Histopath Flashcards
Why do lupus pts have a malar rash
o There is lymphocytic infiltration of the dermis
o You see vacuolisation (dissolution of the cells) of basal epidermis
o Extravasation of red blood cells causes the rash
o Immunofluorescence will show immune complex deposition at the epidermis-dermis junction
Glomerulonephritis histopath
o The glomerular capillaries are thickened (wire-loop capillaries)
o The capillaries are thick due to immune complex deposition in the basement membrane
o Immunofluorescence can be used to visualise the immune complex deposition (electron microscopy will also show dark areas of immune complex deposition)
What sort of endocarditis do you get in lupus?
o This is a non-infective form of endocarditis that is associated with SLE
o Patients may present with emboli, heart failure or murmurs
o The vegetations are made up of lymphocytes, neutrophils, fibrin strands etc
PID causative organism
Usual causes: o Gonococci o Chlamydia o Enteric bacteria Usually starts at the lower genital tract and spreads upwards via the mucosal surface • Other causes: o Staphylococcus o Streptococcus o Coliform bacteria o Clostridium perfringens These tend to occur secondary to abortion Usually starts in the uterus and spreads upwards via lymphatics and blood vessels • Involves the deep tissue layers • Complications o Peritonitis o Intestinal obstructions due to adhesions o Bacteraemia o Infertility
Cx of salpingitis
o Complications • Plical fusion • Adhesions to ovary • Tubo-ovarian abscess • Peritonitis • Hydrosalpinx (enlarged fallopian tube filled with fluid) • Infertility • Ectopic pregnancy
High risk and low risk HPV strains
High risk = 16 and 18
Low risk = 6 and 11
How does HPV cause cervical cancer?
oIn most people with an HPV infection, NOTHING will happen because the immune system will eliminate HPV
oHPV becomes undetectable within 2 years in about 90% of cases
oRelatively few patients develop symptoms
oHowever, persistent infection with high risk HPV types is associated with pre-cancerous and cancerous cervical changes
oTwo proteins (E6 and E7) which is encoded by the virus have transforming genes
oE6 and E7 bind to and inactivate TWO tumour suppressor genes:
• Retinoblastoma (Rb) - E7
• P53 - E6
oThis interferes with apoptosis and increased unscheduled cellular proliferation which contributes to oncogenesis
Cervical cancer screening routine
Screening Intervals • First invitation: 25 years • 25-49 = 3 yearly • 50-62 = 5 yearly • 65+ = only screen those who have not been screened since they were 50 or have recent abnormal tests
Endometrial hyperplasia
o There is an increase in stroma and glands
o Usually driven by oestrogen
o Usually occurs perimenopausal
o Causes
• Persistent anovulation (because of persistently raised oestrogen levels)
• Polycystic ovarian syndrome can also cause persistently elevated levels of oestrogen giving rise to endometrial hyperplasia
• Granuloma cell tumours of the ovary
• Oestrogen therapy
Type II endometrial carcinoma
- SUBTYPES: serous and clear cell tumours
- Older patients
- Less oestrogen-dependent
- Arise in atrophic endometrium
- High grade, deeper invasion and higher stage
- Genetic Mutations
Prognosis of partial and compelte moles in terms of malignancy
- NO partial moles will progress to malignancy
- 2.5% of complete moles progress to malignancy
- 10% of complete moles develop into locally destructive invasive moles
Benign ovarian tumors
- Serous cystadenoma
- Cystadenofibromas
- Mucinous cystadenomas
- Brenner tumour
- Serous cystadenoma
- Cystadenofibromas
- Mucinous cystadenomas
- Brenner tumour
Secondary ovarian tumour
o Krukenberg Tumour
• Bilateral metastases composed of mucin-producing signet ring cells
• Most often from gastric or breast cancer
o Metastatic Colorectal Carcinoma
• Ovaries are prone to metastatic spread of colorectal cancer
Hereditary causes of ovarian cancer
o Up to 10% are familial
o 10% of women with ovarian carcinoma are carriers of a breast/ovarian cancer susceptibility gene
THREE familial syndromes:
1. Familial breast-ovarian cancer syndrome
2. Site-specific ovarian cancer
3. Cancer family syndrome (Lynch type II)
o BRCA1
o Hereditary ovarian cancer occurs at a younger age
o Specific Associations
• Serous = BRCA
• Mucinous = HNPCC
• Endometrioid = HNPCC
Hibernating Myocardium
The concept that chronic sublethal ischaemia leads to lower metabolism (i.e. hibernating) in myocytes which can be reversed with revascularisation
Reperfusion Injury in MI
o This is the consequence of letting blood go back into an area of myocardial necrosis
o The oxidative stress, calcium overload and inflammation can cause further injury
o Arrhythmias are common
o Biochemical abnormalities can last a few days
o It can cause stunned myocardium - reversible cardiac failure lasting several days
MI complications
o Contractile Dysfunction
• 40% of infarcts will go into cardiogenic shock which has a 70% mortality rate
• This tends to be due to an arrhythmia
o Arrhythmia
• Due to myocardial irritability and conduction disturbance
o Myocardial Rupture
o Pericarditis (Dressler’s syndrome)
o RV infarction
o Infarct extension - new necrosis adjacent to old
o Infarct expansion - necrotic muscle stretches
Sudden Cardiac death
- DEFINITION: unexpected death from cardiac causes in individuals without symptomatic heart disease or early (1 hour) after the onset of symptoms
- Usually due to lethal arrhythmia
- Most people will have a background of ischaemic heart disease (90%)
- Acute myocardial ischaemia is the usual trigger
- Causes electrical instability at sites distant from conduction system often near scars from old MIs
- Other associated conditions include aortic stenosis, mitral valve prolapse and pulmonary hypertension
Cardiomyopathy
- Summary: too thin, too thick, too stiff
* Cardiomyopathies are inherent problems with the heart that are not ischaemic or valvular etc.
Different types of cardiomyopathy
Dilated: Caused by progressive loss of myocytes, Leads to a dilated heart
Hypertrophic: Left ventricular hypertrophy, Familial in 50% (autosomal dominant, variable penetrance)
Restrictive cardiomyopathy: Impaired ventricular compliance, Idiopathic or secondary to myocardial disease (e.g. amyloid (image above), sarcoidosis)
Cardiac valve disease
o Caused by immune cross-reactivity with the cardiac valves
o It’s the sequelae of previous rheumatic fever
o Usually the left-sided valves (almost always mitral)
• Mitral > Aortic >Tricuspid > Pulmonary
o Thickening of valve leaflet, especially along the lines of closure (this means that the valve can’t open or close properly)
HIV opportunistic infections
PCP (Pneumonia) CMV (oesophagitis, retina) (causes ulcers in oesophagus, on cytology the have epithelial cells which this large swelling - that is the CMV nuclear inclusion body) Candida TB Cryptococcus meningitis Toxoplasma gondii causing encephalitis JC Papovirus (leukoencephalopath) Herpes Simplex Cryptosporidium
Kaposi Sarcoma cytology
- Dermis shows a mass of spindle shapes cells with blood spaces between them.
Endothelial cells infected with HHV8 undergo altered lymphatic differentiation and manufacture cytokines creating a favorable milieu for angiogenesis.
Slit-like vascular spaces formed by spindled endothelial cells with minimal to moderate atypia; hemorrhage, hemosiderin and plasma cells are key histologic clues
Where can a mycobacterial infection spread too?
Can literally affect ANYWHERE: Lung LN Heart (pericarditis) GIT (peritonitis) Bone (vertebra) CNS (meningitis)
Describe a sarcoid granuloma
Non-caseating granuloma that is a collection of epitheliod macrophages with a border of lymphocytes around the circumference. Giant cells can be present.
