Histopath Flashcards
Describe the appearance of neutrophils.
Multilobed nuclei with lots of granules
In what states might you see an abundance of lymphocytes?
Chronic inflammation
Lymphoma
Describe the appearance of eosinophils.
Bi-lobed nucleus with red granules
List three conditions that could cause an eosinophilia.
Allergic reactions
Parasitic infections
Hodgkin’s lymphoma
Describe the appearance of the oesophagus in eosinophilic oesophagitis.
Horizontal striae are seen within the oesophagus (feline oesophagus)
Describe the appearance of mast cells.
Large cells containing a lot of granules
Describe the appearance of macrophages.
Large cells with lots of cytoplasm
In what states do macrophages tend to appear?
Late acute inflammation (macrophages clear up the debris)
Chronic inflammation (become secretory rather than phagocytic)
Define granuloma.
Organised collection of activated macrophages
Describe the appearance of macrophages in granulomas.
Epithelioid macrophages – they have a lot of cytoplasm making them look like epithelial cells
What cytological feature is suggestive of a good sputum sample?
Pigmented macrophages – this suggests that they have come from the alveoli
What do macrophages in granulomas fuse together to form?
Langerhans giant cells
List some causes of granulomas.
TB
Leprosy
Cat scratch fever
Fungal infections
Sarcoidosis
List three types of carcinoma.
Squamous cell carcinoma
Adenocarcinoma
Transitional cell carcinoma
What are two key features of squamous cell carcinomas?
Keratin production
Intercellular bridges
What are two key features of adenocarcinomas?
Mucin production
Glands
Which stain is used for melanin?
Fontana stain
Which stain is used for iron?
Prussian blue
Which stain is used for amyloid?
Congo Red
When viewed under polarised light, it produces apple green birefringence
What is a key immunological lymphoid marker?
CD45
What is a classic histological feature of HSV infection?
Cells with multiple nuclei
Outline some presenting features of neoplastic bone disease.
Pain
Swelling
Deformity
Fracture
What type of biopsy is often used for diagnosing neoplastic bone disease?
Needle biopsy using a Jamshidi needle under CT or US guidance
List some tumour-like conditions of the bone.
Fibrous dysplasia
Metaphyseal fibrous cortical defect/non-ossifying fibroma
Reparative giant cell granuloma
Ossifying fibroma
Simple bone cyst
What is fibrous dysplasia?
Condition in which fibrous tissue develops in place of normal bone tissue
Can occur in any bone but ribs and proximal femur is most common
Tends to affect patients < 30 years
Causes soap bubble osteolysis on X-ray
Which eponymous syndrome is characterised by polyostotic fibrous dysplasia?
McCune Albright Syndrome – polyostotic fibrous dysplasia + endocrine problems + rough border café-au-lait spots
Describe the histological appearance of fibrous dysplasia.
The marrow is replaced by fibrous stroma with rounded trabecular bone (‘Chinese letters’)
Describe the X-ray appearance of fibrous dysplasia of the femoral head.
Shepherd’s crook
List three types of cartilaginous benign bone tumour.
Osteochondroma
Enchondroma
Chondroblastoma
List three types of bone-forming benign bone tumour.
Osteoid osteoma
Osteoma
Osteoblastoma
What are osteochondromas and which bones tend to be affected?
A benign overgrowth of cartilage and bone that tends to happen at the ends of long bones
They mimic normal tubular bone as they have a cartilaginous surface overlying normal trabecular bone
What is an enchondroma and which bones tend to be affected?
A cartilaginous proliferation within the bone
Most tend to be found in the hands and can cause pathological fractures
X-ray may show popcorn calcification
What are two macroscopic features of benign bone tumours?
Well demarcated
May erode through the cortex of bone but does not burst through the cartilaginous surface
What are giant cell tumours? Where do they tend to be found and what is their histological appearance?
Benign tumour of the bone characterised by the presence of lots of osteoclasts (giant cells)
They tend to be found at the ends of long bones
It has a lytic appearance on X-ray
Histology shows many osteoclasts on a background of spindle/ovoid cells
What is the most common type of malignant bone tumour?
Metastases
Which cancers in adults tend to spread to the bone?
Breast
Prostate
Lung
Kidney
Thyroid
Which cancers in children tend to spread to the bone?
Neuroblastoma
Wilm’s tumour
Osteosarcoma
Ewing’s sarcoma
Rhabdomyosarcoma
List three types of malignant bone tumour.
Osteosarcoma
Chondrosarcoma
Ewing’s sarcoma/PNET
What is an osteosarcoma?
Malignant bone-forming tumour of the bone that mainly occurs at the ends of long bones
Tends to occur at age 10-30 years
Describe the X-ray appearance of osteosarcoma.
Usually metaphyseal
Lytic
Elevated periosteum (Codman’s triangle)
Describe the histological appearance of osteosarcoma.
There are lots of malignant mesenchymal cells with or without bone and cartilage formation
NOTE: this can be stained for using ALP
How can osteosarcoma be classified?
Site within the bone (intramedullary, intracortical, surface)
Degree of differentiation
Multicentricity
Primary or secondary
What is a chondrosarcoma?
Malignant cartilage producing tumour
Tends to occur in patients aged > 40 years
Describe the X-ray appearance of chondrosarcoma.
Lytic with fluffy calcification
List the histological subtypes of chondrosarcoma.
Conventional (myxoid or hyaline)
Clear cell (low grade)
Dedifferentiated (high grade)
Mesenchymal
NOTE: myxoid = composed of clear, mucoid substance
What is an Ewing’s sarcoma?
Highly malignant small round cell tumour
Occurs in people < 20 years old
Describe the X-ray appearance of Ewing’s sarcoma.
Onion skinning of the periosteum
Lytic with or without sclerosis
Describe the histological appearance of Ewing’s sarcoma.
Sheets of small round cells
Which genetic abnormality is associated with Ewing’s sarcoma?
Chromosomal translocation 11:22 (EWSR1/FLI1) (q24:q12)
List three types of soft tissue tumour.
Liposarcoma
Spindle cell sarcoma
Pleomorphic sarcoma
Outline the coding used by cytopathologists when assessing breast aspirates.
C1 = inadequate
C2 = benign
C3 = atypia, probably benign
C4 = suspicious of malignancy
C5 = malignant
Define duct ectasia. Describe its presentation.
Inflammation and dilatation of large breast ducts
Typically presents with a breast lump and nipple discharge
Describe the histology of duct ectasia.
The duct will be distended and full of proteinaceous material
Foamy macrophages will also be present
Which organism is usually responsible for acute mastitis?
Staphylococci
Describe the cytological appearance of acute mastitis.
Lots of neutrophils
Describe the cytological appearance of fat necrosis.
Fat cells surrounded by macrophages
Define fibrocystic disease.
A group of alterations in the breast which reflect normal, albeit exaggerated, responses to hormonal influences
On histology, the ducts are usually dilated and calcified
Define fibroadenoma.
Benign fibroepithelial neoplasm of the breast
Describe the histology of fibroadenoma.
Consists of lots of glandular and stromal cells
Define Phyllodes tumour.
A group of potentially aggressive fibroepithelial neoplasms of the breast.
NOTE: the majority are benign
Describe the histology of Phyllodes tumours.
Cells do not form uniform layers
Whether it is benign or malignant depends on the cellularity of the stroma
Define intraductal papilloma.
A benign papillary tumour arising within the duct system of the breast
What are the two different types of intraductal papilloma
Peripheral papilloma – arises in small terminal ductules
Central papilloma – arises in large lactiferous ductules
Describe the histology of intraductal papillomas.
Histology will show a large dilated duct with a polypoid mass in the middle
The mass tends to have a fibrovascular core
What is a radial scar?
A benign sclerosing lesion characterised by a central zone of scarring surrounded by a radiating zone of proliferating glandular tissue
How do radial scars present?
Seen as stellate masses on mammograms
Describe the histological appearance of radial scars.
Central stellate area with proliferation of ducts and acini in the periphery
Describe the appearance of usual epithelial hyperplasia.
Irregular lumens
What is flat epithelial atypia/atypical ductal hyperplasia?
May be the earliest precursor to low grade DCIS
There are multiple layers of epithelial cells and the lumens become more regular
List some risk factors for invasive breast carcinoma.
Early menarche
Late menopause
Obesity
Alcohol
OCP
Family history
Which histological grading system is used for invasive breast carcinoma?
Nottingham modification of the Bloom-Richardson system
What is histological grading dependent on?
Tubule formation
Nuclear pleomorphism
Mitotic activity
Which three receptors are all invasive breast cancers assessed for?
ER
PR
Her2
Describe the receptor phenotype of Low grade invasive breast cancer
ER/PR positive
Her2 negative
Describe the receptor phenotype of High grade invasive breast cancer
ER/PR negative
Her2 positive
Describe the receptor phenotype of Basal-like carcinoma
Triple negative
What is the most important prognostic factor in invasive breast cancer?
Status of axillary lymph nodes
Which age group is screened in the NHS breast screening programme?
47-73 year olds (every 3 years)
Describe the histology of gynaecomastia.
