Histopathology Flashcards
Neutrophils
associated with acute inflammation
Lymphocytes and plasma cells
associated with chronic inflammation and also lymphomas (sheaths of lymphocytes)
Eosinophils
associated with allergic reactions (and drug-induced), parasitic infections, and tumours (eg. Hodgkin’s lymphoma eosinophils as a reaction to the cancer, they’re not the cancer cells themselves)
Eosinophilic oesophagitis
feline contractions
Mast cells
characteristically large granules containing lots of inflammatory mediators
allergic reactions
Macrophages
lots of cytoplasm, inconspicuous nucleus
associated with late acute inflammation and chronic inflammation (including granulomas)
Granuloma
organised collection of activated macrophages
become more secretory rather than phagocytic
How to tell if sputum sample is actually from alveoli?
if contains macrophages
Stain for TB
acid fast stain
Ziehl-Neelson
(red)
Ontological classification
classified according to cells of origins
Types of carcinomas
= malignant tumours of epithelial cells
most common tumours seen
1. squamous cell carcinoma
2. Adenocarcinoma
3. Transitional cell carcinoma
Squamous cell carcinoma
keratin production (not always)
intercellular bridges
Adenocarcinoma
mucin production
glands
Sites of origin of squamous cell carcinomas
skin
head and neck
oesophagus
anus
cervix
vagina
Sites of origin of adenocarcinoma
lung
breast
pancreas
colon
stomach
Prussian blue stain
stains for ferritin (iron)
Congo red stain
amyloid
under polarised light: apple green birefringence
CD45
lymphoid marker
Van den bergh test
measures serum bilirubin via fractionation
direct reaction measures conjugated bilirubin (addition of methanol causes a complete reaction which measures total bilirubin)
indirect reaction measures unconjugated bilirubin (the difference)
Paediatric jaundice
usually normal due to immaturity of liver and fall of Hb in early life so bilirubin will be high and unconjugated
if it doesn’t settle, may be caused by something else eg. hypothyroidism or other causes of haemolysis (do coombe’s or DAT)
why do we use phototherapy for unconjugated bilirubinaema?
skin can also conjugate bilirubin
can convert bilirubin into 2 other compounds: lumirubin and photobilirubin which are isomers that do not need excretion or conjugation
Gilbert’s syndrome
quite common
recessive inheritance
raised bilirubin with all other LFTs normal
bilirubin increases with fasting and decreased by phenobarb
50% of people carry the gene
prevalence in population is 5.6%
don’t need biopsy or USS
Gilbert’s pathology
UDP glucoronyl transferase activity reduced to 30%
unconjugated bilirubin is tightly bound to albumin and does not enter urine
NB: will still have urobilinogen in urine as entero-hepatic circulation is still functional
No urobilinogen in the urine
obstructive jaundice
Aspartate aminotransferase (AST)
takes the amino acid off aspartate and converts into a glucose derivative
Alanine aminotransferase (ALT)
takes amino acid off alanine
when liver is damaged, leaks into the blood
What is most representative of liver function
Prothrombin time (liver makes clotting factors)
also albumin because made by liver and bilirubin because metabolised by liver
liver enzymes (ALT, AST, ALP, GGT) don’t actually tell you about liver function but leak out when liver is damaged
NB: in paracetamol overdose, PT determines prognosis (if high, will need transplant)
Hepatitis A serology
virus in faeces
incubation period
become infective
immune response begins: IgM
start to get jaundiced and symptomatic
IgG response begins at 5-weeks post-exposure
immune for life
vaccine available
Hepatitis B serology - acute
2 forms: acute (like Hep A) and chronic
acute: become unwell 2-months post exposure, increased HBs Ag and HBe Ag
then start antibody response with anti-HBc, HBs and HBe (only when antigen titre reaches 0 for corresponding antigen) - end up with 3 antibodies and no antigen, probably won’t get it again but may be a carrier
vaccine is against surface antigen (anti-HBs, won’t have HBe antibody)
Chronic hepatitis B (carriers)
surface antigen remains for years
remains infectious to others
only have anti-HBc and anti-HBe but not anti-HBs as remain antigenic
cannot undergo surgery due to infectious risk
Alcoholic hepatitis (histology)
neutrophilic inflammation
balloon cells with mallory’s hyaline (pink cells) - damaged hepatocytes
alcoholic fatty liver is reversible but alcoholic hepatitis may not be reversible
may see fatty change left over from early stages
positive blue collagen stain - high risk of end-stage liver disease (cirrhosis)
megamitochondria (big and swollen - damage due to alcohol)
NASH (non-alcoholic steatohepatitis)
commonest cause of fatty liver disease today
causes: overweight, malnourished
same histological features as alcoholic hepatitis
associated with high BMI and diabetes
10% of people with normal BMI also have it
Alcoholic hepatitis treatment
supportive: stop alcohol
nutrition: vitamins esp b1(IV pabrinex)
occasionally steroids
liver hepatocytes will regenerate (as long as alcohol stops) - not uniform distribution with hexagonal arrangement and portal triads so may develop cirrhotic nodules (regenerating hepatocytes) eventually leading to portal hypertension (continued cycle of drinking alcohol)
Vitamin B1 deficiency
Beri-Beri
Vitamin B3 (niacin) deficiency
Pellagra
Gynaecomastia in liver disease mechanism
liver breaks down oestradiol, dysfunctional liver leads to build-up of oestradiol and decreased testosterone, causing gynaecomastia
Signs of chronic stable liver disease
spider naevi
palmar erythema
gynaecomastia
dupuytren’s contracture (alcohol)
Signs of portal hypertension
1.visible veins on the abdominal wall
2. splenomegaly (portal vein includes splenic vein)
3. ascites
NB: caput medusae from umbilicus (damage to portal triads causes high pressure in umbilical vein because blood can’t leave liver through artery so blood travels back down through the portal vein and ductus venosus to the umbilicus)
Non-shifting dullness
normal - fat (doesn’t move)
Shifting dullness
= ascites
sign of portal hypertension
Flapping tremor
sign of liver failure
possibly caused by ammonia but unsure (same flap as CO2 retention)
Liver failure
failed synthetic function
failed clotting factor and albumin production
failed clearance of bilirubin (jaundice)
failed clearance of ammonia (encephalopathy)
