands are replaced by intestinal type epithelium e.g. goblet cells and absorptive enterocytes
80
How does glandular atrophy affect stomach function
Loss of gastric glands reduces acid and enzyme production, impairing digestion and increasing the risk of infections and malignant e.g. Helicobacter pylori infection, autoimmune gastritis and long-term inflammation
81
What does increased inflammatory cell infiltration in the stomach indicate?
Active gastritis.
82
What are the histological differences between chronic gastritis and atrophic gastritis?
Chronic gastritis shows inflammation without gland loss; atrophic gastritis shows gland loss and stromal expansion.
83
What is microsatellite instability associated with?
with better prognosis in gastric cancer (better response to treatment, improved survival, smaller number of lymph node metastasis)
84
Where can unusual lymph node metastasis be found in gastric cancer?
In the left supraclavicular region.
85
What causes paraneoplastic syndromes in patients with gastric cancers
release of hormones that are associated with the tumour
86
What are some clinical manifestations of gastric conditions
Abrupt appearance of keratosis,
thrombophlebitis,
polyartheritis nodosa (inflammatory necrosis arteries)
trousseau syndrome (acquired blood clotting disorder that results in migratory thrombophlebitis)
Pseudoacalsia
87
what is the appearance of seborrheic keratosis like
waxy light tan, brown or black growths that look scaly or as if they were dripped onto the skin by a candle.
88
What causes polyarthritis nodosa
vascular inflammatory changes
89
What causes trousseau syndrome
acquired blood clotting disorder that results in migratory thrombophlebitis
90
How can gastric cancer be diagnosed early in Japan?
Through a screening programme that allows for mucosectomy of intramucosal tumours (don't need to remove the stomach)
91
What is mucosectomy?
The removal of the mucosal layer, used in early-stage gastric cancer treatment to remove the lesion.
92
What is the role of neutrophils in acute gastritis?
They are the predominant inflammatory cells in acute inflammation.
93
What inflammatory cells are seen in chronic gastritis?
Lymphocytes and plasma cells.
94
What happens during atrophic gastritis?
Destruction of glands and possible progression to intestinal metaplasia
95
How can Helicobacter pylori affect the acidic environment of the stomach?
By neutralising acidity, allowing the bacterium to survive.
96
What is the function of flagella in Helicobacter pylori?
It helps the bacterium move through the mucus layer of the stomach.
97
What is the role of the cytotoxin associated gene A (cagA)?
It contributes to chronic inflammation and may lead to more severe outcomes, such as adenocarcinoma.
98
What is the link between Helicobacter pylori and adenocarcinoma?
Chronic infection with Helicobacter pylori can lead to persistent inflammation, atrophy, and metaplasia, increasing cancer risk.
99
What is the role of proton pump inhibitors (PPIs) in Helicobacter pylori testing?
They can alter test results by affecting stomach acidity.
100
What type of cancer is most commonly associated with Helicobacter pylori infection
Gastric adenocarcinoma.
101
What is intestinal metaplasia an early sign of?
It is a potential precursor to gastric cancer (it is defined as an increase in cell numbers)
102
How is intestinal metaplasia identified histologically?
By the presence of goblet cells, which are normally found in the intestines but not the stomach. (metaplasia is defined by going from one mature native type of cell into another mature type of cell that you don't expect to see there)
103
What is dysplasia in the context of gastric cancer?
Abnormal cell development that is non-invasive but may progress to adenocarcinoma (preneoplastic) .
104
How does Helicobacter pylori contribute to chronic gastritis?
By triggering a prolonged inflammatory response that can lead to gland destruction.
105
What is the significance of the gland-to-stroma ratio in gastric biopsies?
A decreased ratio (decreased number of glands) can indicate atrophy, which is a precursor to cancer.
106
What type of gastric cancer is associated with familial genetic mutations?
Hereditary gastric cancer, which often involves mutations in the E-cadherin gene.
107
What is the primary treatment for early-stage gastric cancer in Japan?
Mucosectomy
108
in what region of the stomach do bacterial gastritis tend to be found
in the lower component of the stomach
109
What is microsatellite instability
A genetic abnormality that is associated with a change in the number of repeated DNA bases in a microsatellite region (repeated sections of non coding DNA)
110
What are clinical manifestations for gastric conditions
- Malaise loss of appetite dyspepsia
- Pain
-Nausea
- Vomit
- Weight loss
- Anemia ( hematemesis and / or melena)
(varies amongst individuals)
111
What are probably the most feared manifestations
anemia and weight loss (because if you haven't significantly changed your diet or exercise regime and anemia indicates bleeding both of which are signs for some chronic condition e.g. adenocarcinoma)
112
where are the common areas for metastasis
lymph nodes, liver, abdominal (peritoneum and intrabd organs .... ovary)
113
what is the survival rate with poor prognosis if advanced
less than 20% have a 5 year survival
114
what is the survival rate if prognosis is made early on in gasrtic cancer
90% survive 5 years
115
where is early gastric carcinoma confined to
the mucosa and submucosa regardless of perigastric lymph nodal mets
116
where is advanced carcinoma
infiltrated the muscularis propria
117
What is MALT lymphoma? - what does it stand for and what is it?