Epithelial hyperplasia with finger-like projections extending into the duct lumen
Periductal stroma is often cellular and oedematous
Similar to fibroadenoma
What types of cell are the anterior and posterior pituitary made up of?
Anterior = epithelial cells
Posterior = nerve cells
What is the blood supply to the anterior pituitary?
Pituitary portal system
Where do the nerves that make up the posterior pituitary originate?
Supraoptic nucleus and paraventricular nucleus
Outline the clinical features of prolactinoma.
Amenorrhoea
Galactorrhoea
Loss of libido
Infertility
What disease is caused by corticotroph cell adenomas?
Cushing’s disease
List some causes of hypopituitarism.
Non-secreting pituitary adenoma
Ischaemia
Iatrogenic (e.g. surgery, radiotherapy)
List some clinical features of hypopituitarism.
Pituitary dwarfism
Gonadotrophin deficiency – amenorrhoea, infertility, impotence, loss of libido
Hypothyroidism and Hypoadrenalism
Which hormones are produced by the posterior pituitary?
ADH and oxytocin
List some consequences of the local mass effect of pituitary tumours.
Bitemporal hemianopia (optic chiasm)
Headaches (raised ICP)
Obstructive hydrocephalus
Describe the histological appearance of the thyroid gland.
Arranged into follicles with a small amount of stromal tissue between them
They are lined by epithelial cells and have a large amount of colloid in the middle
Parafollicular cells are found between the follicles
Which hormone do parafollicular cells produce?
Calcitonin – this promotes the absorption of calcium by the skeletal system
What is the most common cause of non-toxic goitre?
Iodine deficiency
List some causes of thyrotoxicosis that are not associated with the thyroid gland.
Struma ovarii – ovarian teratoma with ectopic thyroid hormone production
Factitious thyrotoxicosis – exogenous thyroid hormone intake
List some primary causes of hypothyroidism.
Post-ablative
Autoimmune (Hashimoto’s)
Iodine deficiency
Congenital biosynthetic defect
Describe the histology of Hashimoto’s thyroiditis.
There are lots of lymphoid cells with germinal centres
The epithelial cells become large with lots of eosinophilic cytoplasm (Hurthle cells)
List some features of a thyroid lump that would be suggestive of neoplasia.
Solitary rather than multiple
Solid rather than cystic
Younger patients
Male more than female
Less likely to take up radioiodine
List some features of adenomas of the thyroid gland.
Usually solitary
Well circumscribed
Well-formed capsule
Small proportion will be functional
List the four types of thyroid cancer in order of decreasing prevalence.
Papillary (80%)
Follicular (15%)
Medullary (5%)
Anaplastic
What is the diagnosis of papillary thyroid cancer based on?
Nuclear features
· Optically clear nuclei
· Intranuclear inclusions (Orphan Annie eye)
There may also be psammoma bodies (little foci of calcification)
Usually non-functional
On histology, they have a papillary structure (central connective tissue stalk with surrounding epithelium)
Where does papillary thyroid cancer tend to metastasise to?
Cervical lymph nodes
Where does follicular thyroid cancer tend to metastasise?
Lungs, bone and liver (via the bloodstream)
Which cells are medullary thyroid cancers derived from?
Parafollicular C cells
NOTE: 80% are sporadic, 20% are familial
What tends to happen to the calcitonin produced by tumour cells in medullary thyroid cancer?
It is broken down and deposited as amyloid within the thyroid
List the actions of PTH.
Activates osteoclasts
Increased renal absorption of calcium
Increases activation of vitamin D
Increases urinary phosphate excretion
Increases intestinal calcium absorption
Describe the histological appearance of a parathyroid adenoma.
Very cellular tissue with no fat (whereas the normal parathyroid gland is quite fatty)
What bone change is seen in hyperparathyroidism?
Osteitis fibrosa cystica – caused by bone resorption with thinning of the cortex
What is the most common cause of secondary hyperparathyroidism?
Renal failure
List some clinical features of hypoparathyroidism.
Neuromuscular irritability
Cardiac arrhythmias
Fits
Cataracts
(CATs go NUMB)
Which cells types constitute the cortex and medulla of the adrenal gland?
Cortex = epithelial
Medulla = neural
What are the layers of the adrenal cortex and which hormones do they produce?
Glomerulosa – aldosterone
Fasciculata – glucocorticoids
Reticularis – sex steroids
What is the most common cause of Cushing’s syndrome?
Administration of exogenous corticosteroids (leads to adrenal atrophy)
What are the causes of hyperaldosteronism?
35% adenoma (Conn’s syndrome)
60% bilateral adrenal hyperplasia
List the two main clinical features of hyperaldosteronism.
Hypertension
Hypokalaemia
Describe the pathophysiology of congenital adrenal hyperplasia.
Autosomal recessive
Hereditary defect in an enzyme involved in cortisol synthesis leads to cortisol deficiency
This leads to increased ACTH release from the pituitary gland
ACTH stimulates androgen synthesis from the adrenal gland
List three causes of acute primary adrenal failure.
Haemorrhage
DIC associated with sepsis (Waterhouse-Friderichson syndrome)
Sudden withdrawal of corticosteroid treatment
List some causes of chronic primary adrenal failure.
Autoimmune (90%)
TB
HIV
Metastatic tumour
What are the two types of tumours of the adrenal medulla?
Phaeochromocytoma
Neuroblastoma
What are the main features of SLE?
Serositis
Oral ulcers
ANA
Photosensitivity
Bloods (low counts)
Renal (proteinuria)
Arthritis
Immunological (anti-dsDNA)
Neurological (psychiatric, seizures)
Malar rash
Discoid rash
List three autoantibodies found in SLE. Which is most specific?
Anti-dsDNA
Anti-smith (against ribonucleoproteins) – most specific but low sensitivity
Anti-histone – drug-related (e.g. hydralazine)
Describe the appearance of skin histology in SLE.
Lymphocytic infiltration of the dermis
Vacuolisation (dissolution of the cells) of the basal epidermis
Extravasation of blood causes a rash
Immunofluorescence will show immune complex deposition at the epidermis-dermis junction
Describe the appearance of renal histology in SLE.
Glomerular capillaries are thickened (wire-loop capillaries) due to immune complex deposition
What is the name of non-infective endocarditis associated with SLE?
Libman-Sacks endocarditis
What is scleroderma?
A condition characterised by excess collagen in the skin and fibrosis
What are the two types of scleroderma? Name the antibodies that they are associated with.
Diffuse – involves the trunk (anti-Scl70 antibodies (aka anti-topoisomerase))
Limited – only affects distal to the elbows and knees (anti-centromere)
What are the main features of limited cutaneous systemic sclerosis?
Calcinosis
Raynaud’s phenomenon
Oesophageal dysmotility
Sclerodactyly
Telangiectasia
Describe the vascular histology in scleroderma.
Intimal proliferation gives an onion skin appearance
What is a major consequence of this vascular change (in scleroderma)?
Renal hypertensive crisis
What pattern of ANA immunofluorescence is seen in scleroderma?
Nucleolar
What ANA immunofluorescence pattern is seen in mixed connective tissue disease?
Speckled
What is dermatomyositis?
A condition characterised by proximal muscle pain and weakness, high CK and skin changes (e.g. Gottron’s papules – purple rash across the knuckles)
List some features of sarcoidosis.
Arthritis
Lupus pernio
Erythema nodosum
Bilateral hilar lymphadenopathy
Pulmonary fibrosis
Lymphadenopathy
Inflammation of layers of the heart
Uveitis
Meningitis
Hepatitis, cirrhosis
Bilateral parotid enlargement
What is the pathological hallmark of sarcoidosis?
Non-caseating granuloma
Which investigations are useful in sarcoidosis?
Hypergammaglobulinaemia
High ACE
Hypercalcaemia (due to activation of vitamin D by macrophages)
What is polyarteritis nodosa? What are its main features?
A necrotising arteritis which is focal and sharply demarcated
It heals by fibrosis and mainly affects the renal and mesenteric vessels
May present with gut ischaemia or renal impairment
It produces a rosary beads appearance on angiography due to multiple aneurysms
Which condition is polyarteritis nodosa associated with?
Hepatitis B
What is a characteristic feature of vasculitis?
Palpable purpuric rash
How is temporal arteritis diagnosed and treated?
High ESR
High dose prednisolone
What will be seen on temporal artery biopsy in temporal arteritis?
Lymphocytic infiltration of the tunica media
What are the main features of granulomatosis with polyangiitis?
ENT – nosebleeds, sinusitis, saddle nose
Lungs – haemoptysis, SOB
Kidneys – haematuria
Which antibody is associated with granulomatosis with polyangiitis?
cANCA – against proteinase 3
What are the main features of Churg-Strauss syndrome?
Asthma
Eosinophilia
Vasculitis
Which antibody is associated with Churg-Strauss syndrome?
pANCA – against myeloperoxidase
What feature of high-risk HPV viruses are responsible for the carcinogenic effects of HPV?
E6 protein – inactivates p53
E7 protein – inactivates retinoblastoma
In which type of epithelium does CIN occur?