IgG4 related disease
•Characterised by large numbers of IgG4 positive plasma cells
o NOTE: as part of a polyclonal response you would expect to have mixed levels of the different IgGs
• May involve the pancreas, bile ducts and almost any other part of the body
• IgG4 related disease is a relatively new phenomenon and is thought to have explained most cases of what has been described as ‘autoimmune pancreatitis’ thus far
• HISTOLOGY (above) - the duct is surrounded by loads of IgG4 expressing plasma cells, inflammatory infiltrative
• These patients respond very well to steroids
Chronic alcohol consumption manifestation
GI: Oesopahgeal varices, ascites, Steatosis -> Steatohepatitis -> fibrosis -> Cirrhosis -> HCC
Pancreatitis
CNS- Werenicke’s and PNS (periphernal neuropathy)
Cardio - dilated cardiomyopathy
FAS
Oral / oesophageal cancer
Types of Renal stones and their relative causes
- Calcium oxalate (Weddelite) - 75% (due to hypercalciuria e.g. increased absorption in gut, decreae reabsorption in PCT)
- Magnesium ammonium phosphate (struvite) - 15%
Form as a consequence of infection with urease-producing organisms (Proteus)
Ammonia produced by the bacteria alkalinises the urine leading to precipitation of magnesium ammonium phosphate salts
They can become LARGE (e.g. staghorn calculus) - Uric acid - 5%
May form in patients with hyperuricaemia
Gout
Rapid cell turnover (e.g. chemotherapy)
HOWEVER, most patients do NOT have hyperuricaemia or increased uric acid excretion in the urine
Thought to be due to a tendency to have slightly more acidic urine
How do stones present?
- Small stones may stay in the kidney and be asymptomatic (may be detected during investigation of haematuria or recurrent UTI)
- Small stones drifting out of the kidney may becomes impacted and cause ureteric colic
Tends to get stuck at places where the urinary tract bends:
• Pelvi-ureteric junction
• Pelvic brim
• Vesico-ureteric junction - Large stones tend to stay in the kidney and can lead to:
• Obstruction
• Risk of infection
• CKD
Types of benign renal neoplasms
Papillary Adenoma
Renal Oncocytoma
Angiomyolipoma
Papillary Adenoma
Benign EPITHELIAL kidney tumour composed of papillae and/or tubules
By definition < 15 mm in size
Well-circumscribed
Trisomy 7, Trisomy 17 or Loss of Y Chromosome
o Frequent incidental finding in nephrectomies and at autopsy
o Especially common in people with CKD and acquired cystic renal disease
Renal Oncocytoma
Often incidental
benign EPITHELIAL kidney tumour composed of oncocytic cells
Well circumscribed
Usually sporadic
Can be seen in Birt-Hogg-Dubé syndrome
o Usually an incidental finding
o Histology (mahogany brown tumour with central scar)
What does an oncocyte look like?
Oncocyte = large cells with VERY PINK granular cytoplasm and a prominent nucleolus (pink due to mitochondria?)
Angiomyolipoma
Angio - vessels
myo - smooth muscle
lipoma - fat
(not necessarily equal proportions)
benign MESENCHYMAL kidney tumour composed of thick-walled blood vessels, smooth muscle and fat.
Derived from PEC cells (perivascular epitheliod cells)
Benign tumour but can be dangerous as can haemorrhage
Again, usually found incidentally
Large tumours (> 4 cm) may present with flank pain, haemorrhage and shock
Renal Cell carcinoma types and how do they present
LOADS of subtypes Top 3: o Clear cell renal cell carcinoma (70%) o Papillary renal cell carcinoma (15%) o Chromophobe renal cell carcinoma (5%)
Half of cases will present with painless haematuria. Most of the remaining cases are only detected on incidental imaging
Small proportion present with metastatic disease
Risk factors for renal CC
o Smoking o Hypertension o Obesity o Long-term dialysis o Genetic syndromes (e.g. von Hippel Lindau)
Clear RCC
appearance, genetics, histology
EPITHELIAL kidney tumour composed of NESTS of clear cells set in a delicate capillary vascular network
o Appears grossly as a GOLDEN-YELLOW tumour with haemorrhagic areas
o Genetics: loss of chromosome 3p is a common finding
The normal renal parenchyma is squashed by the CC and the tumour composed of lots of clear cells.
Papillary RCC
epithelial kidney tumour composed of papillae and/or tubules
• By definition > 15 mm in size
• This is the malignant counterpart of a papillary adenoma
• Genetically shows trisomy 7, trisomy 17 and loss of Y chromosome
• Subdivided into TWO types (type 1 and type 2) based on morphology . Type 2 are quite heterogenous but type 1 is quite well defined.
• Grossly appears as a fragile, friable BROWN tumour
•Type 1-composed of a single layer of small and flat cells. You see lots of islands of cells.
• Type 2 - there is stratification (multi-layering) of the cells. Type 2 tend to do worse than type 1.
Chromophobe
epithelial kidney tumour composed of SHEETS of large cells that display distinct cell BORDERS, reticular cytoplasm and a thick-walled vascular network
o Shows variable genetic aberrations
o Grossly appears as a well-circumscribed solid BROWN tumour
• There are sharply defined cell borders and a thick vascular network - ‘plant like’
Wilm’s
o Malignant TRIPHASIC kidney tumour of childhood
• Blastema (small round blue cells)
• Epithelial
• Stromal
o Typically presents as an abdominal mass in children aged 2-5 years
o 95% of cases show favourable histological features with excellent prognosis
Uroepithelial Carcinoma
AKA transitional cell carcinoma They are a group if malignant epithelial neoplasms arsing in the urothelial tract: o Bladder o Renal pelvis o Ureters Major risk factors: o Smoking o Aromatic amines More present with haematuria THREE main subtypes 1 Non-invasive papillary urothelial carcinoma 2 Infiltrating urothelial carcinoma 3 Flat urothelial carcinoma in situ
Infiltrating Uroepithelial Carcinoma
o Urothelial tumour displaying invasive behaviour
o Once urothelial cells start to invade, the morphology becomes really diverse (e.g. it can be come a squamous cell carcinoma, adenocarcinoma, sarcoma etc.)
o The presence of divergent morphology is associated with a poorer prognosis
o Wide range of subtypes
o Treatment is based on the depth of invasion
• Lamina propria (better prognosis)
• Muscularis propria (worse, requiring extensive surgery)
Flat Urothelial Carcinoma In situ
Most severe of the three
o May be invisible or appear as a reddish area
o This is essentially a high grade in situ lesion
o It is a high grade area that could develop into an invasive tumour
BPH
• Benign enlargement of the prostate as a consequence of increased cell number (hyperplasia)
• VERY COMMON (symptomatic in 25% of men aged > 80 years)
•Aetiology is unclear
?Increased oestrogen in the blood due to ageing may induce androgen receptors and stimulate hyperplasia
Treatment is based on blocking ^:
• 5 alpha-reductase inhibitors
• Alpha-blockers
• Transurethral resection (cores out centre of prostate to ease the flow of urine)
Presents with lower urinary tract symptoms (FUND HIPS)
Alternative presentations include UTI, acute urinary retention of renal failure
What is the other prostate pathology that you need to know?
2 Prostate pathologies covered in this lecture: BPH and Prostate adenocarcinoma
• Malignant epithelial prostate tumour
• MOST COMMON malignant tumour in MEN (25% of all male cancers)
• Arises from prostatic intraepithelial neoplasia
• Identified mutations include PTEN, AMACR, GST-pi and p27
• Usually asymptomatic
• Diagnosed by biopsy following DRE or raised PSA
• May have lower urinary tract symptoms (less likely than in BPH because the tumours tend to lie in the periphery of the gland)
• Rarely may present with metastatic disease (e.g. pathological fracture)
• Gleason score is the most powerful prognostic indicator
What are the types of testicular tumour?