need to decrease protein intake and minimise risk of GI bleed but many die
treatment: liver transplant
Portal hypertension histopathology
micro or macro cirrhotic nodules (caused by regenerating hepatocytes) surrounded by a fibrous fat cuff characteristic of alcohol pathology
fatty changes are reversible
scarring in hepatocytes between portal vein and hepatic vein therefore blood entering liver completely bypasses hepatocytes (intrahepatic shunting of blood) - blood isn’t filtered and liver is not receiving blood
NB: caput medusae and visible veins on abdomen = extrahepatic shunting of blood
Progression of alcoholic liver disease
Alcoholic hepatitis (reversible)
Chronic stable liver disease (cycle)
Portal hypertension
Liver failure (end-stage)
Portosystemic anastamoses sites & portal hypertension consequences
oesophagus (portal hypertension causes varices - if they tear, bleed to death because no muscle in them)
rectal varices
umbilical vein recanalising
spleno-renal shunt
Causes of itching/scratch marks in liver pathology
obstruction of bile ducts only (not just jaundice) - causes by bile salts not bilirubin
bile salts/acids emulsify fats and are reabsorbed in the entero-hepatic circulation but when there’s an obstruction of the bile duct, bile salts/acids enter the systemic circulation and make you itch
Courvoisier’s law
if a gallbladder is palpable in a jaundiced patient the cause is likely pancreatic cancer and not gall stones
(gall stones cause a small, shrunken, fibrotic gallbladder so won’t be palpable)
Pancreatic cancer investigations
Abdo USS:
dilated bile ducts
metastasis
Pancreatic carcinoma histopathology
fibrous white tumour tissue
metastasis through lymphatics
multiple tumour deposits in liver (likely to be secondary as there are multiple deposits) - rapid metastasis through portal vein
usually adenocarcinoma (glandular)
Normal breast histology
Rule of 2s:
2 main structures:
- Large ducts
- TDLU (terminal ductus lobular unit)
2 types of epithelial cells:
- luminal cells
- myoepithelial cells
2 types of stroma:
- interlobular stroma (found between ductules and acini)
- intralobular stroma
Lactiferous ducts divide into extra and intra-lobular terminal ducts which further divide into acini and ductules
Terminal duct lobular unit
= extralobular terminal duct with lobule
= functional unit of the breast
Acinus histology
glandular structure
lined by outer myoepithelial cell layer and inner luminal cell layer
Presentation of breast disease
breast lump
abnormal screening mammogram
nipple discharge
most problems are benign but breast cancer is second biggest cancer killes
Investigating breast disease
triple assessment:
physical exam
imaging (sonography, mammography, MRI)
pathology (cyto/histopathology)
Cytopathology in breast disease
indicated if palpable lump or nipple discharge
Nipple discharge cytology
papilloma is most common breast lesion that presents with nipple discharge
weak association with cancer but increased if discharge is bloody or associated with lump
FNA cytology in breast
safe, reliable, accurate, fast, cost-effective, almost complication-free
good cellular detail and quick to prepare but cannot differentiate atypical ductal hyperplasia from low grade cancer or high grade in situ carcinoma from invasive cancer
ancillary testing not always possible
Cytopathology grading breast lumps
C1- inadequate
C2 - benign
C3 - atypia, probably benign
C4- suspicious of malignancy
C5 - malignant
Histopathology for breast
intact tissue is removed, fixed in formalin, embedded in paraffin wax, thinly sliced and stained with H&E
includes biopsies and surgical excisions
takes 24 hours to process
gives architectural and cellular detail
Histopathology breast grading (biopsies only)
B1 - normal tissue / inadequate sample
B2 - benign lesion
B3 - uncertain malignant potential (need to follow-up with surgical excision eg.)
B4 - suspicious of malignancy
B5 - malignant
Acute mastitis
acute inflammation in the breast
usually seen in context of lactation due to cracked skin and stasis of milk
may complicate duct ectasis or abscess
staph is usual organisms
painful red breast (unilateral)
drainage and antibiotics
histology: lots of inflammatory cells (neutrophils) - may obscure view of normal breast tissue, gram positive
Duct ectasia
5th-6th decade, multiparous women
inflammation and dilation of large breast ducts
aetiology unclear
usually presents with nipple discharge
sometimes: breast pain, breast mass, nipple retraction
benign with no increased risk of malignancy
cytology (of nipple discharge): proteinaceous material and inflammatory cells only
can give rise to giant cell reaction
Fat necrosis (breast)
An inflammatory reaction to damaged adipose tissue.
Caused by trauma, surgery, radiotherapy.
Presents with a breast mass, late stages may show focal calcification.
Benign condition.
histology: lipid vacuoles surrounded by inflammatory cells (macrophages and large cells)
Galactocele
Cystic dilation of a duct during lactation
Usually multiple ducts
Tender palpable nodules
Secondary infection may convert these to acute mastitis or abscess
Proliferative breast diseases
A diverse group of intraductal proliferative lesions of the breast associated with an increased risk, of greatly different magnitudes, for subsequent development of invasive breast carcinoma.
Microscopic lesions which usually produce no symptoms.
Diagnosed in breast tissue removed for other reasons or on screening mammograms if they calcify.
most common = fibrocystic disease
Fibrocystic disease (breast)
A group of alterations in the breast which reflect normal, albeit exaggerated, responses to hormonal influences.
Very common.
Presents with breast lumpiness.
No increased risk for subsequent breast carcinoma.
histology: fibrous tissue, large cystic glands, adenosis (increased number of glands), may also get apocrine metaplasias
Radial scar
A benign sclerosing lesion characterised by a central zone of scarring surrounded by a radiating zone of proliferating glandular tissue.
Range in size from tiny microscopic lesions to large clinically apparent masses.
Lesions >1 cm are sometimes called “complex sclerosing lesions”.
Reasonably common lesions.
Thought to represent an exuberant reparative phenomenon in response to areas of tissue damage in the breast.
Usually present as stellate masses on screening mammograms which may closely a carcinoma.
Excision is curative.