Mucosa Associated Lymphoid Tissue Lymphoma (MALT L) is a slow growing type of non-Hodkin lymphoma that develops in the lymphoid tissue lining
118
How does gastric MALT lymphoma develop?
The process begins with H. pylori infection, which recruits B and T cells to the gastric mucosa (this initiates a cascade of cytokine and chemokine release)
119
How would gastric MALT appear macroscopically?
You would initially see the formation of lympho-epithelial lesions (LELs) which is characterised by aggregates of lymphoma cells invading individual gastric glands (key histological feature - good for diagnosis) and these LELs are thought to be the origin of lymphomas
120
How do epithelial cells contribute to MALT lymphoma development during chronic H. pylori infection?
Chronic infectious stimulation causes epithelial cells to express high levels of HLA-DR and CD80 on their surface, which activate T cells.
121
How do CD4 T cells activate B cells in MALT?
Activated CD4 T cells stimulate B cells through CD40L-CD40 interaction, aided by cytokines and chemokines.
122
Why do lymphoepithelial lesions in MALT persist and avoid apoptosis?
The interaction among epithelial cells, T cells, and B cells allows these cells to cooperatively survive within the lesions and resist apoptosis.
123
What role do cytokines and chemokines play in MALT development?
They facilitate communication between T cells and B cells, supporting their activation and survival.
124
What is thought to be the origin of lymphomas
Lymphoepithelial lesions (LELs)
125
What facilitates the transition from polyclonal to monoclonal lesions
chronic stimulation with exogenous or autoantigens increasing the frequency of their transformation
126
what kind of MALT lymphomas can progress and become H.pylori independent
H.pylori dependent alterations e.g. trisomies 3,12 or 18
127
what will eventually happen to a MALT lymphoma
it may transform into a high grade tumour when there is e.g. complete inactivation of tumour suppressor gene P53, homologous deletion of the P16 gene and chromosomal translocation of cMYC and BCL6 ( all associated with MALT lymphoma transformation)
128
what is the growth of gastric MALT lymphoma linked to
the presence of H.pylori when there are alterations like trisomies 3,12 or 18
129
What happens to gastric MALT if H.pylori is removed, proton pump inhibitors / antibiotics are provided
the inflammation will calm down completely and the normal status quo will be restored
130
What happens to gastric MALT if H.pylori is removed, proton pump inhibitors / antibiotics are provided after there is complete inactivation of the tumour suppressor gene P53, homologous deletion of the P16 gene and chromosomal translocation of cMYC and BCL6
nothing as the tumour / lymphoma has established itself
131
how is MALT lymphoma treated?
Through chemotherapy ( it was believed that MALT lymphoma was the only tumour that could be treated surgically but this is not the case apart from early on e.g. can remove the stomach if it is restricted to this area)
132
what other types of gastric tumours ( apart from MALT lymphoma) are there
tumours of the smooth muscle, fat, gastrointestinal stroma tumour (associated with abnormalities in the tyrosine kinase) and gastric adenocarcinoma diffuse type ( doesn't make glands )
133
what is gasrtic adenocarcinoma : diffuse type made up of
single cells (with a signet ring appearance) and CDH1 E-cadherin mutation that individually infiltrate the gastric wall. They arise directly from gastric foveolar epithelium and have a worse prognosis
134
What stain can be used to distinguish / confirm gastric adenocarcinoma diffuse type
E-cadherin immunohistochemical stain (also the case for lobular carcinoma of the breast)
135
Gastric carcinomas and familiar or hereditary origin
- 10% of gastric carcinomas show familial clustering
- 1-3% of gastric carcinomas arise from inherited gastric cancer predisposition syndromes
136
what are examples of inherited gastric cancer predisposition syndromes which increase your chances of gastric cancers
* Hereditary diffuse gastric carcinoma (HDGC),
* Familial adenomatous polyposis,
* hereditary nonpolyposis colorectal carcinoma (or lynch syndrome),
* Petuz-Jeghers syndrome,
* Li-fraumeni syndrome
* Gasrtic hyperplastic polyposis
(individually these conditions are rare but together they amount to a considerable number in the population)
137
Hereditary diffuse gastric carcinoma
HDGC is an autosomal dominant disorder with high penetrance, approx 30% of individuals with HDGC have a germline mutation in the tumour suppressor gene E-cadherin or CDH1. the inactivation of the second allele of E-cadherin through mutation, methylation and loss of heterozygosity eventually triggers the development of gastric cancer.
138
why are gastrin secreting cells needed in the Antrum
because gastrin increases the release of acid
139
What is a gastrointestinal stromal tumor (GIST)?
the most common mesenchymal tumour of the digestive tract, specifically in cells called interstitial cells of Cajal (ICCs), which are sometimes called the "pacemakers" of the GI tract
140
Which genetic mutations are most commonly associated with GISTs
Most GISTs harbor mutations in the KIT gene (CD117) or less frequently in the PDGFRA receptor tyrosine kinases. This means that treatment often involves tyrosine kinase inhibitors (TKIs) like imatinib
141
What role does imatinib play in managing GISTs?
imatinib targets KIT and PDGFRA inhibiting them, blocking signal transduction of pathways involved in cellular processes: cell proliferation apoptosis, angiogenesis ..... ultimately reducing tumour growth, progression and metastasis.