Non-Germ cell (less common)
- Lymphoma (malignant)
- Sertoli Cell Tumour (usually benign)
- Leydig Cell Tumours (usually benign( (may present as pre-pubertal)
Germ Cell (90%) Tumours of the testis arising from germ cells (cells that give rise to gametes). Typically arise in men 20-45 years
Risk Factors: Undescended testes & LBW
Present as painless testicular lumps. 10% will cause symptoms of metastases: Back pain (due to spread to para-aortic nodes) & Cough/ Dyspnoea
5 Histological types.
Treatment: Testicular germ cell tumours are highly sensitive to platinum-based chemotherapy regimes
EXCELLENT prognosis - 98% 5-year survival
5 subtypes of testicular GC tumour
- Seminoma (clear cells with quite a prominent lymphocytic infiltrate) (MOST COMMON)
- Yolk Sac (Smaller cells, Lace-like pattern, there are some pink inclusions)
- Embryonal carcinoma (very high grade, prominent nucleoli)
- Post-pubertal teratoma (this tumour is trying to produce a variety of tissues (e.g. keratin, cartilage, glands) it is malignant- unlike ovarian teratoma). Each counterpart can also become malignant in its own right - malignancy squared
- Choriocarcinoma
Made up of 2 cells: Cytotrophoblasts (clear looking cells)
and Syncytiotrophoblasts (multinucleated cells)
NB both components are needed to call it a choriocarcinoma. (Worsens prognosis)
Paratesticular disease
Epididymal cyst
Epididymitis - Men < 35: related to C. trachomatis or N. gonorrhoeae. Men > 35: related to E. coli
Varicocoele - Dilated venous plexus
Hydrocoele - Fluid accumulating between the layers of the tunica vaginalis
Adenomatoid tumour - Small tubules lined by mesothelial cells
Penile Diseases
Lichen sclerosis/balanitis xerotica obliterans - Inflammatory condition that causes phimosis
Zoon’s balanitis- Inflammatory condition that causes red areas
Condylomas- HPV 6 and 11
Peyronie’s disease– Scarring, inflammation and thickening of corpus cavernosa
Penile carcinoma
•Rare, seen in elderly men
•Smoking, HPV and chronic lichen sclerosus are risk factors
Urethral Diseases
o Urethritis - Neisseria gonorrhoeae, Chlamydia trachomatis
o Prostatic urethral polyp- Papillary lesion in prostatic urethra
o Urethral caruncle - Common lesion at urethral meatus in women
o Urethral carcinoma - RARE, Usually squamous cell carcinoma, More common in women
o Malignant melanoma
Scrotal Diseases
o Epidermoid cyst
• COMMON
o Scrotal calcinosis
• RARE
• May be related to epidermoid cysts
o Angiokeratomas
• Benign vascular lesions
o Fournier’s Gangrene
• Necrotising fasciitis (15-20% mortality)
o Scrotal squamous cell carcinoma
• VERY RARE
• Used to happen to chimney sweeps
Oesophagus histology/microanatomy
Pale, Squamous epithelium which ends at the border of the Z junction (becomes columnar).
Layers of the oesophagus from lumen inwards:
Epithelium - > Submucosa -> Muscularis Externa -> Adventitia
Stomach anatomy
The body and the fundus contain most of the specialised glands that are responsible for producing acid and enzymes . From lumen inwards: Gastric mucosa (columnar, mucin secreting) -> lamina propria (specialised glands) -> muscularis mucosa
How is the walll anatomy of antrum and the body of the stomach different?
Antrum do not have specialised cells in the lamina propria.
NB •In the antrum and pyloric canal, you tend to see H. pylori-associated gastritis
Duodenal wall anatomy
Glandular epithelium with goblet cells made up of villi and crypts.
The crypt is where cells proliferate. They then migrate upwards to the tip of the villous and shed at the top
• In terms of length, there is usually a 2:1 villous to crypt ratio (This is dependent on the height of the villi and the depth of the crypts)
• If the villi are shorter, the crypts take up a bigger proportion of the total length
• When the villi get damaged, the crypts will proliferate to replace the damage villi
IMPORTANT: goblet cells are NOT normally seen in the stomach. The presence of goblet cells in the stomach is a feature of intestinal metaplasia
Acute Oesophagitis
• The redness is a cardinal sign of inflammation
• The histology shows the presence of loads of neutrophils, which is the hallmark of acute inflammation
Cause: usually GORD
It can result in: Ulceration (produces a necrotic slough, inflammatory exudate and granulation tissue) & Fibrosis.
Complications:
• Haemorrhage
• Perforation
• Stricture
• BARRETT’s OESOPHAGUS
Barrett’s oesophagus
• This is a classic metaplastic process by which the normal squamous epithelium of the lower oesophagus gets replaced by columnar epithelium
• This is also known as columnar-lined oesophagus (CLO)
• The metaplasia can go one step further when goblet cells become visible - this is called intestinal metaplasia
• The risk of cancer is MUCH HIGHER in cases of Barrett’s oesophagus with intestinal metaplasia
Metaplasia –> Dysplasia –> Cancer
Metaplasia is NOT technically pre-malignant because it is REVERSIBLE
However, once you have metaplasia you can progress to dysplasia
Adenocarcinoma is when the abnormal cells invade through the basement membrane
NOTE: adenocarcinomas can spread underneath the columnar epithelium - this is a massive issue for surgeons because they don’t know exactly where to stop cutting
Dysplasia definition
changes showing some of the cytological and histological features of malignancy but with no invasion through the basement membrane
SCC Of the oesophagus
• In Africa, squamous cell carcinoma is the most common type of oesophageal cancer
• Classically associated with smoking and alcohol
• Tends to affect the mid/lower oesophagus
• Invades into the submucosa
Histology: cells make keratin (normally, the squamous epithelium of the oesophagus is non-keratinised) and the cells also have intercellular bridges.
These are the hallmarks of squamous cell carcinoma
Causes of acute vs chronic gastritis and how their histology differs
(Inflammation of the gastric mucosa )
ACUTE Gastritis caused by chemical (aspirin, nsaids, OH, corrosives) or by infection ( H pylori commonly. CMV, strongyloides in the immuno/c)
CHRONIC Gastritis is caused by ABC. AI, bacteria and chemical. (chemical also includes bile reflux).
AI (auto-antibodies e.g. anti-parietal cell, Crohn’s)
oThe key inflammatory cells are lymphocytes as this is chronic inflammation
oHowever, be aware as the presence of co-existing acute processes can mean that you may also see a lot of neutrophils
Why does MALT occur?
- Chronic gastritis associated with H. pylori infection induces lymphoid tissue in the stomach
- It induces the development of lymphoid follicles in germinal centres
- If you see lymphoid follicles in a stomach biopsy, it is highly suggestive that the patient has had an H. pylori infection (i.e. the presence of lymphoid follicles is NOT part of the normal stomach mucosa)
- The fact that H. pylori induces MALT formation is important because it is associated with an increased risk of lymphoma
How does H Pylori colonise the gut and what are the long term consequences?
H. pylori can bind to epithelial cells and inject toxins into them but they do NOT directly invade the epithelium
Consequences of H. pylori associated gastritis:
• CLO –> IM –> Dysplasia
• Adenocarcinoma (8 x increased risk)
• Lymphoma (MALToma)
Cag-A positive H. pylori have a needle like appendage that injects toxins into intercellular junctions allowing the bacteria to attach more easily
• Cag-A is a toxin and this strain is associated with more chronic inflammation
IMPORTANT: treatment of H. pylori infection with antibiotics drastically reduces the risk of cancer
pathologies of the stomach covered in this lecture
- Gastritis (acute and chronic)
- Ulcers (acute and chronic)
- Cancer
Gastric Ulcer
• Technical Definition of Ulcer: the depth of the loss of tissue goes beyond the muscularis mucosa (into the submucosa)
o I.e. if you only get loss of the surface epithelium +/- lamina propria, then it is an erosion, not an ulcer
Difference between acute ulceration and chronic ulceration: Chronic ulcers are accompanied by scarring and fibrosis
!IMPORTANT: ALL ULCERS SHOULD BE BIOPSIED TO EXCLUDE MALIGNANCY
Complications:
o Bleeding –> anaemia, shock (massive haemorrhage)
o Perforation –> peritonitis
What is intestinal metaplasia
- The presence of goblet cells in the mucosa of the stomach is intestinal metaplasia
- This occurs in response to long term damage
- Intestinal metaplasia is associated with an increased risk of cancer
Where is there a higher incidence of gastric cancer?