Usually squamous
Which staging system is used for cervical cancer?
FIGO staging
What are the two HPV vaccines that are currently available?
Bivalent = 16 + 18
Quadrivalent = 6 + 11 + 16 + 18
What is a leiomyoma? Outline its key features.
A benign smooth muscle cell tumour in the uterus (MOST COMMON uterine tumour)
Present in > 20% of women > 35 years
Often multiple
Usually asymptomatic
What are the three types of leiomyoma?
Intramural
Submucosal
Subserosal
What are the key features of type I endometrial carcinoma?
Younger patients
Oestrogen-dependent
Often associated with atypical endometrial hyperplasia
Low-grade tumours that are superficially invasive
Genetic mutations: PTEN, P13KCA, K-Ras, CTNNB1, FGFR2, p53
What are the key features of type II endometrial carcinoma?
Older patients
Less oestrogen-dependent
Arise in atrophic endometrium
High grade, deeper invasion and higher stage
Which genetic mutations are associated with the two types of type II endometrial carcinoma?
Endometrial Serous Carcinoma
· P53 (90%)
· P13KCA (15%) Her2 amplification
Clear Cell Carcinoma
· PTEN
· CTNNB1
· Her2 amplification
List some prognostic factors in endometrial carcinoma.
Type
Grade
Stage
Tumour ploidy (diploid has a better prognosis)
Hormone receptor expression
What is choriocarcinoma?
Rare (1 in 20,000) rapidly invasive and widely metastasising tumour
Responds well to chemotherapy
50% arise in moles
25% arise in patients with previous abortion
22% arise in normal pregnancy
List two types of non-neoplastic functional cysts.
Follicular and luteal cysts
Endometriotic cyst
List three types of primary specific ovarian tumour.
Surface epithelial tumours
Sex cord stromal tumours
Germ cell tumours
List some risk factors for ovarian cancer.
Nulliparity
Early menarche
Late menopause
Genetic predisposition (MOST SIGNIFICANT)
Infertility
Endometriosis
HRT
Inflammation (PID)
Outline the classification of epithelial ovarian tumours.
Type 1
· Low grade
· Relatively indolent and arise from well characterised precursors (benign tumours) and endometriosis
· Mutations: K-Ras, B
Type 2
· HIGH GRADE
· Aggressive
· P53 mutation in 75% of cases
· NO precursor lesion
List some benign ovarian tumours.
Serous cystadenoma
Cystadenofibroma
Mucinous cystadenoma
Brenner tumour
What are the key features of serous tumours?
MOST COMMON type of ovarian tumour
Usually cystic
30-50% bilateral
Benign tumours are lined by bland epithelium
Borderline tumours have a more complex, atypical epithelial lining with papillae but no invasion through the basement membrane
Malignant tumours are invasive with a poor prognosis
What are the key features of mucinous tumours?
10-20% of ovarian tumours
Composed of mucin-secreting epithelium (may resemble endocervical or GI epithelium)
What are the key features of endometrioid tumours?
10-24% of ovarian tumours
10-20% associated with endometriosis
Better prognosis than mucinous and serous
What are the key features of clear cell tumours?
Strong association with endometriosis
NOTE: called clear cell because the cytoplasm contains a lot of glycogen
List four types of sex cord stromal tumours.
Fibroma
Granulosa cell tumour (may produce oestrogen)
Thecoma (may produce oestrogen (rarely androgens))
Sertoli-Leydig cell tumour (may be androgenic)
What are the key features of germ cell tumours?
20% of ovarian tumours
95% are benign
Mainly occur in < 20 years
Classified based on how they differentiate
What are the four main types of germ cell tumour?
Dysgerminoma – no differentiation
Teratoma – from embryonic tissues
Endodermal sinus tumour – from extraembryonic tissue (e.g. yolk sac)
Choriocarcinoma – from trophoblastic cells which would form the placenta
What are the key features of an immature teratoma?
Indicates presence of embryonic elements (most commonly neural tissue)
Malignant tumour that grows rapidly, penetrates the capsule and forms adhesions
Spreads within peritoneal cavity and metastasises to the lymph nodes, lungs, liver and other organs
Name two secondary ovarian tumours.
Krukenberg Tumour – bilateral metastases composed of mucin-producing signet ring cells (usually from breast or gastric cancer)
Metastatic colorectal cancer
List some specific genetic associations for serous, mucinous and endometrioid carcinoma.
Serous – BRCA
Mucinous and endometrioid - HNPCC
What is lichen sclerosus?
Thinning of the vulval epithelium with a layer of hyalinisation underneath
List some other types of malignant tumour of the vulva.
Squamous cell carcinoma (85%)
Paget’s disease (adenocarcinoma in situ)
Adenocarcinoma
Malignant melanoma
BCC
What are the most common sites for atheromatous plaques within the coronary circulation?
First few centimetres of the LAD and left circumflex
Entire length of right coronary artery
Which arteries tend to be involved in myocardial infarction (in order of most to least frequent)?
LAD – 50%
RCA – 40%
LCx – 10%
List some causes of aortic regurgitation.
Rigidity (rheumatic, degenerative)
Destruction (endocarditis)
Disease of the aortic valve ring (dilatation, dissection, Marfan’s, syphilis, ankylosing spondylitis)
Which valves are most commonly affected by endocarditis?
Left-sided valves (unless you are an IVDU)
What is the role of stellate cells and what could happen to them when activated?
Storage of vitamin A
When activated, they become myofibroblasts that lay down collagen (this is responsible for scarring in liver disease)
Describe how these arrangements change in liver disease.
Kupffer cells become activated (inflammatory response)
Endothelial cells stick together so blood finds it more difficult to get into the space of Disse
Stellate cells become activated and secrete basement membrane-type collagens into the space of Disse
Hepatocytes lose their microvilli
All these changes make it difficult for blood to be exposed to hepatocytes
List some complications of cirrhosis.
Portal hypertension
Hepatic encephalopathy
Hepatocellular carcinoma
NOTE: cirrhosis may be reversible
What is a common histological feature of all acute hepatitis?
Spotty necrosis
List some histological features of alcohol hepatitis.
Ballooning – cell swell and may contain pink deposits within cells (Mallory Denk bodies/Mallory hyaline)
Apoptosis
Pericellular fibrosis
In which part of the liver do the histological features of alcoholic hepatitis tend to be seen and why?
Zone 3
Alcohol is not toxic, but acetaldehyde is toxic
Zone 3 cells contain the most alcohol dehydrogenase thereby producing the most acetaldehyde
Furthermore, by the time blood reaches zone 3 (after passing zones 1 and 2) it is relatively hypoxic making the cells in zone 3 even more vulnerable to damage
Describe the histological appearance of non-alcoholic fatty liver disease.
Looks like alcoholic hepatitis
NOTE: caused by insulin resistance associated with a raised BMI and diabetes
What is primary biliary cholangitis?
Autoimmune conditions characterised by bile duct loss associated with chronic inflammation (with granulomas)
What is the diagnostic test for PBC?
Anti-mitochondrial antibodies (AMA)
What is the histological appearance of PBC?
Bile ducts surrounded by epithelioid macrophages, suggestive of chronic granulomatous destruction of bile ducts
What is primary sclerosing cholangitis?
Autoimmune condition characterised by periductal bile duct fibrosis leading to loss of bile ducts
NOTE: in PBC, bile duct loss is caused by inflammation, whereas in PSC it is caused by fibrosis
NOTE: PSC is associated with ulcerative colitis and is associated with an increased risk of cholangiocarcinoma
What is the diagnostic test for PSC?
Bile duct imaging
What causes haemochromatosis and which gene is implicated?
Caused by increased gut iron absorption
HFe gene on chromosome 6
NOTE: women tend to present later because they have naturally lower iron levels
What is haemosiderosis?
Type of iron overload characterised by the accumulation of iron in macrophages
Usually occurs as a result of receiving blood transfusions
How does Wilson’s disease lead to movement disorders?
Accumulation of copper in the lentiform nucleus of the basal ganglia leads to movement disorders
How is autoimmune hepatitis diagnosed?
Anti-smooth muscle antibodies (ASMA)
How is autoimmune hepatitis treated?
Steroids (usually responds well)
Describe the levels of alpha-1 antitrypsin in the blood and liver in a patient with alpha-1 antitrypsin deficiency.
The mutation means that the protein cannot fold properly and cannot exit hepatocytes
This leads to alpha-1 antitrypsin forming globules within hepatocytes which causes damage leading to chronic hepatitis
An inability to exit the liver leads to a deficiency of alpha-1 antitrypsin elsewhere in the body which leads to an increased risk of emphysema
List some causes of hepatic granulomas.
Specific: PBC, drugs
General: TB, sarcoidosis
List the main types of benign liver tumour. State which is most common.
Liver cell adenoma
Bile duct adenoma
Haemangioma (MOST COMMON)
What is the most common type of malignant liver tumour?
Secondary tumours
What are some risk factors for cholangiocarcinoma?
PSC
Worm infections
Cirrhosis
Describe the three main patterns of injury in acute pancreatitis and describe what they result from.