Scar is a misnomer; not related to prior trauma or surgery
Radiological presents as spiculated mass, architectural distortion, may be indistinguishable from invasive carcinoma – often biopsied
Associated risk with invasive breast cancer debated
Usual epithelial hyperpalasia
Not considered a direct precursor lesion to invasive breast carcinoma but is a marker for a slightly increased risk (relative risk of 1.5-2.0) for subsequent invasive carcinoma
Proliferation of cells of luminal and myoepithelial lineages
Cytologic features Mild variation in cellular and nuclear size and shape
Architectural features Cohesive proliferation with haphazard, jumbled cell arrangement or streaming growth pattern, Irregular slit-like fenestrations are common, especially along periphery
Flat epithelial atypia
Emerging genetic data suggests FEA may represent the earliest morphological precursor to low grade ductal carcinoma in situ.
relative risk ~1.5 of developing cancer
Frequent secretions andcalcificationswithin cystically dilated glands
One to several layers of low columnar or cuboidal cells with low grade cytologic atypia
Prominent apical tufting (snouts)
Nuclei are usually round with variably prominent nucleoli
In-situ lobular neoplasia
Current evidence suggests that in situ lobular neoplasia is a risk factor for subsequent invasive breast carcinoma in either breast in a minority of women.
The relative risk is quoted as between 8-10 times that expected in women without lobular neCurrent evidence suggests that in situ lobular neoplasia is a risk factor for subsequent invasive breast carcinoma in either breast in a minority of women.
The relative risk is quoted as between 8-10 times that expected in women without lobular neoplasia.
More commonly diagnosed in the 50s
Does NOT form a palpable mass
Solid, (so no arcades, lumens or papillary projections) discohesive proliferation of cells that are monomorphic, small, have pale pink cytoplasm, uniform oval nuclei and indistinct nucleoli, distends >50% of the acini in the lobule
Fibroadenoma
A benign neoplasm composed of fibrous and glandular tissue.
Common.
Presents as a circumscribed mobile breast lump in young women aged 20-30.
Simple “shelling out” curative.
cytology: stromal naked cells (no cytoplasm), luminal cells (honeycomb epithelial cells), Antlo-horn formations (reassuring its benign)
histology: fibrous tissue around ducts or stromal overgrowth compressing ducts
Phyllodes tumours
A group of potentially aggressive fibroepithelial neoplasms of the breast.
Uncommon tumours.
Present as enlarging masses in women aged over 50.
Some may arise within pre-existing fibroadenomas.
Vast majority behave in a benign fashion, but a small proportion can behave more aggressively.
cytology: only stromal cells (no glandular features)
histology: increasing stromal proliferation –> leaf-like architecture
Intraductal papilloma
A benign papillary tumour arising within the duct system of the breast.
Arise within small terminal ductules (peripheral papillomas) or larger lactiferous ducts (central papillomas).
Common.
Seen mostly in women aged 40-60.
Central papillomas present with nipple discharge.
Peripheral papillomas may remain clinically silent if small.
Excision of involved duct is curative.
cytology: Large stellate tissue fragments of benign ductal cells in a proteinaceous background
histology: intraductal proliferation comprised of arborizing fibrovascular cores lined by outer layer of luminal cells and an inner layer of myoepithelial cells
Myoepithelial cells also present at the periphery of the involved duct
associated with usual type ductal hyperplasia and apocrine metaplasia, less frequently squamous, osseous or chondroid metaplasia may be seen
May undergo ischemic or hemorrhagic changes, either spontaneously or secondary to biopsy / trauma
May show prominent fibrosis / sclerosis which may contained entrapped glands (sclerosing papilloma)
Paget disease of nipple
Proliferation of malignant glandular epithelial cells (in situ carcinoma) in the nipple areolar epidermis.
Uncommon clinical presentation of breast cancer, occurs in 1 - 4% of women and 1 - 2% of men
Peak incidence between 6th and 7th decade.
Pathogenesis:
Epidermotropic theory (most widely accepted) - Paget cells are DCIS cells that migrate along the basement membrane of the nipple, supported by the presence of DCIS deeper in the breast identical to Paget cells in almost all cases;
Transformation theory - Paget cells originate from malignant transformation of keratinocytes or Toker cells; it would explain rare cases (< 5%) in which cancer is not present in underlying breast - could also be due to biopsy not sampling cancer cells
Underlying high grade DCIS or invasive carcinoma is present in > 95% of patients.
Majority of Paget cells and associated underlying carcinoma are HER2+
Paget disease presentation & histology
Nipple areolar complex with red-pink crusting lesion, discoloration, thickening, ulceration, exudate, nipple retraction
Paget cells have abundant pale, clear cytoplasm, which often contains mucin. The nuclei are large and show prominent nucleoli. Paget cells are typically present at the basal portion of the epidermis but can extend throughout the entire thickness and be present very superficially.
Ductal carcinoma in situ (DCIS)
A neoplastic intraductal epithelial proliferation in the breast with an inherent, but not inevitable, risk of progression to invasive breast carcinoma (2 - 8.6 times).
Common.
Incidence has markedly increased since the introduction of breast screening programs.
85% are detected on mammography as areas of microcalcification.
10% produce clinical findings such as a lump, nipple discharge, or eczematous change of the nipple (Paget’s disease of the nipple).
5% are diagnosed incidentally in breast specimens removed for other reasons.
Subclassified histologically into low, intermediate and high grade.
Treatment is surgical excision.
Complete excision with clear margins is curative.
Recurrence is more likely with extensive disease and high grade DCIS.
Low grade DCIS
Fenestrated proliferation with multiple, round, rigid extracellular lumens with punched out appearance
Neoplastic cells are frequently evenly distributed equidistant and polarized with long axis of cell perpendicular to the central lumen
Monotonous, round nuclei with smooth contours, small size nuclei
High grade DCIS
Lumen of ducts or lobules filled with sheets of cohesive cells
Cells are evenly spaced especially in low or intermediate grade DCIS
Prominent pleomorphism, large size nuclei
Comedonecrosis (central necrosis with specks of calcification)
Invasive breast carcinomas
A group of malignant epithelial tumours which infiltrate within the breast and have the capacity to spread to distant sites.
The most common cancer in women with a lifetime risk of 1 in 8.
Incidence rates rise rapidly with increasing age, such that most cases occur in older women.
Aetiology: Early menarche, late menopause, increased weight, high alcohol consumption, oral contraceptive use, and a positive family history are all associated with increased risk.