- High incidence in Japan, Chile, Italy, China, Portugal and Russia
- More common in MALES
Gastric Cancer
> 95% of all malignant tumours in the stomach are ADENOCARCINOMAS
• These adenocarcinomas can be split morphologically into:
INTESTINAL (Well-differentiated, Presence of big glands containing mucin)
DIFFUSE (poorly differentiated, composed of single cells with no attempt at gland formation) Subtypes: Linitis plastica & Signet ring cell carcinoma.
Remaining 5% of Gastric Cancers o Squamous cell carcinoma o Lymphoma (MALToma) o Gastrointestinal stromal tumour (GIST) o Neuroendocrine tumours
IMPORTANT: overall survival rate = 15%
Duodenitis
•Caused by increased acid produced in the stomach that spills into the duodenum (almost all causes of duodenal ulcer is H Pylori -> acute denitis -> chronic which can actually develop metaplasia (gastric mucosa)
(The intestinal epithelium will change to look more like gastric epithelium because the gastric epithelium is well designed to deal with acid)
• Chronic inflammation can also lead to duodenal ulceration (same definition of ulcers)
Other pathogens affecting the duodenum
o CMV
o Cryptosporidium
o Giardiasis (unicellular parasite) (Travel hx St. Petersburg in competent, or I/C)
o Whipple’s disease (Tropheryma whippelii) (infection of macropahges)
Malabsorption
1 . Villous atrophy
- Crypt hyperplasia
- Increased intraepithelial lymphocytes (Normal Range: < 20 per 100 enterocytes)
NB: the T cell response to gliadin in Coeliac disease is responsible for the damage to the villi. Crypt hyperplasia occurs in an attempt to regenerate the damaged villi
In coeliac disease, you get architectural changes (loss of villi and crypt hyperplasia) and you get inflammatory changes (increased intraepithelial lymphocytes)
What is Lymphocytic duodenitis?
When you have inflammatory changes (increased intraepithelial lymphocytes) without architectural changes. Many people with this condition either have coeliac disease or are going to develop coeliac disease.
Different types of lymphomas in GIT?
• Patients with coeliac disease have an increased risk of GIT cancers
• MALTomas associated with coeliac disease are found in the duodenum. They are T cell lymphomas
o NOTE: lymphomas in the stomach due to H. pylori are B cell lymphomas
Layers of skin
Epidermis, Dermis and Subcutaneous
Epidermis - kertainocytes and squamous (act as barrier)
Dermis - collage, elastic fibres, blood vessels, sweat glands, hair follicles, sebaceous glands and nerve fibres
Layers of epidermis can be split into:
Come Lets Get Some Beers
Stratum corneum, lucidum, gravidarum, spinosum, basale.
NB Skin is different parts of your body will be slightly different e.g. on your face, you will have a lot more sebaceous glands than on your torso and arms. Different layers will be thicker - corneum will be thicker on your toes/feet. In elderly population will have a thinner epidermis and more fragile
Pemphigus disorders
Bullous Pemphigoid
Pemphigoid vulgaris
Bullous Pemphigoid
Sub-epidermal pathology (between epidermis and basement membrane)
• This is a classic vesiculobullous condition
• They commonly occur in elderly patients on their flexor surfaces
• This condition is characterised by the formation of tense bullae
• This has a 10-20% mortality so they need to be recognised
• This is an autoimmune disorder driven by IgG and C3, which attack the basement membrane
• They recruit eosinophils which release elastase which further damages the anchoring proteins that are anchoring the lower keratinocytes onto the basement membrane
• Immunofluorescence can be used to detect IgG and C3 at the dermo-epidermal junction
Analogy:
o Think of it as a house with a solid foundation (basement membrane)
o The house is made of bricks (keratinocytes) that are joined together by cement
o The house has a roof (keratin layer on the surface)
o In bullous pemphigoid, all the damage is occurring between the lowest layer of bricks and the concrete foundation
o The house becomes lifted off the basement membrane and the space gets filled with fluid
Pemphigus Vulgaris
Intra-epidermal pathology (between keratinocytes)
• In this condition, the blisters are much more flaccid
• They rupture easily leaving this raw, red surface underneath
• This is an IgG disease
• The damage is occurring within the keratinocyte layers (i.e. within the bricks)
• This is called acantholysis (loss of intercellular connections leading to loss of cohesion between keratinocytes)
• This can occur in a lot of dermatological conditions so you want to do immunofluorescence to see whether there is a line of IgG lining the disrupted keratinocytes
Pemphigus Foliaceus
- You rarely see the intact bullae in this condition because they are so thin that they come off easily
- In this condition it is the roof that is coming apart (the outer layer of keratinocytes where the stratum corneum is)
- This is also IgG mediated
Atopic Dermatitis
Group of disorders that are itchy in nature, can be atopic or due to a particular substance (i.e. contact dermatitis)
Described as a spongiform condition due to the oedema between the keratinocytes.
Over time you get hyperparakeratosis - thickening of the skin on the surface where you have been scratching as a result the epidermis gets thicker.
This is T cell mediated and EOSINOPHILS are recruited.
Plaque Psoriasis
• This is a part of psoriasiform reaction pattern
• This tends to occur on the EXTENSOR surfaces.
• It produces a classical silvery plaques
Skin turnover is very rapid (The normal turnover time for a keratinocyte is around 50 days (to go from the bottom to the top. In psoriasis, the turnover is around 7 days)
Histology:
There is a layer formed at the top (parakeratosis)
The granular cell layer (stratum granulosum) disappears in this condition because there just is NOT enough time to form it
There is also NEUTROPHIL recruitment (forms Munro’s microabscesses) in the epidermis and vessel dilation.
Lichen Planus
• This is an example of a lichenoid reaction pattern
• This is also T-cell mediated
• It presents as purple/pink papules and plaques on the wrists and arms
• In the mouth it presents as white lines (Wickam striae)
Histology Analogy: loads of ants have decided to destroy your foundation
You can barely see where the dermis finishes and the epidermis starts because the bottom layer of keratinocytes are eaten away by lymphocytes
There is a band-like lymphocytic infiltrate just under the epidermis (can be seen in lichen planus and also in mycosis fungoides)
Pyoderma Gangrenosum
- This is a form of vasculitis
- This is NOT actually gangrenous
- It presents as an ulcer
- This is often the first manifestation of a systemic disease (e.g. colitis, hepatitis, leukaemia)
Seborrhoeic Keratosis
• These are very common in the elderly and have a classic ‘stuck on’ appearance
• Under the microscope you will see horn cysts
• This is entrapped keratin surrounded by a proliferating epidermis
• However, the epidermis is proliferating in an orderly manner
Often get removed because they get stuck on items of clothing etc.
Sebhorreic Cyst
- SMOOTH,
- Non-mobile
- Punctum
They can get infected, inflamed and rupture
(has a necrotic smell)
Histopath: Epidermis has invaginated and gotten caught in the dermis and produces a cyst of keratin, lined with squamous cells. Kertain smells.
Basal CC
- It has a rolled, pearly edge with a central ulcer and telangiectasia
- It doesn’t tend to cause any significant morbidity or mortality
- However, they can be disfiguring if they form on the face
- The cancer arises from the keratinocytes along the bottom of the epidermis
- These cells then infiltrate through the basement membrane
- They can spread via the nerves and lymphovascular system or they can cause local infiltration
- BCCs are locally infiltrative but they don’t metastasise
Bowen’s disease
Kertainocytes are still within epidermis. They become larger, darker and more pleimorphoic. There is disorganised growth pattern. (same sort of epithelial cancer in cervix, colon etc)
Full thickness dysplasia. Low, medium and high grade.