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 – results from worsening periductal or perilobular inflammation
Outline the pathway of inflammation in acute pancreatitis.
Activated enzymes à acinar necrosis à release of more enzymes
What is saponification?
Lipases break down fats to release free fatty acids
Calcium binds to the free fatty acids forming soaps
List some complications of acute pancreatitis.
Pseudocyst formation, abscesses
Shock
Hypoglycaemia
Hypocalcaemia
List some causes of chronic pancreatitis.
Metabolic/Toxic: alcohol (80%), haemochromatosis
Duct obstruction: gallstones, abnormal anatomy, cystic fibrosis (mucoviscoidosis)
Tumours
Idiopathic
Outline the pattern of injury in chronic pancreatitis.
Chronic inflammation with parenchymal fibrosis and loss of parenchyma
There will be duct strictures with calcified stones with secondary dilatations
What is the characteristic feature of autoimmune pancreatitis?
Large numbers of IgG4 positive plasma cells typically found around the ducts
How is autoimmune pancreatitis treated?
Steroids – usually responds well
What are the two types of pancreatic cancer and which is more common?
Ductal (85%)
Acinar (15%)
Name two types of dysplastic precursor lesion that ductal carcinoma can arise from.
Pancreatic intraductal neoplasia (PanIN)
Intraductal mucinous papillary neoplasm
Which mutation is very common in pancreatic cancer?
K-ras (95%)
Describe the macroscopic appearance of ductal carcinoma?
Gritty and grey
Invades adjacent structures
NOTE: tumours in the head of the pancreas present earlier
Describe the microscopic appearance of ductal carcinoma.
Adenocarcinomas (secrete mucin and form glands)
Mucin-secreting glands are set in desmoplastic stroma
What are the usual sites of metastasis of ductal carcinoma?
Direct: bile ducts, duodenum
Lymph nodes
Blood: liver
Serosa: peritoneum
By what mechanism does pancreatic cancer cause migratory thrombophlebitis?
Circulating pancreatic cancer cells release mucous which activates the clotting cascade
List some key features of pancreatic neuroendocrine neoplasms.
Usually non-secretory
Contains neuroendocrine markers (e.g. chromogranin – can be measured as a screening test for neuroendocrine tumours)
May be associated with MEN1
What is the most common type of functional neuroendocrine tumour?
Insulinoma
What are the two types of gallstone and what are their distinguishing features?
Cholesterol
· May be single
· Mostly radiolucent (NOT seen on AXR)
Pigment
· Often multiple
· Contain calcium salts of unconjugated bilirubin
· Mostly radio-opaque
What is the term used to describe diverticula of the gallbladder? How do they form?
Rokitansky-Aschoff sinuses – form as a result of the gallbladder contracting against an obstruction
Outline the presentation of polycystic kidney disease.
Hypertension
Haematuria
Flank pain
What is the inheritance pattern of polycystic kidney disease and which genes are implicated?
Autosomal dominant (most of the time)
Genes: PKD1 and PKD2
NOTE: PKD is associated with an increased risk of berry aneurysms (and subarachnoid haemorrhage)
List some causes of acute renal failure.
Pre-renal: failure of perfusion (shock, heart failure)
Renal: ATN, acute glomerulonephritis, thrombotic microangiopathy
Post-renal: obstruction
What is the most common cause of acute renal failure?
Acute tubular injury
How does acute tubular injury lead to reduced GFR?
Blockage of tubules by casts
Leakage from tubules into interstitial space
Secondary haemodynamic changes
Describe the histological appearance of acute tubulo-interstitial nephritis.
Heavy interstitial infiltration with eosinophils and granulomas
What causes crescents to appear in acute glomerulonephritis?
Occurs in severe glomerulonephritis due to proliferation of cells within Bowman’s capsule
List some causes of acute crescentic glomerulonephritis.
Immune complex deposition
Anti-GBM disease (Goodpasture’s)
Pauci-immune (ANCA)
NOTE: these can rapidly lead to irreversible renal failure
List some causes of immune complex-associated crescentic glomerulonephritis.
SLE
IgA nephropathy
Post-infectious glomerulonephritis
What are the antibodies directed against in anti-GBM disease?
Against the C-terminal domain of type IV collagen
NOTE: these antibodies can cross-react with the alveolar basement membrane leading to pulmonary haemorrhage and haemoptysis
Describe the immunohistochemistry picture produced in anti-GBM disease.
Linear deposition of IgG on the glomerular basement membrane
What is thrombotic microangiopathy?
Damage to the endothelium in glomeruli, arterioles and arteries resulting in thrombosis
Red cells can be damaged by fibrin causing MAHA or HUS
List some causes of thrombotic microangiopathy.
Diarrhoea-associated: E.coli – toxins can target the renal epithelium
Non-diarrhoea associated: defects in complement regulation, deficiency of ADAMTS13, drugs, radiation, hypertension, scleroderma, antiphospholipid syndrome
List some causes of nephrotic syndrome.
Primary glomerular disease (non-immune complex mediated)
· Minimal change disease
· Focal segmental glomerulosclerosis
Primary renal disease (immune complex mediated)
· Membranous glomerulonephritis
Systemic disease
· SLE
· Amyloidosis
· Diabetes mellitus
What is minimal change disease?
Most common cause of nephrotic syndrome in children
Glomeruli look normal on light microscopy, but electron microscopy shows loss of foot processes
Generally responds well to steroids and immunosuppression
Describe the histological appearance of focal segmental glomerulosclerosis.
Some glomeruli are partially scarred
NOTE: this responds less well to immunosuppression
What is membranous glomerulonephritis?
Common cause of nephrotic syndrome in adults
Characterised by immune deposits outside the glomerular basement membrane (subepithelial)
Primary disease is autoimmune
It can occur secondary to epithelial malignancy, SLE, drugs and infections
Which antibodies are often found in primary membranous glomerulonephritis?
Antibodies against phospholipase A2 type M receptor (PLA2R)
List and describe the stages of diabetic nephropathy.
Stage 1: thickening of the basement membrane on electron microscopy
Stage 2: increase in mesangial matrix, without nodules
Stage 3: nodular lesions/Kimmelstein-Wilson nodules
Stage 4: advanced glomerulosclerosis
What are the two types of amyloidosis?
AA – derived from serum amyloid protein and associated with chronic inflammatory disease
AL – derived from immunoglobulin light chains usually as a result of multiple myeloma
Name two causes of isolated microscopy haematuria.
Thin basement membrane
IgA nephropathy
How can the cause of asymptomatic proteinuria be confirmed?
Renal biopsy (could be caused by several abnormalities)
What is thin basement membrane disease and what causes it?
Basement membrane < 250 nm thickness
Caused by a hereditary defect in type IV collagen synthesis
Microscopic haematuria is the only consequence in most cases
What is Alport syndrome?
X-linked disease caused by a mutation in the alpha-5 subunit of type IV collagen (some forms affect alpha-3 and alpha-4)
Leads to progressive damage resulting in renal failure in middle-age
Often accompanied by deafness and ocular disease
What is IgA nephropathy?
Most common cause of glomerulonephritis
Caused by mesangial IgA immune complex deposition
NOTE: Henoch-Schonlein purpura is a type of IgA nephropathy
30% will progress to end-stage renal failure
What are consequences of hypertensive nephropathy?
Shrunken kidneys with granular cortices
Nephrosclerosis on histology (arterial hyalinosis, arterial intimal thickening, ischaemic glomerular changes, segmental and global glomerulosclerosis)
What is a key histological feature of the oesophageal mucosa?
Presence of submucosal glands
What is the Z-line?
The point in the oesophagus at which the epithelium transitions from being squamous to being columnar
Which part of the stomach tends to be affected by H. pylori-associated gastritis?
Pylorus and antrum
What are the three layers of the gastric mucosa?
Columnar epithelium
Lamina propria
Muscularis mucosa
What is the normal villous: crypt ratio?
2:1
What does the presence of goblet cells in the stomach signify?
Intestinal metaplasia
NOTE: goblet cells are NOT normally seen in the stomach
What is the characteristic histological feature of acute oesophagitis?
Presence of lots of neutrophils
This is usually caused by GORD
Define Barrett’s oesophagus.
Metaplastic process by which the normal squamous epithelium of the lower oesophagus is replaced by columnar epithelium
NOTE: this is also known as columnar-lined epithelium (CLO)
What further degree of metaplasia is associated with an even greater risk of cancer than Barrett’s oesophagus?
Intestinal metaplasia – goblet cells become visible
NOTE: metaplasia is reversible
What is squamous carcinoma of the oesophagus associated with?
Smoking and alcohol
It tends to affect the middle/lower oesophagus
It is the most common type of oesophageal cancer in Africa
What are the main histological features of squamous cell carcinoma of the oesophagus?
Cells produce keratin (normal oesophageal squamous epithelium is non-keratinised)
Intercellular bridges
What is mucosa-associated lymphoid tissue and what is their presence indicative of?
Chronic gastritis caused by H. pylori infection induces lymphoid tissue in the stomach
The presence of lymphoid follicles in a stomach biopsy, is highly suggestive of H. pylori infection
This is important because it is associated with an increased risk of lymphoma
Name a key virulence factor that enables H. pylori to cause chronic infection.