About 5% show clear evidence of inheritance. BRCA mutations cause a lifetime risk of invasive breast carcinoma of up to 85%.
Presentation: Most cases present symptomatically with a breast lump.
An increasing proportion of asymptomatic cases are detected on screening mammography.
Invasive ductal carcinoma
Most common type of invasive breast carcinoma (75 - 80%).
Majority are sporadic; 5 - 10% of all breast cancers are associated with hereditary cancer susceptibility genes
lacks the histologic features to classify morphologically as a special subtype of breast cancer
Cytology - cellular pleomorphism, nuclear size, nucleoli, lack of naked nuclei, cellular dyscohesion and mitoses & necrosis
Invasive lobular carcinoma
Comprises about 10% of invasive breast carcinomas
Most common special subtype of invasive breast carcinoma
Only comprises 1% of male breast carcinomas
More frequently bilateral and multifocal (need MRI of other breast to identify if another lesion)
histology: monotonous proliferation of cells distending the ducts –> break basement membrane and into adjacent stroma –> indian filing (nuclei on top of eachother)
Invasive tubular carcinoma
A well differentiated variant with very favorable prognosis
Histology: irregular angulated contours of glands (“teardrop-like”), open lumina with apocrine-like snouts and basophilic secretions
Invasive mucinous carcinoma
Clusters / nests of tumor cells with low or intermediate nuclear grade floating in pools of extracellular mucin, associated with favorable prognosis
Basal-like breast carcinoma
Recently described type of carcinoma discovered following genetic analysis of breast carcinomas.
Histologically characterised by sheets of markedly atypical cells with a prominent lymphocytic infiltrate.
Central necrosis is common.
Immunohistochemically characterised by positivity for “basal” cytokeratins CK5/6 and CK14.
Often associated with BRCA mutations.
Seem to have particular propensity to vascular invasion and distant metastatic spread.
Invasive breast cancers histological grading
graded histologically by assessing 1) tubule formation 2) nuclear pleomorphism, and 3)mitotic activity.
Each parameter is scored from 1-3 and the three values are added together to produce total scores from 3-9.
3-5 points = grade 1 (well differentiated).
6-7 points = grade 2 (moderately differentiated).
8-9 points = grade 3 (poorly differentiated).
Histologic grading is based on the Nottingham / modified Bloom & Richardson Score
Assessing receptor status of breast cancers
All invasive breast carcinomas are assessed for oestrogen receptor (ER), progesterone receptor (PR) and Her2 status.
Low grade tumours tend to be ER/PR positive and Her2 negative.
High grade tumours tend to be ER/PR negative and Her2 positive.
Basal-like carcinomas are often ER/PR/Her2 negative (“triple negative”).
Breast cancer prognosis
The single most important prognostic factor is the status of the axillary lymph nodes.
Other important factors include tumour size, histological type, and histological grade.
NHS Breast screening programme (BSP)
The aim of screening is to pick up DCIS or early invasive carcinomas.
Women aged 50-71 are invited for screening every three years.
The screening test is a mammogram which looks for abnormal areas of calcification or a mass within the breast.
About 5% of women have an abnormal mammogram and are recalled to an assessment clinic for further investigation.
This may include more mammograms, or an ultrasound followed by sampling of the abnormal area, usually by core biopsy. - given b grade –> B4 and B5 need further investigation (B5a = DCIS, B5b = invasive carcinoma, B5c = certain it is malignant but cannot tell if DCIS or invasive)
Male breast histology
Composed of ductal structures only within collagenized stroma, with no / rare acini (no/very rare diseases that affect acini)
pathologies: gynaecomastia and male breast cancer
Male gynaecomastia
Refers to enlargement of the male breast.
Pubertal boys and older men aged over 50.
Idiopathic or associated with drugs (both therapeutic and recreational).
Histologically the breast ducts show epithelial hyperplasia with typical finger-like projections extending into the duct lumen. The periductal stromal is often cellular and oedematous.
Benign, no risk of malignancy.
Male breast cancer
rare (0.2% of all cancers).
Median age at diagnosis 65 years old.
Most present with a palpable lump.
Histologically the tumors show similar features to female breast cancers.
(lobular cancers rare due to lack of lobules)
New breast cancer predictive methods
Oncotype DX assay is a genomic test that predicts adjuvant (radiotx for DCIS, Chemotx/radiotx for IDC) therapy benefit and the likelihood of 10-year breast cancer local recurrence risk in patients with DCIS treated with breast conserving surgery and low stage ER positive invasive breast cancers
Novel biomarkers not used in routine clinical practice
High Ki67 proliferation index has reported to correlate with increased recurrence risk
tumor immune microenvironment is an important factor in identifying DCIS cases with the highest risk for recurrence
Normal oesophagus histology
lined by stratified squamous epithelium
transition into columnar epithelium of stomach: Z-line
Acute oesophagitis histology
oedema
neutrophils (inflammatory cells)
causes: alcohol, drugs, GORD
appearance on endoscopy: red and inflamed
Complications of reflux oesophagitis
ulceration (goes through muscularis into submucosa wheras erosion is superficial)
haemorrhage
perforation
stricture
Barrett’s oesophagus
Barrett’s Oesophagus
The same as columnar lined oesophagus (CLO)
Replacement of squamous epithelium by metaplastic columnar epithelium:
2 types:
- without goblet cells = gastric metaplasia
- with goblet cells = intestinal type metaplasia
Flat pathway: metaplasia -> LGD -> HGD -> adenocarcinoma (want to diagnose at metaplasia or dysplasia stage due to very poor prognosis)
Adenocarcinoma of oesophagus
The commonest oesophageal carcinoma in Developed Countries
Associated with reflux (flat pathway)
Lower oesophagus –> commonly at gastro-oesophageal junction
Squamous cell carcinoma of oesophagus
Commonest oesophageal cancer in Developing Countries
Associated with alcohol and smoking
Mid/lower oesophagus (higher up than adenocarcinoma)
also association with HPV
histology: production of keratin, intercellular bridges
Oesophageal varices
= varicose veins in oesophagus
associated with portal hypertension (caused by extrahepatic shunting of blood)
important cause of mortality and morbidity
Normal stomach (body) histology
lined by gastric mucosa columnar epithelium (foveolar, mucin secreting)
specialised glands in the lamina propria (secrete IF, acid, pepsinogen)
muscularis mucosae
Normal stomach (antral) histology
lined by gastric mucosa columnar epithelium (fovelolar, mucin secreting)
Non-specialised glands in the lamina propria
(gastric pits)
mucularis mucosae
Acute Gastritis causes
Chemical:
aspirin/NSAIDs
alcohol
corrosives
Infection:
e.g. Helicobacter pylori
Causes of chronic gastritis
Autoimmune (antiparietal antibodies etc. body)
Bacterial (H. pylori; antrum )
Chemical (NSAIDs, bile reflux; antrum)
Other causes of gastritis
Infection
e.g. CMV (commonest opportunistic viral pathogen), strongyloides (worms)
Inflammatory bowel disease
Crohn’s Disease (gastric involvement more common in children)
Helicobacter associated gastritis
Cause
H. pylori
Pattern
chronic gastritis +/- activity
Outcome
Peptic ulcer (gastric and duodenal) - commonest cause
Metaplasia +/- dysplasia,
Adenocarcinoma
Lymphoma (MALToma) - can be reversible if treat helicobacter
Complications of ulcers
Bleeding
Anaemia
Shock (massive haemorrhage)
Perforation
Peritonitis
Cancer (rare)
Helicobacter as a carcinogen
Helicobacter infection is associated with an 8x increased risk of (non-cardia) gastric cancer
cag-A-positive H.pylori have a needle like appendage that injects toxin into intercellular junctions allowing the bacteria to attach more easily.