If left, there is a chance they’l turn into cancer.
Screening is aimed at catching cancer at this stage.
Melanocyte dervied conditions
- Benign junctional naevus- It is circumscribed and uniformly pigmented. Normally melanocytes sit on the basal layer. Melanocytes can expand in that position and form nests. This is a junctional naevus
- Malginant melanoma. Irregular, ulcerated and bleeding - all are bad signs .Think of the ABCDE
Histology: melanocytes are starting to migrate upwards through the epidermis - this is NOT normal and is called pagetoid spread. Once the cells go into the dermis, become mitotically active and lack the ability to mature, then you get a diagnosis of malignant melanoma UNLESS PREGNANT.
•A melanoma with a thickness > 4 mm, it has a very high mortality (> 50%) . Breslow scale is used to score.
Where do melanocytes live?
Normally melanocytes sit on the basal layer, but there are melanocytes in the epidermis and the dermis
• As melanocytes mature they will become smaller and go deeper down
• So, seeing melanocytes in the dermis is not a problem
ABCDE of skin cancer
o Asymmetry o Border irregularity o Colours (heretogeneous) o Diameter o Evolution
What is the bone made up of?
Inorganic (65%) – calcium hydroxyapatite, storehouse of 99% of body calcium (and 85% of phosphorus, 65% of sodium and magnesium)
Organic (35%) – bone cells and protein matrix
Different types of bone
Cortical: Long bones 80% of skeleton Appendicular 80-90% calcified Mainly mechanical and protective
Cancellous: Axial Skeleton 20% of skeleton 15% Calcified Mainly metabolic Bone matrix, haematopoietic stem cells
Microanatomy of the bone
Made up of several micro-columns
Haversian canals are found at the middle of the micro-columns
Volkmann canals are canals that connect the Haversian canals
Around the Haversian canals are concentric lamellae and in between these units will be interstitial lamellae
Around the entire bone you will find circumferential lamellae
In the middle the bone will be trabecular lamellae
Give an example of paracrine communication between bone cells
Osteoblasts produce osteoprotegrin which blocks the RANK-RANKL interaction which prevents the differentiation of an osteoclast precursor into a fully functioning osteoclast. This protects the bone.
What investigations are available to us in bone disease
• Histology requires bone biopsy from the iliac crest
• The sample must be processed and un-decalcified for histomorphometry
• Static parameters include:
o Cortical thickness
o Trabecular bone volume
o Thickness, number and separation of trabeculae
• Bone mineralisation is studied using osteoid parameters
• Histodynamic parameters are obtained from fluorescent tetracycline labelling
Chronic Rheumatic Heart disease
Chronic rheumatic valve disease is predominantly left-sided and most commonly mitral. Mitral > Aortic > Tricuspid > Pulmonic. There is thickening of valve leaflet, especially along lines of closure and fusion of commissures. There is also thickening, shortening and fusion of chordae tendineae.
Mitral Valve Prolapse
clinically appears in middle-aged woman, short of breath with chest pains. Clinical signs often described as mid systolic click + late systolic murmur.
Infective Endocarditis
Clinical features: ● constitutional: ○ fever ○ malaise ○ rigors ○ anaemia ● cardiac: ○ new murmur (MR/AR usually) ● immune phenomena: ○ Roth spots ○ Osler’s nodes ○ haematuria due to glomerulonephritis ● thromboembolic phenomena: ○ Janeway lesions ○ septic abscesses in lungs/brain/spleen/kidney ○ microemboli ○ splinter haemorrhages ○ splenomegaly Usually mitral/aortic valve unless IVDU when right-sided valves involved
Histopath features of obstructive lung diseases
Chronic Bronchitis - goblet cell hyperplasia, hypertrophy of mucous glands, airway dilatation.
Bronchiectasis - dilatation of airways, fibrosis extending into parenchyma (remember can occur 2ndary to infection in CF pts)
Asthma - Dilated blood vessels, Charco Leyden crystals (eosinophils), Curshmann spirals (epithelium in sputum), goblet cell hyperplasia, smooth muscle hypertrophy, increased mast and eosinophils
Emphysema - Centrilobular parenchyma loss (smoking), pan-acinar loss (alpha anti trypsin)
Emphysema causes
Smoking alpha 1 antitrypsin Cadmium Exposure (electroplating, work) IVDU
Fibrosing respiratory disorders
- IPF
- Histological pattern of fibrosis = Usual Interstitial Pneumonia, required for diagnosis (also seen in connective tissue disease, asbestosis and EAA). Progressive patchy interstitial fibrosis with loss of normal lunga rchitecture
honeycomb change, beginning at periphery of the lobule, usually sub-pleural
o Hyperplasia TII pneumocytes > cyst formation–honeycombfibrosis.
Can have inflammatory cause e.g. RA, SLE, systemic sclerosis, but usually idiopathic
PC: increasing exertional dyspnoea and non-productive cough. 40-70y at presentation, with hypoxaemia > cyanosis and pulmonary HTN +/- cor pulmonale, and clubbing.
Rx: steroids, cyclophosphamide, azathioprine, but little impact on survival - Pneumoconiosis
- Occupational lung disease, most affecting upper lobe apart from asbetosis affecting lower lobe.
e.g. coal worker’s pneumoconiosis, silicosis
NB asbestosis can cause benign pleural lesions (plaques, fibrosis) but can also cause malignant lesions (adenocarcinoma, mesothelioma). - Drug Induced
- Radiation
- Connective Tissue Disease
- Radiation
Interstial Lung Disease
Inflammation and fibrosis of pulmonary connective tissue and parenchyma between the airways -> RESTRICTIVE picture. Normally presents with end inspiratory crackles and honey comb lung.
- Fibrosing Disorders
- Granulomatous Disorders
- Eosinophillic
- Smoking
Granulomatous Disorders
Granuloma = collection of histiocytes, macrophages +/- multi-nucleate giant cells.
Granulomatous infections include TB, fungal (histoplasma, Cryptococcus, coccidioides, aspergillus, mucor) and others (pneumocystis, parasites).
Non-infectious granulomatous conditions include sarcoid, foreign body (aspiration or IVDU), drugs or occupational lung disease.
3 main categories: 1) Sarcoid 2) EAA 3) Vasculitides
1) Sarcoid
2) Group of immune-mediated lung disorders caused by intense/prolonged exposure to inhaled ORGANIC antigens → widespread ALVEOLAR inflammation
3) Wegener’s, Churg-Strauss, microscopic
polyangiitis
Types and presentation of EAA
Acute presentation: inhalation of antigenic dust in SENSITISED individual -→ systemic symptoms (fever, chills, chest pain, SOB, cough) within hours of exposure, usually settle by following day. Progresses to chronic EAA.
Chronic presentation: progressive persistent productive cough and SOB, finger clubbing and
severe weight loss
e.g. Farmers lung (mouldy hay/grain/silage – Saccharopolyspora rectivirgula), Pigeon fancier’s lung (proteins in excreta/feathers), Humidifier’s lung (heated water reservoirs – thermactinomyces spp.), Malt-workers lung (germinating barley – Aspergillus clavatus/fumigatus), Cheese washer’s lung (mouldy cheese – Aspergillus clavatus/penicillium casei).
Pulmonary Oedema
Pulmonary oedema: Intra alveolar fluid accumulation leads to poor gas exchange. Main aetiology: left heart failure. Histology: intra-alveolar fluid, iron laden macrophages (“heart failure cells”).
Other causes: High altitude, neurogenic e.g. from head injury, alveolar injury
Transudate vs Exudate
Exudate -> leaky vessels usually due to inflammatory cause allows cells to leak out and deal with inflammation. Contents of exudate are therefore fluid, protein and large particles- these can form granulomas ‘organising pneumonia’*
Transudate - > endothelium is intact. Fluid is forced out due to hydrostatic pressure e.g. backlog of pressure from LVH.