Cag-A positive H. pylori has a needle-like appendage that injects toxins into intercellular junctions allowing bacteria to attach more easily
What must you do with all gastric ulcers?
They should all be biopsied to rule out malignancy
What type of cancer is gastric cancer?
95% adenocarcinoma
5%: squamous cell carcinoma, lymphoma (MALToma), gastrointestinal stromal tumour (GIST), neuroendocrine tumours
Name two types of diffuse adenocarcinoma of the stomach.
Linitis plastica
Signet ring cell carcinoma
What is the overall survival rate of gastric cancer?
15%
What is gastric lymphoma?
Lymphoma of the gastric mucosa that is driven by chronic inflammation (H. pylori gastritis)
Consists of lots of B lymphocytes (marginal zone)
NOTE: if H. pylori is also present, crypts may also contain neutrophils
What causes duodenitis and duodenal ulcers?
Caused by increased acid produced in the stomach that spills into the duodenum
It can also occur due to chronic inflammation and gastric metaplasia with H. pylori infection
List some histological features of malabsorption.
Villous atrophy
Crypt hyperplasia
Increased intraepithelial lymphocytes (> 20 per 100 enterocytes)
NOTE: the T cell response to gliadin in Coeliac disease is responsible for the damage to villi
What is lymphocytic duodenitis?
When you get the inflammatory changes (increased intraepithelial lymphocytes) without architectural changes
Many people with this condition either have coeliac disease or will go on to develop coeliac disease
How is coeliac disease diagnosed?
Antibodies: anti-tTG, anti-endomysial
Duodenal biopsy
NOTE: duodenal biopsy will be normal in people with coeliac disease who have been following a strict gluten-free diet
Which other condition has very similar clinical and histological features to coeliac disease?
Tropical sprue
What type of lymphoma is duodenal lymphoma?
T cell lymphoma
How is palmar-plantar skin different from skin in other parts of the body?
There are no sebaceous glands
There is a very thick corneal layer
List some different types of inflammatory reactions patterns in the skin.
Vesiculobullous – forms bullae
Spongiotic – becomes oedematous
Psoriasiform – becomes thickened
Lichenoid – forms a sheeny plaque
Vasculitic – associated with vasculitis
Granulomatous – associated with granulomas
What is bullous pemphigoid? Describe the macroscopic appearance.
Vesiculobullous condition
Occurs in elderly patients on their flexor surfaces
Characterised by the formation of tense bullae
NOTE: it has a 10-20% mortality
Outline the pathophysiology of bullous pemphigoid.
Autoimmune disorder driven by IgG and C3 which attack the basement membrane
They recruit eosinophils which release elastase which further damages anchoring proteins (anchoring lower keratinocytes to the basement membrane)
How can bullous pemphigoid be definitively diagnosed?
Immunofluorescence will show IgG and C3 along the dermo-epidermal junction
Describe the macroscopic appearance of pemphigus vulgaris.
Blisters are flaccid meaning that they rupture easily exposing a red raw surface underneath
Describe the macroscopic appearance of pemphigus foliaceus.
You rarely see intact bullae because they are so thin and fragile
You are likely to see some flaky remnants of old bullae
Describe the appearance of discoid eczema.
Very itchy and found on the flexural surfaces
Presents with discoid plaques
What is hyperparakeratosis?
Thickening of the skin on the surface where the patient has been scratching
The epidermis gets thicker
What type of inflammatory skin reaction is eczema?
Spongiotic because there is oedema between the keratinocytes
What are the main immune mediators in eczema?
T-cell mediated
Eosinophils are also recruited
Describe the typical presentation of plaque psoriasis.
This is a psoriasiform reaction pattern
Tends to present as silvery plaques on the extensor surfaces
How is the keratinocyte turnover time different in psoriasis compared to normal skin?
Normal skin turnover = 50 days (time for a keratinocyte to go from the bottom of the epidermis to the top)
Psoriasis = 7 days
This leads to thickening of the epidermis and you get a layer of parakeratosis at the top
Which layer of the epidermis disappears in plaque psoriasis and why?
Stratum granulosum – there is not enough time to form it
What can neutrophil recruitment to the epidermis in plaque psoriasis cause?
Formation of Munro’s microabscesses
What is lichen planus and what are its main features?
Lichenoid reaction pattern
T-cell mediated
Presents with papules and plaques that are slightly purplish in colour on the wrists and arms
In the mouth it presents as white lines (Wickham striae)
Describe the histological appearance of lichen planus.
Distinction between dermis and epidermis is difficult to see due to lymphocyte-mediated destruction of the bottom layer of keratinocytes
There is band-like lymphocytic infiltration just under the epidermis
NOTE: this is also seen in mycosis fungoides
What type of inflammatory skin reaction results in pyoderma gangrenosum?
Vasculitic
Describe the appearance of a sebaceous/epidermal cyst.
Smooth surface
Non-mobile
Tend to have a punctum
Can get infected/rupture
Can smell really bad
Describe the histological appearance of a sebaceous cyst.
Looks like the surface has become invaginated to form a cyst
Lined by squamous epithelium
Describe the macroscopic appearance of a basal cell carcinoma.
Rolled, pearly edge with a central ulcer and telangiectasia
Describe the histological appearance of a basal cell carcinoma.
Cancer arises from the keratinocytes along the bottom of the epidermis (basal cells)
They can infiltrate through the basement membrane
They are locally infiltrative but don’t metastasise
What is Bowen’s disease?
Squamous cell carcinoma in situ
List the three main types of urinary tract calculi in order of prevalence.
Calcium oxalate (Weddelite) – 75%
Magnesium ammonium phosphate – 15%
Urate – 5%
List some underlying conditions that can lead to the formation of calcium oxalate stones.
Absorptive hypercalciuria – excessive calcium absorption from the gut
Renal hypercalciuria – impaired absorption of calcium in the proximal renal tubule
Hypercalcaemia (e.g. hyperparathyroidism)
Which patients are predisposed to the formation of urate stones?
Gout
Rapid cell turnover (e.g. chemotherapy)
NOTE: however, most patients with urate stones will not have these risk factors
Where do urinary calculi stones tend to get stuck within the urinary tract?
Pelvi-ureteric junction
Pelvic brim
Vesico-ureteric junction
Define papillary adenoma.
Benign epithelial kidney tumour composed of papillae and/or tubules
They must be < 15 mm in size
They tend to be well circumscribed
What are the genetic associations of papillary adenomas?
Trisomy 7 and 17
Loss of Y chromosome
What is a renal oncocytoma?
Benign epithelial kidney tumour composed of oncocytic cells
They are usually well-circumscribed and usually sporadic
NOTE: often an incidental finding
Name a syndrome that is associated with renal oncocytoma.
Birt-Hogg-Dubé syndrome
Describe the histological appearance of oncocytes.
Large cells with pink granular cytoplasm and a prominent nucleolus
What is an angiomyolipoma?
Benign mesenchymal kidney tumour composed of thick-walled blood vessels, smooth muscle and fat
Derived from perivascular epithelioid cells
NOTE: often an incidental finding but may cause flank pain, haemorrhage and shock (if > 4 cm)
Which hereditary condition is associated with angiomyolipoma?
Tuberous sclerosis
How does renal cell carcinoma tend to present?
Painless haematuria
Name the subtypes of renal cell carcinoma in order of prevalence.
Clear cell renal carcinoma (70%)
Papillary renal cell carcinoma (15%)
Chromophobe renal cell carcinoma (5%)
Define clear cell renal carcinoma.
Epithelial kidney tumour composed of nests of clear cells set in a delicate capillary vascular network
Grossly appears golden-yellow with haemorrhagic areas
What is a common genetic finding in clear cell renal carcinoma?
Loss of chromosome 3p
Define papillary renal cell carcinoma.
Epithelial kidney tumour composed of papillae and/or tubules
By definition > 15 mm in size
NOTE: this is the malignant counter part of papillary adenoma. They appear grossly as a fragile, friable brown tumour
Describe the histological appearance of the two types of papillary renal cell carcinoma.
Type 1: composed of a single layer of small and flat cells. You see a lot of islands of cells.
Type 2: there is stratification (multi-layering) of the cells
NOTE: type 2 tends to have a worse prognosis than type 1
Define chromophobe renal cell carcinoma.
Epithelial kidney tumour composed of sheets of large cells that display distinct cell borders, reticular cytoplasm and a thick-walled vascular network
NOTE: grossly appears as a well-circumscribed solid brown tumour
What grading system is used for clear cell and papillary renal cell carcinoma?
ISUP Nuclear Grade
What risk progression index is used for clear cell carcinoma?
Leibovich risk model
What is Nephroblastoma (Wilm’s tumour)?
Malignant triphasic kidney tumour of childhood:
· Blastema (small round blue cells)
· Epithelial
· Stromal
Typically present with an abdominal mass in children aged 2-5 years
NOTE: 95% have an excellent prognosis
What are the major risk factors for urothelial carcinoma?