This strain is associated with more chronic inflammation.
Treatment of the infection with antibiotics drastically reduces the risk of cancer.
Flat dysplasia pathway in stomach
chronic gastritis –> intestinal metaplasia –> dysplasia –> cancer
Intestinal metaplasia
Presence of goblet and Paneth cells
In response to chronic gastritis
Increased cancer risk
(if significantly widespread –> need careful follow-up)
Gastric epithelial dysplasia
Abnormal epithelial pattern of growth
Some of the cytological and histological features of malignancy are present, but no invasive through the basement membrane
Gastric cancer
High incidence in Japan, Chile, Italy, China, Portugal, Russia
More common in men (1.8:1 ♂:♀)
>95% of all malignant tumors in stomach are adenocarcinomas (glandular - secrete mucin)
These are split morphologically into:
- Intestinal – form glands, well differentiated
- Diffuse – poorly differentiated (Linitis plastica), includes signet ring cell carcinoma
The remaining 5% is mainly made up of:
- Lymphoma (MALToma)
- Gastrointestinal stromal tumour (GIST)
- Neuroendocrine tumours (mostly in terminal ileum)
Gastric MALToma / Lymphoma
Chronic inflammation
- Chronic immune stimulation
B cell (marginal zone) lymphocytes
Treatment
- If limited to the stomach and H.pylori is present: H.pylori eradication
Gastro-intestinal stromal tumour (GIST)
Derived from the interstitial cells of Cajal.
Spindle cell tumours
Stain with CD117 (not smooth muscle actin)
Anywhere in the GIT but stomach is the commonest site.
Prognosis depends on site (stomach best), size (the smaller the better) and mitotic index (the lower the better)
Normal duodenum histology
Glandular epithelium
with goblet cells
(intestinal type epithelium)
Villous architecture
villous:crypt ratio of >2:1
Duodenitis, duodenal ulcers and H. pylori
Increased acid production in the stomach which spills over into duodenum
Chronic inflammation and gastric metaplasia with helicobacter infection
no significant risk of dysplasia and cancer
Other pathogens causing duodenitis and duodenal ulcers
Immunosuppressed
CMV
Cryptosporidiosis
Giardia lamblia infection
Whipple’s disease -Tropheryma whippelii.
Malabsorption - partial villous atrophy (coeliac)
Histology
- Villous atrophy
- Crypt hyperplasia
- Increased Intraepithelial lymphocytes
(normal range less than 20 lymphocytes /100 enterocytes)
Coeliac disease
Diagnosis requires:
endomysial antibodies and tissue transglutaminase antibodies
Duodenal biopsies:
- On gluten rich diet showing villous atrophy
- Off gluten showing normal villi (can make it difficult to diagnose if pt has already stopped consuming gluten)
There are other causes of malabsorption with similar histology e.g. tropical sprue (from developed countries go to developing countries and exposed to new mircobiome), drugs
Duodenal MALToma/ Lymphoma
Patients with coeliac disease have an increased risk of GIT cancers
MALToma associated with Coeliac is
in the duodenum
T-cell origin
(Enteropathy Associated T-cell Lymphoma)
histology: big nuclei and lots of nucleoli
Pancreatic histology
Exocrine: ducts and acini
Endocrine: islets of langerhan cells, alpha and beta cells
Acute pancreatitis
Acute inflammation of the pancreas caused by aberrant release of pancreatic enzymes. (can lead to positive feedback loop)
Relatively common, incidence increasing.
Causes:
Duct obstruction:
- Gall stones (50%)
- Trauma
- Tumours
Metabolic/toxic:
- Alcohol (33%) - 5% of alcoholics develop acute pancreatitis
- Drugs (e.g. thiazides)
- Hypercalcaemia
- Hyperlipidaemia
Poor blood supply:
- Shock
- Hypothermia
Infection/ inflammation:
- Viruses (e.g. mumps)
Autoimmune
Idiopathic (15%)
Acute pancreatitis pathogenesis
2 major pathways:
(1) Duct obstruction:
- Gallstone stuck distal to where the common bile duct and pancreatic ducts join leads to:
reflux of bile up the pancreatic duct followed by damage to acini and release of proenzymes which then become activated
-Alcohol leads to spasm/oedema of Sphincter of Oddi and the formation of a protein rich pancreatic fluid which obstructs the pancreatic ducts
(2) Direct acinar injury (eg. mumps) –> rest of causes
Patterns of injury in acute pancreatitis
Periductal - necrosis of acinar cells near ducts (usually secondary to obstruction)
Perilobular – necrosis at the edges of the lobules (usually due to poor blood supply)
Panlobular – develops from both of the above
Activated enzymes –> acinar necrosis –> enzyme release etc.