*They will then develop hyaline membranes (this is serum protein that has leaked out and ended up lining the alveolar spaces). Eventually, you get organisation of the exudates to form granulation tissue sitting within the alveolar spaces (organising pneumonia).
Pancreatic Malformation
Ectopic Pancreas – esp. stomach, small intestine.
Pancreas Divisum – failure of fusion of dorsal and ventral buds, increased risk of
pancreatitis.
Annular pancreas – can present with duodenal obstruction approx. 1yo
Gall stone risk factors
o More common as you get older
o More common in WOMEN
o Ethnic factors can contribute (e.g. Native Americans have a very high incidence of gallstones)
o Hereditary factors (e.g. disorders of bile metabolism)
o Drugs (e.g. oral contraceptive)
o Acquired disorders (e.g. rapid weight loss)
Complications of Gall stones
- Acute cholecystitis (+++Neutrophils)
- Chronic cholecystitis (Fibrosis, diverticuli formation (rokitansky-aschoff))
- Pancreatitis
- Gall bladder cancer (90% adenocarcinoma, uncommon)
Liver injury and progression to fibrosis
A normal liver has hepatocytes with microvilli and stellate cells which lie quiescent in the space of Disse (space between hepatocytes and sinusoid)
Chronic inflammation causes the loss of microvilli and activation of stellate cells, which produce collagen.
They become myofibroblasts that initiate fibrosis by deposition of collagen in the space of Disse.
Myofibroblasts contract constricting sinusoids and increasing vascular resistance.
Undamaged hepatocytes regenerate in nodules between fibrous septa
Histopath of acute vs chronic liver damage
Acute - SPOTTY necrosis (small foci of inflammation and infiltrates)
Chronic - Portal inflammation, peicemeal necrosis (cannot see border between parenchyma and portral tract), lobular inflammation and bridging of portal to central vein (hepatitis is classed as cirrhosis).
Cirrhosis - Nodules of regenerating hepatocytes and Disturbance of vascular architecture (which increases the vascular resistance). Aforementioned fibrotic bridges cause extrahepatic shunting.
Genetic causes of liver failure
a) Haemochromatosis- HFE gene Chr 6
b) Wilson’s disease- ATP7B gene Chr 13
c) Alpha 1 antitrypsin deficiency (A1AT)
d) Galactosaemia
e) Glycogen storage disease
Oncocyte
Oncocyte = large cells with pink granular cytoplasm and a prominent nucleolus
Osteoporosis
Reduced bone density either from high (high bone resorption) or low (low bone formation) turnover 90% are due to insufficient calcium intake or post-menopausal oestrogen deficiency Primary – age, post-menopause Secondary – steroids (affect all three bone cell types), systemic disease Presentation: Back pain Pathological fractures • Wrist (Colles’) • Hip (NOF, intertrochanteric) • Pelvic • Vertebra (60% asymptomatic) Ix: Serum calcium, phosphate and ALP (should be NORMAL) Urinary calcium Collagen breakdown products Imaging DEXA
Osteomalacia
Defective bone mineralisation due to deficiency of vitamin D or Deficiency of phosphate
Histologically: Reduced amount of mineralised bone compared to the amount of osteoid (xs unmineralised bone)
PC: Bone pain/tenderness
Fracture
Proximal weakness
Bone deformity
XR: Bowing of the legs in Rickets
Horizontal pseudofractures in Looser’s zones
↔/↓Ca
↓ PO4 ↑ALP
Describe how the urine excretion of calcium and phosphate changes in primary hyperparathyroidism.
Both increase
NOTE: PTH causes a minor increase in reabsorption of calcium from the urine, however, as it causes a large increase in serum calcium concentration (and hence an increase in the calcium concentration of the glomerular filtrate) it causes an overall increase in urine calcium excretion
Describe the bone disease that occurs with primary hyperparathyroidism?
Osteitis Fibrosa Cystica
Remember, primary hyperparathyroidism increases calcium reabsorption from bone. As a result, bone resorption with thinning of the cortex an cyst formation (osteitis fibrosa cystica)
This can lead to fractures.
How would hyperparathyroidism present then?
- Hypercalcaemia (most often due to primary hyperparathyroidism than not)
- Osteitis Fibrosa Cystica (bone changes) and BROWN CELL TUMOUR (What are these? These are multinucleate giant cells on a background of fibrous stroma with haemorrhage)
- Renal stones and obstructive uropathy
- GI disturbance (constipation, pancreatitis, gallstones)
- CNS alterations (depression, lethargy, seizures)
- Neuromuscular abnormalities (weakness)
- Polyuria and polydipsia
Causes of primary and secondary hyperparathyroidism?
Primary: - Adenoma (80%) - 10-20% are due to hyperplasia of ALL four glands • Sporadic • Part of MEN 1 - < 1% are due to carcinoma Other • Surgical ablation • Congenital absence • Autoimmune
Secondary:
- Chronic Renal Disease
Paget disease of the bone
TRIPHASIC
ALP SUPER RAISED
SKULL FRACTURES
ASSCIATED WITH PARVOMYXOVIRUS
• THREE phases:
o Osteolytic
o Osteolytic-osteosclerotic
o Quiescent osteosclerotic
During the mixed stage a combination of osteoclast and osteoblast activity results in new bone formation
Typically you will see lines between areas of new bone formation so it looks like a mosaic or JIGSAW puzzle
PC:
o Pain
o Microfractures
o Nerve compression (e.g. spinal cord and spinal nerves)
o Skull changes can put the medulla at risk
• This can result in haemodynamic changes and cardiac failure
o Rarely, sarcomas can develop in areas of disease bone
o Paget’s disease affecting the tibia can cause bowing
Fracture repair steps
o Organisation of a haematoma at the site of fracture (pro-callus)
o Formation of a fibrocartilaginous callus
o Mineralisation of fibrocartilaginous callus
o Remodelling of bone along weight-bearing lines
• Factors influencing fracture healing
o Type of fracture
o Presence of infection
o Pre-existing systemic condition (neoplasia, metabolic disorder, drugs, vitamin deficiency)
Osteomyelitis
PC: General – FLAWS Local – pain, swelling, redness Ix: Blood cultures (positive in 60%) X-ray (will eventually show lytic areas) - often much after presention shows lifting of periosteum NOTE: osteomyelitis is almost always bacterial Transmission: Haematogenous Direct extension Traumatic (penetrating injury) Organisms: Staphylococcus aureus (90%) E. coli Klebsiella Pseudomonas (IVDU) sickle cell disease? Salmonella
XR: 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
Pott’s histology
o In between the trabeculae you can see a lot of inflammatory cells with granuloma formation
o In addition, you can see Langerhans-type giant cells (they have a horse-shoe shaped nucleus)
What is the vector for lyme disease?