Smoking
Aromatic amines
What are the three main subtypes of urothelial carcinoma?
Non-invasive papillary urothelial carcinoma
Invasive urothelial carcinoma
Flat urothelial carcinoma in situ
List some treatment options for BPH.
5a-reductase inhibitors
Alpha-blockers
TURP
How can BPH present?
LUTS (most common)
UTI
Acute urinary retention
Renal failure
What is the precancerous lesion that prostate cancer arises from?
Prostatic intraepithelial neoplasia
List some mutations that are implicated in prostate cancer.
PTEN
AMACR
P27
GST-pi
What scoring system is used for prostate cancer? Explain how it is calculated.
Gleason score
Expressed as x + y = z
Calculated by adding the top two most common patterns/grades seen on histological grading
Higher scores are associated with a poorer prognosis
List some risk factors for testicular germ cell tumours.
Undescended testicles
Low birth weight
Which genetic factor is associated with testicular germ cell tumours?
Amplification of i12p
List the five histological subtypes of testicular germ cell tumours.
Seminoma
Embryonal carcinoma
Post-pubertal teratoma
Yolk sac tumour
Choriocarcinoma
How are testicular germ cell tumours treated?
They are highly sensitive to platinum-based chemotherapy
5-year survival: 98%
Name three types of testicular non-germ cell tumours.
Lymphoma – more in older men, poor prognosis
Leydig cell tumour – may cause precocious puberty (if pre-pubertal)
Sertoli cell tumour – 90% benign
What are the causes of epididymitis?
< 35 years = N. gonorrhoea and C. trachomatis
35+ years = E. coli
List some describe a few types of benign penile diseases.
Lichen sclerosus/balanitis xerotica obliterans – inflammatory condition that causes phimosis
Zoon’s balanitis – inflammatory condition that causes red areas
Condylomas – HPV 6 and 11
Peyronie’ disease – scarring, inflammation and thickening of the corpus cavernosa
List some risk factors for penile carcinoma.
HPV
Smoking
Lichen sclerosus
In which part of a bone is the growth plate found?
Metaphysis
What are the main features of cortical bones?
Long bones
80% of skeleton
Appendicular
80-90% calcified
Mainly mechanical and protective
What are the main features of cancellous bones?
Vertebrae and pelvis
20% of skeleton
Mainly axial
15-25% calcified
Mainly metabolic
Large surface
Which protein is important in regulating the action of osteoclasts?
Osteoblasts produce osteoprotegrin which blocks the RANK-RANKL interaction which prevents the differentiation of an osteoclast precursor into a fully functioning osteoclast
Where is bone usually sampled from for histological analysis of bone in metabolic bone disease?
Iliac crest
NOTE: the sample must be processed and un-decalcified for histomorphometry
Which static parameters are measured in the histological analysis of bone in metabolic bone disease?
Cortical thickness
Trabecular bone volume
Thickness, number and separation of trabeculae
Which technique is used to measure histodynamic parameters when investigating metabolic bone disease?
Tetracycline labelling
Which investigations may be used in a patient with suspected osteoporosis?
Serum calcium, phosphate and ALP (should be NORMAL)
Urinary calcium
Collagen breakdown products
Imaging
DEXA
Which four organs are affected by PTH and have a role in calcium homeostasis?
Kidneys
Bone
Proximal small intestine
Parathyroid gland
What two underlying abnormalities can cause osteomalacia?
Deficiency of vitamin D
Deficiency of phosphate
What is the main histological feature of osteomalacia?
Reduced amount of mineralised bone compared to the amount of osteoid
Name some radiological features of osteomalacia.
Bowing of the legs in Rickets
Horizontal pseudofractures in Looser’s zones
Describe how the urine excretion of calcium and phosphate changes in primary hyperparathyroidism.
Both increase
What skeletal change is seen in primary hyperparathyroidism?
Osteitis fibrosa cystica
What histological feature is typically seen in hyperparathyroidism?
Brown cell tumour – several multinucleated giant cells on a background of fibrous stroma with haemorrhage
What is Paget’s disease and what are its three phases?
Disorder of bone turnover
Three phases
· Osteolytic
· Osteolytic-osteosclerotic
· Quiescent osteosclerotic
NOTE: the combination of osteoblast and osteoclast activity results in new bone formation
NOTE: 85% are polyostotic
Describe the histological appearance of Paget’s disease.
Lines will be seen between areas of new bone formation so it looks like a mosaic/jigsaw puzzle
Which virus is associated with Paget’s disease?
Parvomyxovirus
Describe the presentation of Paget’s disease.
Most lesions affect the skull and lumbar spine
Pain
Microfractures
Nerve compression
Skull changes (can put the medulla at risk leading to haemodynamic changes)
Sarcoma
Paget’s disease of the tibia can cause bowing
What are the four stages of fracture repair?
Organisation of a haematoma at the site of the fracture (pro-callus)
Formation of a fibrocartilaginous callus
Mineralisation of the fibrocartilaginous callus
Remodelling of the bone along weight-bearing lines
Which sites are most commonly affected by osteomyelitis?
Vertebra
Jaw (secondary to dental caries)
Toe
Long bones (usually metaphysis)
Describe the typical presentation of osteomyelitis.
General – FLAWS
Local – pain, swelling, redness
Which investigations may be used in suspected osteomyelitis?
Blood cultures (positive in 60%)
X-ray (will eventually show lytic areas)
NOTE: osteomyelitis is almost always bacterial
Which organisms can cause osteomyelitis?
Staphylococcus aureus (90%)
E. coli
Klebsiella
Pseudomonas (IVDU)
Which bacterium is associated with osteomyelitic in patients with sickle cell disease?
Salmonella
Describe the X-ray changes seen in osteomyelitis.
Usually appear about 10 days after onset
Mottled rarefaction and lifting of periosteum
First week changes – irregular sub-periosteal new bone formation (involucrum – layer of new bone that forms around dead bone)
Later changes – irregular lytic destruction
Some areas of the necrotic cortex may become detached (sequestra). This takes 3-6 weeks
What are the potential consequences of TB osteomyelitis of the vertebrae?
Aka Pott’s disease
May result in psoas abscess or skeletal deformity
NOTE: TB osteomyelitis tends to only occur in immunocompromised patients
NOTE: systemic amyloidosis may occur in some cases
Describe the histological appearance of TB osteomyelitis.
Lots of inflammatory cells can be seen in between trabeculae
Langerhans-type giant cells (with a horse-shoe nucleus) will be seen
What congenital skeletal lesions are associated with syphilis?
Osteochondritis
Osteoperiostitis
Diaphyseal osteomyelitis
List some acquired skeletal lesions that are associated with syphilis.
Non-gummatous periostitis
Gummatous inflammation of joints and bones
Neuropathic joints (tabes dorsalis)
Neuropathic shaft fractures
What is the organism and vector in lyme disease?
Organism: Borrelia burgdorferi
Vector: Ixodus dammini
What is the skin rash that is classically associated with lyme disease?
Erythema chronicum migrans
Describe the clinical features of lyme disease.
Early localised – rash (90%) often on thigh, groin or axilla, 1-50 cm in diameter
Early disseminated – affects many organs (musculoskeletal, heart, nervous system)
Late, persistent – dominated by arthritis
Outline the treatment of lyme disease.
Aim for prevention
Antibiotics
No effective prophylaxis
Diagnosis is clinical
What are the HLA associations of rheumatoid arthritis?
HLA DR4 and HLA DR1 (Chr6p21)
Other alleles: TFNA1P3, STAT4
What is rheumatoid factor and what proportion of patient’s with rheumatoid arthritis are rheumatoid factor positive?
IgM antibody against IgG
80% positive
May be responsible for extra-articular disease
Which sites tend to be affected by rheumatoid arthritis?
Small joints of the hand and feet (except DIP)
Wrists, elbows, ankles and knees
List some characteristic deformities associated with rheumatoid arthritis.
Radial deviation of the wrist
Ulnar deviation of the fingers
Swan neck and Boutonniere deformity
Z-shaped thumb
Describe the histological features of rheumatoid arthritis.
Proliferative synovitis with thickening of synovial membranes, hyperplasia of surface synoviocytes, intense inflammatory cell infiltrate and fibrin deposition and necrosis
A pannus can form (exuberant inflamed synovium)
Which type of multinucleate giant cell may be seen in rheumatoid arthritis?
Grimley-Sokoloff cell (like a Langerhans cell but does not have horseshoe nuclei)
What type of crystals cause gout?
Needle-shaped negatively birefringent urate crystals
NOTE: big toe is involved in 90% of cases
NOTE: a tophus is pathognomonic of gout
Which crystals cause pseudogout?
Calcium crystals
Calcium pyrophosphate – mainly knees
Calcium phosphate (hydroxyapatite) – knees and shoulders
Rhomboid-shaped positively birefringent crystals
Which tumours most commonly metastasise to the bone in adults
Breast
Prostate
Lung
Kidney
Thyroid
Which tumours most commonly metastasise to the bone in children
Neuroblastoma
Wilm’s tumour
Osteosarcoma
Ewing’s
Rhabdomyosarcoma
What are the key clinical and radiological features of osteosarcoma?