Ranges from stromal oedema, to haemorrhagic necrosis
e.g. Lipases –> fat necrosis:
1. Lipase splits triglycerides into glycerol and free fatty acids
2. calcium ions bind to the free fatty acids forming soaps which are seen as yellow-white foci (calcium levels will be normal as being used up to bind to fatty acids unless cause of pancreatitis was hypercalcaemia in which case the calcium may be normal)
Complications and prognosis of acute pancreatitis
Complications
Pancreatic : pseudocyst (lacks an epithelial lining, fluid-filled, localised and looks like a cyst), abscess (very infected pseudocyst)
Systemic: shock, hypoglycaemia (damage to islets), hypocalcaemia (calcium binds to free fatty acids forming fat necrosis)
Prognosis
Overall mortality up to 50% for haemorrhagic pancreatitis
Chronic pancreatitis
Relapsing or persistent, associated with acute pancreatitis in half of cases
Relatively uncommon
Mortality 3% per year
Causes:
Metabolic/toxic:
- Alcohol (80%)
- Haemochromatosis (iron deposition in pancreas causing damage)
Duct obstruction: - Gallstones - Abnormal pancreatic duct anatomy
- Cystic fibrosis (“mucoviscoidosis”) - thick secretions causing obstruction
Tumours
Idiopathic Autoimmune
Pathogenesis & Pattern of injury for chronic pancreatitis
Pathogenesis = same as acute but with fibrosis and atrophy , loss of acini –> loss of secretory function
Pattern of injury:
Chronic inflammation with parenchymal fibrosis and loss of parenchyma
Duct strictures with calcified stones with secondary dilatations
Complications of chronic pancreatitis
Malabsorption (loss of exocrine function)
Diabetes mellitus (eventual loss of islets of langherhans)
Pseudocyst
Carcinoma of the pancreas (?) (multi-directional ie. can both cause eachother)
Pancreatic pseudocyst
Associated with acute and/ or chronic pancreatitis
Lined by fibrous tissue (no epithelial lining), contain fluid rich in pancreatic enzymes or necrotic material
Connect with pancreatic ducts
May resolve, compress adjacent structures, become infected or perforate (-> peritonitis)
Autoimmune pancreatitis
= IgG4 related diseases
Characterised by large numbers of IgG4 positive plasma cells.
May involve the pancreas, bile ducts and almost any other part of the body.
Benign
Tumours of the pancreas
3 categories:
Carcinomas
- Ductal (85% of all neoplasms)
- Acinar
Cystic neoplasms
- Serous cystadenoma
- Mucinous cystic neoplasm
Pancreatic neuroendocrine tumours (Islet cell tumours)
Risk factors for pancreatic carcinoma
Smoking
BMI and dietary factors
Chronic pancreatitis
Diabetes
Pancreatic ductal carcinoma
5% of cancer deaths
Increasingly common with age, 2M: 1F
5 year survival: 5%
Arise from dysplastic ductal lesions:
Pancreatic Intraductal Neoplasia (PanIN)
Intraducal Mucinous Papillary Neoplasm (IMPN)
K-Ras mutations in 95% of cases
Ductal carcinoma histopathology
Macroscopic Appearance
- Gritty and grey
- Invades adjacent structures
- Tumours in the head present earlier (early obstruction and clinical presentation)
Microscopic Appearance
Adenocarcinomas: mucin secreting glands set in desmoplastic stroma (response to cancer growing in it)
very aggressive: peri-neural invasion (common way of spread)
Pancreatic ductal carcinoma sites & spread
Sites:
Head (60%)
Body
Tail
Diffuse
Spread:
Direct: Bile ducts, duodenum
Lymphatic: Lymph nodes
Blood: Liver
Serosa: Peritoneum
Complications of ductal pancreatic carcinoma
Due to spread
Chronic pancreatitis
Venous thrombosis (“migratory thrombophlebitis”) - hypercoagulable state
Cystic tumours
Contain serous or mucin secreting epithelium
(cf. ovarian tumours)
Usually benign
Pancreatic endocrine neoplasms
usually non-secretory (most common secretion = insulin –> present with hypogylcaemia)
contain neuroendocrine markers e.g. chromogranin (granules) - can stain for it or measure blood levels (for diagnosis and follow-up)
behaviour difficult to predict (usually associated with mitotic index)
may be associated with the Multiple Endocrine Neoplasia (MEN) 1 syndrome
Insulinomas
derived from beta cells
= commonest type of secretory tumour
Gall bladder pathology
- Gall stones
- Inflammation
- Cancer
All associated with stones
stones are very common: 20% of adults
Risk factors for gall stones
Age and gender: increasing age, F>M
Ethnic and geographic: e.g. Native Americans
Hereditary: e.g. disorders of bile metabolism
Drugs e.g. oral contraceptive (increased oestrogen)
Acquired disorders e.g. rapid weight loss (causing more bile secretion and movement)
Types of gall stones
Cholesterol (more than 50% cholesterol)
May be single, mostly radiolucent (not picked up on abdo x-ray)
Pigment (contain calcium salts of unconjugated bilirubin)
Multiple, mostly radio-opaque
Mixed type
Complications of gall stones
most cause no problems
Bile duct obstruction
Acute and chronic cholecystitis
Gall bladder cancer
Pancreatitis
Acute cholecystitis
Acute inflammation
90% associated with gall stones
Chronic cholecystitis
Chronic inflammation
Fibrosis (thick and hard GB wall)
Diverticula (mucosa going through muscularis) – Rokitansky-Aschoff sinuses
90% contain gall stones