Ixodus dammini
Rheumatoid factor (antibody and HLA association)
Genetic predispositions
o Risk alleles: TNFA1P3, STAT4
o HLA associations: DR4 and DR1 (Chr 6p21)
80% of patients are rheumatoid factor positive
o RF is mainly IgM
o These antibodies form immune complexes with IgG
• These circulating immune complexes may be responsible for extra-articular disease
Rheumatoid Histology
o Proliferative synovitis with:
• Thickening of synovial membranes (villous)
• Hyperplasia of surface synoviocytes
• Intense inflammatory cell infiltrate
• Fibrin deposition and necrosis
o Pannus formation with exuberant inflamed synovium overlying the articular surface
o There may also be a particular type of multinucleate giant cell called Grimley-Sokoloff cells (look similar to Langerhans-type giant cells but don’t have the same horseshoe shaped nucleus)
Types of Hydrocephalus
- Non-Communicating: involves obstruction to the flow of CSF (usually involving the cerebral aqueduct)
• One of the main causes of hydrocephalus in the neonate is due to some of the choroid plexus getting stuck in the cerebral aqueduct and blocking CSF flow - Communicating: involves NO obstruction but is associated with problems with the reabsorption of CSF into the venous sinuses
• This can be caused by infection (e.g. meningitis)
• Inflammation of the meninges can impinge and interfere with the normal flow of CSF back to the venous sinuses
Types of brain herniation
- subfalcine - the cortex is pushed under the rigid falx cerebri of the dura (this is usually due to space-occuyping lesions)
- Transtentorial (Uncal) - this is herniation of the median temporal lobe through the tentorial notch
• The posterior cranial fossa is covered by the tentorium cerebelli
• It has a rigid opening through which the brainstem passes through
• When you have supratentorial pressure, the tissue can get pushed down over the rigid edge of the tentorium cerebelli - Tonsillar - the medial aspect of the cerebellum (tonsil) is pushed through the foramen magnum
• It puts pressure on the medulla and can kill
What cerebrovascular disorders are included in the stroke definition and which aren’t?
o Cerebral infarction o Primary intracerebral haemorrhage o Intraventricular haemorrhage o Subarachnoid haemorrhage (most cases) It EXCLUDES: o Subdural haemorrhage o Epidural haemorrhage o Intracerebral haemorrhage o Infarction caused by infection or tumour
TIA definition
- Caused by a clot but the blockage is temporary
- Symptoms resolve within 24 hours
- Most TIAs last < 5 mins
- There is usually NO permanent injury to the brain
- 1/3 of people with TIA will get a significant infarct within 5 years
- IMPORTANT: TIA is an important predictor of a future infarct
What is Non-Traumatic Intra-parenchymal Haemorrhage?
DEFINITION: haemorrhage into the substance of the brain (parenchyma) due to rupture of a small intraparenchymal vessel • Most common in the basal ganglia • Hypertension plays a role in > 50% of bleeds • Presentation o Severe headache o Vomiting o Rapid loss of consciousness o Focal neurological signs
AVM
• Can occur anywhere in the CNS • The capillary network is, in effect, bypassed meaning that you have arteries connecting directly to veins • Become symptomatic between 2nd and 5th decade (mean = 31 years) • Presentation o Haemorrhage o Seizures o Headache o Focal neurological deficits • Tend to occur under high pressure, therefore causing a MASSIVE BLEED • Can be visualised on angiography • High morbidity and mortality (15%) • Treatment o Surgery o Embolisation o Radiosurgery
Cavernous Angioma
Well-defined malformative lesion composed of closely-packed vessels with no parenchyma interposed between vascular spaces
o It is similar to an AVM but there is no brain substance wrapped up amongst the vessels
• Can be found anywhere in the CNS
• Usually symptomatic over the age of 50 years
• Pathogenesis is unknown
• Presentation
o Headache
o Seizures
o Focal deficits
o Haemorrhage
• These tend to occur at lower pressure (causing recurrent small bleeds)
• TREATMENT
o May not be necessary
o Surgery
• NOTE: this shows a ‘target sign’ on T2 weighted MRI
Cerebral infarction
Cereberal infarction is defined as tissue death due to ischaemia due to atheroscleorsi / emboli.
MOST COMMON form of cerebrovascular disease
Responsible for 70-80% of strokes
Cerebral atherosclerosis is the MOST COMMON cause
Rf: hypertension, smoking and diabetes mellitus
Focal cerebral ischaemia - due to lack of blood flow to a particular vascular territory
Global cerebral ischaemia - when the systemic circulation fails
Location:
- Atherosclerosis can badly affect the carotid bifurcation or the basilar artery
- Embolic occlusion usually occurs in the middle cerebral artery branches
On histopath: Loss of the distinction between the grey and white matter is suggestive of tissue necrosis
TBI
Single largest cause of death in people < 45 years old
• Accounts for 25% of all trauma deaths
• High morbidity
o 19% in a vegetative or severely disabled state
o 31% good recovery
Classification of Head Trauma
- Missile injuries are mainly associated with warzones (e.g. shrapnel and bullets)
- Acceleration and deceleration (e.g. road traffic accidents, falls onto hard surfaces) (Rotation - rotational acceleration (boxing) > damage midline structures)
- Focal or diffuse
- Fractures (often base of skull, rinohhorea otorrhoea racoon and battle sign)
- Contusions: When the brain collides with the internal surface of the skull, causes bruising of the surface. If this causes rupture of the pia mater, it is called laceration
Contrecoup damage
Rebound of the brain after a direct impact can cause contrecoup damage to the opposite side of the brain
What is the msot common cause of coma when ther is no bleed?
Diffuse Axonal Injury
oOccurs at the moment of injury
oShear and tensile forces causes damage to the axons
oMOST COMMON cause of coma (when there is no bleed)
oMidline structures are particularly affected (e.g. corpus callosum, rostral brainstem and septum pellucidum)
Different types of CJD?
New variant
- Younger pts (median onset 26)
- Slower progressing
- Present with psych symptoms, neuro sx appear later
- Ix: Positive tonsillar biopsy (100% spec and sens), increased signal from the pulvinar nuclei (Pulvinar sign) and florid plaques on biopsy
- All bar 1 pt have had the polymorphism methyinine-methyinine at PRNP gene
Sporadic
- Positive tonsillar
Most common brain tumours
Most common in adults is CNS METS!!
Most common primary brain tumour is GBM
In kids most common brain tumour is pilocytic and then second most common is medulloblastoma
Pilocytic Astrocytoma
Grade 1 Glial tumour that is most commonly in the cerebellar.
Assoicated with NF1, and BRAF mutations (in the MAPK pathway).
It is a well circumscribed (hence pilocytic), cystic lesions that is enhancing on MRI.
Hist: Piloid (hairy) cells with rosenthal fibres.
It rarely undergoes malignant transformation
Diffuse Astrocytoma
2nd group of glial tumours.
This is not well circumscribed as the cells bud out into the brain parenchyma and so is therefore always grade 2 or more. It is more commonly seen after the age of 20 (range 20-40) and tends to be located in the cerebral hemisphere.
It is strongly associated with IDH2 mutations.
Non ehancing on MRI
It will eventually become gliombastoma if untreated.
GBM
A diffuse glial tumour that is “basically the only brain tumour we see in those over 50”. It is the most common primary brain tumour in adults.
90% have a wild type IDH mutation and 10% are progressors from diffuse astrocytomas (IDH mutations)
They are in the cerebral hemispheres
They are enhancing post contrast due to the pathological mutli-layered blood vessel (described as glomerular to due similarity with renal vessels) and necrosis.
Medulloblastoma
2nd most common brain tumour in kids
Really poor prognosis
Always in cerebellum
Homer WRight Rosette and small round blue cell on histology.
Oligodendroglioma
see board
Meningioma
see board
What does the WHO grading system tell us
Survival
Genetic Predispositions to brain tumours
NF1 - peripheral nerve tumours (neurofibromas), pilocytic
NF2 - Schawnnoma and meningioma
Tuberous Sclerosis - Haemartoma
Von Hippel Lindau - Haemangioma.
Duct Ectasia
Inflammation and dilatation of large breast ducts
Typically presents with a breast lump and nipple discharge
The duct will be distended and full of proteinaceous material
Foamy macrophages will also be present
Fibrocystic Breast 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
Histo shows glandular and stromal cells.
Normal breast histology
Glandular tissue will be stained purple with pink stroma around it
The duct and extralobular terminal duct are together referred to as a the terminal duct lobular unit (TDLU)
Myoepithelial cells will be seen around the outside of the epithelial cells – they help pump milk
Phyloddes Tumours
A group of potentially aggressive fibroepithelial neoplasms of the breast in those over 50.
Majority are benign
Histology
Cells do not form uniform layers - overlapping cells
Histology: fibroepithelial cells with stromal elements
Whether it is benign or malignant depends on the cellularity of the stroma
Intraductal Papilloma
A benign papillary tumour arising within the duct system of the breast
Two types: Peripheral papilloma – arises in small terminal ductules (remain clinically silent.)