Peak in adolescence
60% around the knee
X-ray: usually metaphysial, lytic, permeative, elevated periosteum (Codman’s triangle)
Describe the histological appearance of osteosarcoma.
Malignant mesenchymal cells with or without bone and cartilage formation
What are the main clinical, radiological and histological features of chondrosarcoma?
Malignant cartilage producing tumour
Affects axial skeleton, proximal femur and proximal tibia
X-ray: lytic with fluffy calcification
Histology: malignant chondrocytes with or without chondroid matrix
What are the main clinical, radiological and histological features of Ewing’s sarcoma?
Highly malignant small round cell tumour
Occurs in < 20 years
Mainly affect diaphysis and metaphysis of long bones
X-ray: onion skinning of the periosteum, lytic with or without sclerosis
Histology: sheets of small round cells
Which chromosomal translocation is associated with Ewing’s sarcoma?
11;22 (ESWR1:Fli1)
What is a volvulus?
Twisting of a loop of bowel at the mesenteric base around a vascular pedicle
Which part of the intestines tend to be affected by volvulus in children and the eldery?
Children – small bowel
Elderly – sigmoid colon
What can cause pseudomembranous colitis?
Exotoxins by C. difficile
How is pseudomembranous colitis treated?
Metronidazole or vancomycin
Where in the intestines does ischaemic colitis tend to occur?
Watershed zones (e.g. splenic flexure, rectosigmoid)
List some characteristic features of Crohn’s disease.
Can occur anywhere from mouth to anus
Skip lesions
Transmural inflammation
Non-caseating granulomas
Sinus/fistula formation
Mostly affects large bowel and terminal ileum
Thick rubber hose-like wall
Cobblestone mucosa
Narrow lumen
List some extra-intestinal features of inflammatory bowel disease.
Arthritis
Uveitis
Stomatitis/cheilitis
Skin lesions (pyoderma gangrenosum, erythema multiforme, erythema nodosum)
List some characteristic features of ulcerative colitis.
Involves rectum and colon in a continuous fashion
May see backwash ileitis (involvement of the terminal ileum)
Inflammation is confined to the mucosa
Bowel wall is normal thickness
List some complications of ulcerative colitis.
Severe haemorrhage
Toxic megacolon
Adenocarcinoma (20-30 x increased risk)
Which liver condition is associated with UC?
Primary sclerosing cholangitis
List some features of an adenoma that are associated with increased risk of becoming a carcinoma.
Size of polyp (> 4 cm = 45%)
Proportion of villous component
Degree of dysplastic change within a polyp
List some familial syndromes that are characterised by intestinal polyps.
Peutz-Jegher’s syndrome
FAP (Gardner’s, Turcot)
HNPCC
What is the inheritance pattern of FAP?
Autosomal dominant
Which gene is mutated in FAP?
APC gene – chromosome 5q21
NOTE: almost 100% will develop cancer in 10-15 years
What is Gardner’s syndrome?
Same features of FAP but with extra-intestinal manifestations: multiple osteomas of the skull and mandible, epidermoid cysts, desmoid tumours and supernumerary teeth
What is the inheritance pattern of HNPCC?
Autosomal dominant
Where do carcinomas in HNPCC tend to occur?
Proximal to the splenic flexure
NOTE: poorly differentiated and mucinous cancers are more common. Polyps do not necessarily precede the cancer
Outline Dukes’ staging of colorectal cancer.
A – confined to bowel wall
B – through the bowel wall
C – lymph node metastases
D – distant metastases
Describe the radiological classification of brain tumours.
Extra-axial (coverings) – tumours of the bone, meninges and metastatic deposits
Intra-axial (parenchyma) – derived from normal cell populations of the CNS (e.g. glia, neurones, vessels) or derived from other cell types (e.g. lymphomas, metastases)
What is the most common genetic syndrome associated with brain tumours?
Neurofibromatosis
What is the inheritance pattern of neurofibromatosis?
Autosomal dominant
Where are the genes that cause neurofibromatosis located?
NF1 – 17q11
NF2 – 22q12
List some manifestations of brain tumours that are supratentorial
Focal neurological defect
Seizures
Personality changes
List some manifestations of brain tumours that are subtentorial
Cerebellar ataxia
Long tract signs
Cranial nerve palsy
Outline the management options for brain tumours.
Surgery – aim for maximal safe resection with minimal damage to the patient. Debulking may be performed and biopsies may be taken.
Radiotherapy – used for gliomas and metastases
Chemotherapy – mainly for high-grade gliomas
Outline the meaning of the different WHO grades for brain tumours.
Grade I = benign, long-term survival
Grade II = death in > 5 years
Grade III = death in < 5 years
Grade IV = death in < 1 year
NOTE: grades I and II are low grade
What is the most common type of primary brain tumour?
Glial tumours
How are the types of glial tumours seen in children and adults different?
Diffuse Infiltration – mainly seen in adults, become more malignant with time, can either be astrocytomas or oligodendrogliomas
Circumscribed Gliomas – mainly seen in children, tend to be low-grade, rarely undergo malignant transformation
Which genetic mutations are associated with gliomas in adults and in children?
Diffuse infiltration (adults) – IDH1/2
Circumscribed gliomas (children) – MAPK (BRAF)
List some examples of circumscribed gliomas.
Pilocytic astrocytoma (MOST COMMON)
Pleiomorphic xanthoastrocytoma
Subependymal giant cell astrocytoma
List some key features of pilocytic astrocytoma.
Usually grade I
Mainly occurs in children
Associated with NF1
Often cerebellar
BRAF mutation in 70% of cases
What is the hallmark histological feature of pilocytic astrocytoma?
Piloid (hairy) cell
Often see Rosenthal fibres and granular bodies
Slow-growing with low mitotic activity
List some key features of astrocytoma.
Usually Grade II-IV
Cerebral hemispheres are the most common site in adults
Can progress to become a higher grade (malignant progression)
IDH2 mutation in 80% of cases
Mitotic activity and vascular proliferation is absent
What can astrocytomas eventually become?
Glioblastoma (after 5-7 years)
What is the most aggressive and most common type of glioblastoma?
De novo glioblastoma (stage IV)
List some key features of glioblastoma multiforme.
Grade IV
Most patients > 50 years
High cellularity and high mitotic activity
Microvascular proliferation and necrosis
What does glioblastoma multiforme tend to arise from?
90% occur de novo and have wildtype IDH
10% occur secondary to astrocytoma and have IDH mutation
List some key features of oligodendrogliomas.
Grade II-III
Tends to present with a long history of neurological signs (usually seizures)
Slow-growing
Better prognosis than astrocytoma (better response to chemotherapy and radiotherapy)
What is a characteristic histological feature of oligodendroglioma?
Round cells with clear cytoplasm (fried egg)
Which gene mutations are associated with oligodendroglioma?
IDH1/2
Co-deletion of 1p/19q
What is the second most common primary intracranial tumour after gliomas?
Meningioma
List some key features of meningioma.
Mainly low grade (I and II)
Can be multiple (e.g. in NF2)
Can cause focal symptoms (e.g. seizures, compression)
Which histological feature of a meningioma is important in determining grade?
Mitotic activity (number of mitoses per 10 high power fields)
Grade 1 < 4
Grade 2: 4-20
Grade 3 > 20
NOTE: brain invasion is also an important thing to assess (presence of brain invasion makes it grade II)
How does the grade of meningioma affect the management options?
Grade II and III requires radiotherapy as well as surgery
What is a medulloblastoma?
Embryonal tumour originating from neuroepithelial precursors of the cerebellum and dorsal brainstem
They are always found in the cerebellum
Describe the histological appearance of medulloblastoma.
Small blue round cell tumour with expression of neuronal markers (very little differentiation)
NOTE: synaptophysin is an example of a neuronal marker
What histological feature is suggestive of partial neuronal differentiation?
Homer-Wright rosettes
Which tumours most commonly metastasise to the brain?
Lung
Breast
Melanoma
What radiological appearance is characteristic of cerebral oedema?
Loss of gyri
Name and describe the two types of hydrocephalus.
Non-communicating – caused by obstruction of CSF flow (usually in the cerebral aqueduct)
Communicating – caused by reduced reabsorption of CSF into the venous sinuses (this could be caused by infection (e.g. meningitis))
What is the normal range for ICP?
7-15 mm Hg
Name and describe the three sites of brain herniation.
Subfalcine – the cortex is pushed under the falx cerebri
Transtentorial (uncal) – the posterior cranial fossa is covered by the tentorium cerebelli which has a rigid opening for the brainstem. Supratentorial pressure can result in herniation of the medial temporal lobe over the rigid end of the opening of the tentorium cerebelli
Tonsillar – herniation of the cerebellar tonsils through the foramen magnum (this can put pressure on the medulla and kill)
What is a non-traumatic intraparenchymal haemorrhage?
Haemorrhage into the substance of the brain (parenchyma) due to rupture of small intraparenchymal vessels
Where do non-traumatic intraparenchymal haemorrhages tend to occur most frequently?