Gall bladder cancer
Adenocarcinomas
90% associated with gall stones
most common in Chile and Andes, less common in UK
Tumours of the nervous system
CNS:
Brain and coverings
Spinal cord and coverings
Pituitary gland
PNS:
Small nerves in any organ – usually neurofibromas of soft tissue or skin
Large nerves – cranial and spinal nerve schwannomas
Most are benign tumours
Classification of CNS tumours by origin
Primary:
tumours that originated within CNS
Secondary:
Metastases - 10x more frequent than primary tumours in adults (30% of patients with systemic cancer develop CNS metastases)
NB: primary tumours most common CNS tumours in children
Classification of CNS tumours by location
EXTRA-AXIAL (coverings)
Tumours of bone, cranial soft tissue, meninges, nerves
INTRA-AXIAL (parenchyma)
Derived from normal cell populations of the CNS: glia, neurons and neuroendocrine cells
Derived from other cell types: lymphomas, germ cell tumours
WHO grade 1 tend to be more extra-axial
WHO grade 2-4 tend to be more intra-axial
Glioblastomas grade 4 and have worst prognosis
CNS tumours aetiology
Largely unknown
Only known environmental factor:
Previous radiotherapy to head and neck associated with increased risk of meningiomas (and rarely gliomas)
Genetic predisposition <5% of primary brain tumours
Familial syndromes:
Autosomal dominant inheritance with frequent de novo mutations
Some examples:
Neurofibromatosis 1 (17q11) neurofibroma, astrocytoma
Neurofibromatosis 2 (22q12) schwannoma, meningioma
Brain Tumour Polyposis syndrome 1 malignant gliomas
Gorlin syndrome (PTCH1, 9q31) medulloblastoma
Von Hippel Lindau (3p25) hemangioblastoma
CNS tumours clinical presentation
Not specific but can be subtle in slow growing tumours whereas there may be a very short history for malignant tumours
Intracranial hypertension:
headache
vomiting
change in mental status
Supratentorial:
focal neurological deficit
seizures
personality changes
Infratentorial (posterior fossa):
cerebellar ataxia
long tract signs
cranial nerve palsy
Neuroimaging
Modalities:
CT-scan
MR-scan
MR-spectroscopy (metabolism)
Perfusion MRI
Functional MRI
PET-scan
Uses:
Assess tumour type
Guide resection & biopsy
Assess post-surgery
Assess response to treatments
Follow-up recurrence and progression
Management of CNS tumours
SURGERY:
Maximal safe resection with minimal damage to adjacent normal tissue gives best outcome
Resection: location, size, number of lesions
RADIOTHERAPY:
Low and high-grade gliomas, metastases, some benign tumours
External fractionated RT, stereotactic radiosurgery
CHEMOTHERAPY:
Mainly for high-grade gliomas (temozolomide) and lymphomas
Biological agents (EGFR inhibitors, PD-L1 inhibitors, etc.)
Types of surgery for CNS tumours
Craniotomy for debulking
may be sub-total or complete resections
remove as much tumour as possible
Open biopsy
inoperable but approachable tumours (about 1cm of tissue)
usually representative
Stereotactic biopsy
if open biopsy not indicated (about 0.5cm of tissue)
tissue may be insufficient
WHO classification of CNS tumours
Tumour type:
Putative cell of origin or lineage of differentiation
Tumour grade:
Tumour aggressiveness
It is based on morphological criteria of malignancy (proliferative activity, cell differentiation, necrosis) and increasingly on genetic profile
Molecular profile:
Most tumour types have molecular markers
A four-tier system:
Grade 1 – benign – long-term survival (eg. meningiomas)
Grade 2 – more than 5 yrs
Grade 3 – less than 5 yrs
Grade 4 – less than 1 yr (eg. glioblastomas)
Some tumour types have only one possible grade, but others have more than one
CNS cell types and tumours
Astrocytes – astrocytoma
Oligodendrocytes – oligodendroglioma
Ependyma – ependymoma
Neurons- neurocytoma
Embryonal cells – medulloblastoma
Meningothelial cells – meningioma
Schwann cells - schwannoma, neurofibroma
Glial tumours
Diffuse gliomas:
Grades ≥ 2, adults, supratentorial, malignant progression
Astrocytomas (grades 2-4)
Oligodendrogliomas (grades 2-3)
Circumscribed gliomas:
Grades 1-2, children, often posterior fossa, rare malignant transformation
Pilocytic astrocytoma (grade 1)
Subependymal giant cell astrocytoma (grade1)
Ependymomas (usually)
Pilocytic astrocytoma
Usually 1st & 2nd decade (account for 20% CNS tumours below 14 yrs)
Often cerebellar, optic-hypothalamus, brainstem
Genetic profile: BRAF mutation in 70% of PA
MRI – well circumscribed,
cystic, enhancing lesion
Histology:
Piloid “hairy” cells
Very often Rosenthal fibres
Slowly growing, low mitotic activity
IDH mutant diffuse gliomas
Patients usually 20-40 yrs
Astrocytoma (IDH mutant) and Oligodendroglioma (IDH mutant)
Pathogenic point mutation in the IDH1/2 gene
IDH mutation is associated with longer survival and a better response to chemotherapy and radiotherapy
Astrocytomas
Patients usually 20-40 yrs, cerebral hemispheres
Genetic profile: point mutation in IDH1/2
MRI – T1 hypointense, T2 hyperintense,
non-enhancing lesion. Low choline/creatinine
ratio in MR spectroscopy
Histology: low to moderate cellularity
Mitotic activity is low. No vascular
proliferation or necrosis.