Central papilloma – arises in large lactiferous ductules (present with nipple discharge)
Histology will show a large dilated duct with a polypoid mass in the middle. The mass tends to have a fibrovascular core.
Mulitple populations can increase the risk of breast carcinoma.
Radial Scar
A benign sclerosing lesion characterised by a central zone of scarring surrounded by a radiating zone of proliferating glandular tissue
Exuberant reparative phenomenon in response to areas of tissue damage in the breast
They present Seen as stellate masses on mammograms
Histo: Central stellate area with radiating zone of proliferative glandular tissue (ducts and acini in the periphery)
Proliferative Breast Disease
A diverse group of intraductal proliferative lesions of the breast associated with an increased risk of subsequent development of invasive breast cancer
Microscopic lesions that usually produce no symptoms.
4 disorders in this category: Usual epithelial hyperplasia, flat epithelial hyperplasia, atypical duct hyperplasia in situ hyperplasia.
1. Usual epithelial hyperplasia have irregular lumens
2 & 3. 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
4. in situ lobular neoplasia - A solid proliferation of cells within the acinus
DCIS
Ductal Carcinoma in situ is a neoplastic proliferation that hasn’t reached the basement membrane yet.
Low grade histology: Lumens are compact and regular (cribriform (punched out) appearance) (assoc w/16q loss)
Rapid death and proliferation of cells leads to calcification
High grade: Cells are large and few lumens left
Cells are pleomorphic and occlude the duct
Invasive breast carcinoma
A group of breast carincoma classified on origin. They have the capacity to metastasise, They can arise from low grade DCIS or high grade DCIS.
- Invasive ductal carcinoma - Cells are pleomorphic and have large nuclei
- Invasive lobular carcinoma
Cells have a linear arrangement and are monomorphic
NOTE: cords of cells are sometimes referred to as ‘Indian File’ pattern - Invasive tubular carcinoma
Elongated tubules of cancer cells invade the stroma - Invasive mucinous carcinoma
Lots of ‘empty’ spaces containing mucin - Basal like carcinoma - Sheets of markedly atypical cells with a prominent lymphocytic infiltrate
Central necrosis is common. Positive for basal cytokeratins (CK5/6 and CK14)
How do we classify invasive breast carcinoma
Nottingham modification of the Bloom-Richardson system
What is a low grade vs high grade invasive breast carincoma
Low grade invasive breast cancer ER/PR positive Her2 negative High grade invasive breast cancer ER/PR negative Her2 positive 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)
Gynaecomastia histology
Epithelial hyperplasia with finger-like projections extending into the duct lumen
Periductal stroma is often cellular and oedematous
Similar to fibroadenoma
What is a brown cell tumour?
Brown cell tumour – several multinucleated giant cells on a background of fibrous stroma with haemorrhage seen in hyperparathyroidism
Section 1 and 2 of death certificate
Section 1 → cause of death
1a immediate cause
1b lead to 1a
1c lead to 1b etc.
Section 2 → contributing factor that did not directly cause the death
Long term chronic conditions should be added here
Cause of death cannot be a mode of death such as HF
Example: Pt has congestive HF
1a: Cause of death is hypertensive and ischemic heart disease
With the 1b cause hypertension and coronary artery disease
When / how do we use the word [organ] failure on death certificate?
Mode such as cardiac failure, respiratory failure, renal failure. AVOID writing these on a death certificate
They cannot be given alone on a death certificate
There are too many causes of cardiac failure, it doesn’t really give any information. Must specifiy:
1a: type 1 respiratory failure
1b: pulmonary embolism, LRTI
Renal failure can only be used if the cause is also given
immediately after, e.g. SLE, diabetes, infection
Tend to put these in number 2.
Death certificate examples
1a: Aspiration pneumonia
1b: Stroke
1a: Hypovolemic shock following haemoptysis
1b: Lung cancer
2: Smoking, asbestos exposure
1a: Ischaemic stroke
1b: Embolism
1c: Arrhythmia following MI
What are the different type of bone cells?
Osteoblasts – build bone by laying down osteoid
Osteoclasts – multinucleate cells of the macrophage family that resorb bone
Osteocytes – osteoblast-like cells that sit in the lacunae
How do we measure bone features in bone histopath of a metabolic bone disease?
static parameters: Cortical thickness Trabecular bone volume Thickness, number and separation of trabeculae histodynamic parameters: Tetracycline labelling
Causes of hyperparathyroidism
Primary • Parathyroid adenoma (90%) • Chief cell hyperplasia Secondary • Chronic renal deficiency • Vitamin D deficiency • Malabsorption
Renal Osteodystrophy
Term used to describe all the skeletal changes of chronic renal disease:
• Increased bone resorption (osteitis fibrosa cystica)
• Osteomalacia
• Osteosclerosis
• Osteoporosis
• Growth retardation
Syphilis bone histology
Osteochondritis
Osteoperiostitis
Diaphyseal osteomyelitis
Non-gummatous periostitis
Gummatous inflammation of joints and bones
Neuropathic joints (tabes dorsalis)
Neuropathic shaft fractures
Rheum Arthritis vs Osteoarthritis sites
Osteo: Vertebrae Hips Knees DIP and PIP of the hand NOTE: the synovium becomes very inflamed with lots of (lymphocytes)
Rheum: Small joints of the hand and feet (except DIP) Wrists, elbows, ankles and knees Radial deviation of the wrist Ulnar deviation of the fingers Swan neck and Boutonniere deformity Z-shaped thumb
Contrast the primary bone cancers
1Osteosarcoma 2Chondrosarcoma 3 Ewing’s sarcoma/PPNET
1Osteosarcoma
Peak in adolescence
60% around the knee
X-ray: usually metaphysial, lytic, permeative, elevated periosteum (Codman’s triangle)
Histo: Malignant mesenchymal cells with or without bone and cartilage formation
- 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
3 Ewing 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
11;22
MODY inhertiance pattern
AD
What type of bladder cancer is associated with chronic cystitis?
Squamous Carcinoma
Which hepatobillary condition may be described as a slow, insidious process of autoimmune destruction of intrahepatic bile ducts, associated with cholestasis?
Primary Biliary Sclerosis
What is focal segmental glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is a cause of nephrotic syndrome in children and adolescents, as well as a leading cause of kidney failure in adults.[1] It is also known as “focal glomerular sclerosis” or “focal nodular glomerulosclerosis.”[2] It accounts for about a sixth of the cases of nephrotic syndrome
Biopsy will show thickening of GBM and Immunofluorescence shows the presence of antibody complexes and complement deposits at areas of scarring of the glomerular basement membrane.
Damage to which artery is commonly associated with an extradural haemorrhage?
Middle Meningeal Artery
Breast Tripple Assessment
Clinical Assessment
Imaging
Histology
What intracerebral tumour is Multiple Endocrine Neoplasia Type 1 associated with?
Pituitary Adenoma
What cancer is associated with the presence of “oat shaped cells” on biopsy?
Small Cell lung cancer
Wilsons treatment
Chelation with pencillamine
Staining with rhodanine
A 58-year-old woman presents to her GP with a painful lump in her left breast.
There is palpable axillary lymphadenopathy and she reports recent significant weight loss and malaise.
She is assessed for breast cancer.
What histological subtype of breast cancer will this patient most likely have?
Invasive Ductal Carcinoma
A 80-year-old man presents to his primary care physician with increasing shortness of breath, weight loss and a dry cough over a period of several months. Prior to his retirement, he was a plumber.
Physical examination reveals decreased breath sounds and dullness to percussion in the left lung base.
Chest X ray reveals irregular pleural thickening and a peripheral homogenous opacity in the left lower lung field.
What is the likely diagnosis?
mesothelioma bitches
Which neuroendocrine tumour is associated with Zollinger-Ellison syndrome?
Gastrinoma
ACD vs IDA
IDA will have a low ferritin