Basal ganglia
NOTE: hypertension is implicated in > 50% of bleeds
What is an arteriovenous malformation?
A malformation where blood bypasses quickly from artery to vein without going through a normal capillary network
They can occur anywhere in the CNS and they can rupture
As they occur under high pressure, they tend to cause massive bleeds
Define cavernous angioma.
Well-defined malformative lesion composed of closely-packed vessels with no parenchyma interposed between vascular spaces
NOTE: it is similar to an arteriovenous malformation but there is no brain substance wrapped up amongst the vessels
NOTE: these tend to bleed at lower pressure causing recurrent small bleeds
Describe the appearance of cavernous angiomas on MRI.
Shows target sign
What causes subarachnoid haemorrhages?
Rupture of a berry aneurysm
NOTE: berry aneurysms are congenital
Where are berry aneurysms typically found?
80% at the internal carotid bifurcation
20% within the vertebro-basillar circulation
NOTE: highest risk of rupture if diameter of 6-10 mm
Where is atherosclerosis most commonly found within the cerebral vasculature?
Carotid bifurcation
Basilar artery
Which part of the cerebral vascular tends to be affected by infarcts resulting from emboli?
Middle cerebral artery branches
What are the consequences of base of skull fractures?
The fracture may pass through the middle ear or anterior cranial fossa
It can cause otorrhoea or rhinorrhoea
Increased risk of infection
NOTE: battle sign and raccoon eyes are manifestations of basal skull fractures
With regards to brain injury, what is a laceration?
Bruising of the brain that causes rupture of the pia mater
What is the term used to describe rebound injury to the opposite side of the brain?
Contrecoup injury
What is diffuse axonal injury?
Occurs at the moment of injury
Shear and tensile forces causes damage to the axons
This is the most common non-bleed related cause of coma
Midline structure are particularly affected (e.g. corpus callosum)
Some people suffer cognitive and behavioural changes further down the line
What are prion diseases?
Proteinaceous infections only
They are transmissible diseases that have no DNA or RNA
List some examples of prion diseases.
Creutzfeldt-Jakob disease
Gerstmann-Straussler-Sheinker syndrome
Kuru
Fatal familial insomnia
Describe the histological appearance of brains affected by prion diseases.
The tissue is full of vacuoles (spongiform encephalopathies)
What are the key features of new variant CJD?
Sporadic neuropsychiatric disorder occurring in mainly younger patients (< 45 years) and associated with BSE
Clinical features include cerebellar ataxia and dementia
Which part of the brain is often affected by cortical atrophy in Alzheimer’s disease?
Inferior horn of the lateral ventricles where the hippocampus is found (this is responsible for loss of short term memory)
Describe the Braak stages of Alzheimer’s disease
Stage 1: tau pathology in the transentorhinal cortex
Stage 2: posterior hippocampus
Stage 3: immunostaining is visible by eye, affects substantia nigra
Stage 4: superior temporal gyrus
Stage 5: peristriate cortex
Stage 6: striate cortex
NOTE: clinically, symptoms tend to arise in stage 3 or 4
Outline the main histological features of Parkinson’s disease.
Characterised by the presence of Lewy bodies which are intracellular accumulations of alpha-synuclein
Parkinson’s disease is caused by abhorrent metabolism of alpha-synuclein
NOTE: this was discovered because mutations in the alpha-synuclein gene are associated with rare familial forms of Parkinson’s disease
What is the diagnostic gold standard for Parkinson’s disease?
Alpha-synuclein immunostaining
What are some non-extrapyramidal symptoms of Parkinson’s disease?
Sleep disorders
Depression
Anosmia
What are three important differentials to consider in a patient with Parkinson’s disease?
Multiple system atrophy
Corticobasal degeneration
Progressive supranuclear palsy
What is multisystem atrophy?
It is an alpha-synucleinopathy like Parkinson’s disease which targets glial cells
It presents similarly to Parkinson’s disease
It mainly affects the cerebellum so the patients are more likely to present with falls
What are the main histological features of Pick’s disease?
Marked gliosis and neuronal loss
Balloon neurones
Tau-positive Pick bodies
NOTE: mutations in tau are associated with a fronto-temporal dementia phenotype often associated with Parkinson’s disease
NOTE: there are 17 autosomal dominant syndromes resulting from mutations in tau
What is a characteristic feature of frontotemporal dementia associated with progranulin mutations?
Atrophy tends to be unilateral
What type of epithelium lines the airways?
Ciliated respiratory epithelium
Which types of cells line the alveoli?
Type 1 pneumocytes
What is the main histological feature of pulmonary oedema?
Intra-alveolar fluid
Describe the appearance of the lungs on post-mortem examination in a patient who died from ARDS.
Plum-coloured
Heavy
Airless
Describe the main histological features of asthma.
Lots of eosinophils and mast cells
Goblet cell hyperplasia
Mucus plugs within airways
Thickening of bronchial smooth muscle and dilatation of blood vessels
Define chronic bronchitis.
Chronic cough productive of sputum presents for most days for at least 3 months over 2 consecutive years
List some histological features of chronic bronchitis.
Dilated airways
Mucus gland hyperplasia
Goblet cell hyperplasia
Mild inflammation
Describe how the pattern of alveolar damage is different with smoking compared to alpha-1 antitrypsin deficiency.
Smoking – centrilobular damage
Alpha-1 antitrypsin deficiency – panacinar (throughout the lungs)
Define bronchiectasis.
Permanent abnormal dilatation of the bronchi with inflammation and fibrosis extending into adjacent parenchyma
Which part of the lungs tends to be affected most frequently in idiopathic bronchiectasis?
Lower lobe
List some causes of bronchiectasis.
Infection (MOST COMMON)
· Post-infectious (e.g. CF)
· Abnormal host defence (e.g. chemotherapy, immunodeficiency)
· Ciliary dyskinesia
Obstruction
Post-inflammatory (aspiration)
Interstitial disease (e.g. sarcoidosis)
Asthma
Where is the CFTR gene found?
7q3
What is the most common mutation associated with CF?
Delta F508
List some clinical manifestations of CF.
GI – meconium ileus, malabsorption
Pancreas – pancreatitis
Liver – cirrhosis
Male reproductive system – infertility
Recurrent chest infections
List some causes of community-acquired bacterial pneumonia.
Streptococcus pneumoniae
Haemophilus influenzae
Mycoplasma
List some causes of hospital-acquired bacterial pneumonia.
Gram-negatives (Klebsiella, Pseudomonas)
What is bronchopneumonia?
Infection is centred around the airways
Tends to be associated with compromised host defence (mainly the elderly) and is caused by low virulence organisms (e.g. Staphylococcus, Haemophilus, Pneumococcus)
It will show patchy bronchial and peribronchial distribution often involving the lower lobes
What is lobar pneumonia?
Infection is focused in a lobe of the lung
90-95% caused by S. pneumoniae
Widespread fibrinosuppurative consolidation
What are the histopathological stages of lobar pneumonia?
Stage 1: congestion (hyperaemia and intra-alveolar fluid)
Stage 2: red hepatisation (hyperaemia, intra-alveolar neutrophils)
Stage 3: grey hepatisation (intra-alveolar connective tissue)
Stage 4: resolution (restoration of normal tissue architecture)
Describe the histological appearance of atypical pneumonia.
Interstitial inflammation (pneumonitis) without accumulation of intra-alveolar inflammatory cells
NOTE: causes include Mycoplasma, viruses, Coxiella and Chlamydia
What is a long term consequence of repeated small pulmonary emboli?
Pulmonary hypertension
What are the main types of lung cancer?
Non-small cell carcinoma
· Squamous cell carcinoma (30%)
· Adenocarcinoma (30%)
· Large cell carcinoma (20%)
Small cell carcinoma (20%)
Which types of lung cancer are most strongly associated with smoking?
Squamous cell carcinoma
Small cell carcinoma
Which type of lung cancer tends to occur in non-smokers?
Adenocarcinoma
What feature of squamous epithelium makes it vulnerable to undergoing malignant changes?
It does not have cilia leading to a build-up of mucus
Within the mucus carcinogens accumulate
Where do squamous cell carcinomas tend to arise?
Centrally – arising from the bronchial epithelium
NOTE: there is an increasing incidence of peripheral squamous cell carcinomas (possibly due to deeper inhalation of modern cigarette smoke)
Which mutations are associated with adenocarcinoma in smokers?
Kras
Issues with DNA methylation
P53
Which mutation is associated with adenocarcinoma in non-smokers?
EGFR
What is large cell carcinoma of the lung?
Poorly differentiated tumour composed of large cells
There is no evidence of squamous or glandular differentiation
It has a poor prognosis
Where does small cell lung cancer tend to arise?
Central – around the bronchi
NOTE: 80% present with advanced disease and it carries a poor prognosis
List some common mutations seen in small cell lung cancer.
P53
RB1
What is the difference in the chemosensitivity of small cell lung cancer and non-small cell lung cancer?
Small cell – sensitive
Non-small cell – not very chemosensitive
Which molecular changes are important to test for in adenocarcinoma?
EGFR (responder or resistance)
ALK translocation
Ros1 translocation