IDH1 mutants can be detected
Immunocytochemically
Progression to higher grades over time
Glioblastoma multiforme
Most aggressive and most frequent glioma; incidence increase with age
Most patients >50 yrs, cerebral hemispheres
Median survival 8 months
Genetic profile
IDH1 wildtype
Common mutations in:
TERT, PTEN, EGFR
MRI – heterogenous,
enhancing post contrast
Histology:
High cellularity
Neoangiogenesis
Necrosis
Meningiomas
38% of primary CNS tumours
Rare in patients < 40, incidence ↑ with age
Originate from meningothelial cells of the arachnoid mater
Any site of craniospinal axis, can be multiple (NF2)
MRI: extraxial, iso-dense, contrast-enhancing
80% Grade 1: benign, recurrence <25%
20% Grade 2: atypical, recurrence 25-50%
1% Grade 3: malignant, recurrence 50-90%
(Grading is most useful predictor of recurrence)
Mitotic activity (CNS tumours)
Determines grade
Mitosis per 10HPF (0.16mm2)
<4 = grade 1
4-20 = grade 2
>20 = grade 3
CNS metastases
Most frequent CNS tumour in adults (10 x intrinsic tumours)
Increasing incidence due to longer survival
Often multiple, located at grey/white matter junction and/or leptomeningeal disease
May be the first presentation of the disease
Origin can be challenging to determine: immunohistochemical markers
Any cancer can give CNS metastasis, but most frequent tumours are: lung ca, breast ca, melanoma, renal cell ca
Very poor prognosis
Medulloblastoma (WHO grade 4)
EMBRYONAL TUMOUR: originates from neuroepithelial cells/neuronal precursors of the cerebellum or dorsal brainstem
Rare (2 per 1,000,000 year), but second most common brain malignancy in children; also in young adults
Outcome considerably improved with radio-chemotherapy and subtype stratification
Histology
4 histological subtypes: classic, nodular/desmoplastic, extensive nodularity, large cell anaplastic
3 molecular subtypes by transcriptome or methylome profiling: WNT-activated, SHH-activated, nonWNT/nonSHH
Methylome profile
Most tumours have characteristic patterns of DNA methylation of CpG islands
The methylation signature is stable and reflects the tumour cell of origin or early transformed cells
- Gives information on tumour type not progression/grade
The DNA methylation status of a subset of CpG islands is assessed with DNA arrays and compared to a reference dataset (“Classifier”)
Mechanisms of CNS damage
Oedema
Hydrocephalus
Raised intracranial pressure
Stroke
- Haemorrhage
- Infarction
Traumatic brain injury
Cerebral Oedema
Excess accumulation of fluid in the brain parenchyma
Two main types:
- Vasogenic – disruption of the blood brain barrier
- Cytotoxic – secondary to cellular injury e.g. hypoxia/ ischemia
Result is raised intracranial pressure
Hydrocephalus
Non-communicating involves obstruction of flow of CSF (most common site = at cerebral aqueduct)
Communicating involves no obstruction but problems with reabsorption of CSF into venous sinuses (often a complication of meningitis)
Consequences of raised ICP
ICP is normally 7–15 mm Hg for a supine adult
Raised ICP due to space occupying lesions, oedema or both
Unyielding bony wall of skull and inflexible dural folds
Herniation of brain structures (subfalcine [supratentorial, cingulate cortex herniation through falx cerebri), transtentorial/uncal [at level of midbrain, medial temporal lobe into posterior fossa] and tonsillar [at level of cerebellum passing through foramen magnum])
Non-traumatic parenchymal haemorrhage
Haemorrhage into the substance of the brain - rupture of a small intraparenchymal vessel
Most common in basal ganglia
Hypertension (chronic) account for more than 50% of bleeds
Presentation with severe headache, vomiting, rapid loss of consciousness, focal neurological signs (more acute than tumours)
Arteriovenous malformation (AVM)
Close interweaving of arterial and venous vessels
Occur anywhere in the CNS
Present from birth
Become symptomatic between 2nd and 5th decade (mean age 31.2 years)
Present with haemorrhage, seizures, headache, focal neurological deficits
High pressure – MASSIVE BLEEDING!!!
Seen on angiography
Morbidity after rupture 53-81% - high in eloquent areas
Mortality 10-17.6%
Treatment: surgery, embolization, radiosurgery
Cavernous angioma
“Well-defined malformative lesion composed of closely packed vessels with no parenchyma interposed between vascular spaces”
Can be found anywhere in the CNS, usually symptomatic after age 50
Pathogenesis unknown
Present with headache, seizures, focal deficits, haemorrhage
Low pressure – recurrent bleeds
Treatment: surgery
Subarachnoid haemorrhage
Rupture of a berry aneurysm (present in 1% of general population)
80 % of berry aneurysms- internal carotid artery bifurcation, 20% occur within the vertebro-basilar circulation
30% of patients have multiple aneurysms
Greatest risk of rupture when 6-10mm diameter
Present with sudden onset of severe headache (‘thunderclap’), vomiting, loss of consciousness
Mixed prognosis
Treatment: endovascular platinum coil into aneurysm (radiologists through femoral artery)
Infarction
Tissue death due to ischemia
Commonest form of cerebrovascular disease
70-80% of strokes
Cerebral atherosclerosis most common cause
hypertension, diabetes, smoking are major risks factors
Worst atherosclerosis in larger vessels (extracerebral arteries) – thrombosis
Often near carotid bifurcation or in basilar artery
Other cause - emboli (intracerebral arteries)
Usually from heart or atherosclerotic plaques
Embolic occlusion usually in middle cerebral artery branches
a) Focal cerebral ischaemia: defined vascular territory
b) Global cerebral ischaemia: systemic circulation fails
Stroke differential diagnoses
Infarct:
Tissue necrosis
Rarely haemorrhagic
Permanent damage in the affected area
No recovery
Haemorrhage:
Bleeding
Dissection of parenchyma
Fewer macrophages
Limited tissue damage
Partial recovery
(really important: don’t want to give thrombolytics to haemorrhagic patients)
Head fractures
Fissure fractures often extend into base of skull
May pass through middle ear or anterior cranial fossa (resulting in CSF leakage)
Otorrhea or rhinorrhea (may be mixed with blood and therefore less obvious)
Battle sign: bruising behind ears due to skull base fracture
Infection risk
Head contusions
Brain in collision with skull caused by impact
Surface “bruising”
If pia mater torn, then becomes laceration
Lateral surfaces of hemispheres, inferior surfaces of frontal and temporal lobes
Coup or contrecoup (rebound causing damage on both the front and back of skull)
Diffuse axonal injury
Occurs at moment of injury
Shear & tensile forces affecting axons causing white matter damage
Commonest cause of coma (when no bleed)
Midline structures particularly affected e.g. corpus callosum, rostral brainstem and septum pellucidum
Chronic traumatic encephalopathy
multiple repetitive sub-clinical/sub-concussive impacts initiating a neurodegenerative process
seen in american football players who presented after retirement with psychiatric/early dementia symptoms
now also seen in rugby and football players in the UK
Alzheimer’s neuropathology
Extracellular plaques (beta amyloid protein, can be diffuse or classic [target-shaped])
Neurofibrillary tangles (Paired helical filaments (PHF), Tau = a microtubule associated protein (MAP), Stabilization of microtubules dependent on phosphorylation state. In AD, tau hyperphosphorylated)
Cerebral amyloid angiopathy (CAA) (amyloid in blood vessel walls)
Neuronal loss (cerebral atrophy; cortical and hippocampal)
