HISTOPATHOLOGY ICSM MED ED 5TH YEAR REVISION SERIES 2013 Part 2 28 th March 2013

MR GUY MARTIN MBBS BS C MRCS CORE SURGICAL TRAINEE T HE R OYAL LONDON & S T B ARTHOLOMEW ’ S H OSPITAL OVERVIEW

° Revision sessions organised and run by The Medical Education Society ° We are not examiners / lecturers ° These lectures are not formal Imperial College lectures

° No promises about completeness ° General overview, key principles, example questions ° You will require more in depth specific knowledge

° Please fill in the feedback forms! OVERVIEW

° General principles

° System specific pathology ° Cardiovascular ° Bone and joint ° Connective tissue ° Breast ° Neurological and cerebrovascular ° Respiratory ° GI Tract ° Hepatobiliary and pancreas ° Genitourinary tract QUIZ TIME HOW MUCH DID YOU PAY ATTENTION ?

NEUROPATHOLOGY, CEREBROVASCULAR DISEASE & TRAUMA

“Alzheimer’s is the cleverest thief, because she not only steals from you, but she steals the very thing you need to remember what’s been stolen” - Jaord Kintz EMQ – DEMENTIA

° A 75yr man with a previous history of a CABG and fem-pop bypass. His memory has been deteriorating steadily over the last year or so, with a marked deterioration just after the Christmas period ° A 75yr man complains that he is losing his memory, and his wife says that he tends to be better in the evening. He also has mobility problems, and now finds it difficult to complete tasks like making a cup of tea before the water goes cold. – alpha synuclein deposits in cortex ° A 75 year old retired vicar is brought to see his GP by his concerned wife. Her concern was his behaviour over the last few months, he was becoming quite verbally abusive, recently calling his son a “massive wanker” at Christmas Dinner. Histology – Neuronal Tau Bodies arranged spherically

A. Alzheimar’s Disease D. Multi-infarct dementia B. Pick’s disease E. Normal pressure C. Lewy body dementia hydrocephalus EMQ – DEMENTIA

° A 75yr man with a previous history of a CABG and fem-pop bypass. His memory has been deteriorating steadily over the last year or so, with a marked deterioration just after the Christmas period -D ° A 75yr man complains that he is losing his memory, and his wife says that he tends to be better in the evening. He also has mobility problems, and now finds it difficult to complete tasks like making a cup of tea before the water goes cold. Histology – alpha synuclein deposits in cortex -C ° A 75 year old retired vicar is brought to see his GP by his concerned wife. Her concern was his behaviour over the last few months, he was becoming quite verbally abusive, recently calling his son a “massive wanker” at Christmas Dinner. Histology – Neuronal Tau Bodies arranged spherically -B

A. Alzheimar’s Disease D. Multi-infarct dementia B. Pick’s disease E. Normal pressure C. Lewy body dementia hydrocephalus CEREBROVASCULAR DISEASE

° Cerebrovascular disease – 3 key pathologies ° Infarction ° Haemorrhage ° Aneurism BASIC NEUROANATOMY CEREBRAL PERFUSION -ANATOMY

http://missinglink.ucsf.edu/lm/ids_104_cns_injury/response%20_to_injury/watershed.htm WATERSHED AREAS OF CEREBRAL PERFUSION

http://missinglink.ucsf.edu/lm/ids_104_cns_injury/response%20_to_injury/watershed.htm INFARCTION

° The most common form of cerebrovascular disease ° CVA vs TIA

° Thrombotic vs embolic ° Embolic more common – ICA / LA / PICA ° Thrombosis commonly at carotid bifurcation

° Localisation / distribution ° Site of occlusion ° Time of development ° Presence / absence collateral flow ° Systemic perfusion pressure HAEMORRHAGE

° Traumatic vs non-traumatic INTRA-PARENCHYMAL HAEMORRHAGE

° Haemorrhage into the substance of the brain ° Middle age to late adulthood ° Typically non-traumatic

° Hypertension Ï 50% clinically significant cases ° Atherogenic ° Charcot-Bouchard micro-aneurysms

° Sudden onset with signs/symptoms raised ICP ° Poorly localised INTRA-PARENCHYMAL HAEMORRHAGE SUB-ARACHNOID HAEMORRHAGE

° Sub-arachnoid haemorrhage ° Traumatic ° Non-traumatic – Berry aneurysm rupture / AVM ° Congenital defect of tunica media ° 1% population ° PCKD, coaractation of the aorta ° Poor prognosis – 70% mortality

° Sudden onset ° Thunderclap headache ° Severe headache, vomiting and LOC ° 20% with herald bleed SUB-ARACHNOID HAEMORRHAGE CNS TRAUMA

° CNS Trauma ° ¼ all accidental deaths ° Significant mortality/morbidity

° Principle injury patterns in CNS trauma ° Extra-dural haemorrhage ° Sub-dural haemorrhage ° Sub-arachnoid haemorrhage ° Parenchymal injury CNS TRAUMA -HAEMORRHAGE

Imaging / Location Injury Clinical Features Management Lucid interval – Disruption of Lens shaped Outside deterioration – death Extra-dural arteries from middle haematoma dura mater Associated with skull meningeal artery Surgical drainage fracture Insidious onset Between (alcoholics/elderly) Concave Rupture of bridging Sub-dural arachnoid Headache, haematoma veins and dura sensory/motor Surgical drainage symptoms “star shaped Thunderclap Under the Traumatic / non- appearance” Sub-arachnoid headache arachnoid traumatic Conservative/em Meningism bolisation

Within Damage to brain Compressive / Intra-cerebral Surgical drainage brain tissue substance localising signs CNS TRAUMA CNS TRAUMA –PARENCHYMAL INJURY

° Traumatic parenchymal injury ° Traumatic intra-cerebral haemorrhage ° Concussion ° DAI (diffuse axonal injury) ° Contusions ° Vasogenic / cytotoxic oedema CEREBRAL OEDEMA

° Swelling of brain substance ° Generalised – hypoxia, metabolic disturbance, trauma, HTN ° Local – haematoma, ischaemia, tumour ° Acute – cytotoxic ° Damaged cells leak Na/K Ï osmotic shift ° Chronic – vasogenic ° Dilation of cerebral vessels Ï hydrostatic shift

° Complications ° Vascular injury/damage ° Intracranial nerve damage ° Obstruction to CSF flow ° Herniation CNS TRAUMA –MONRO-KELLIE CNS TRAUMA –PRESSURE EFFECTS

http://missinglink.ucsf.edu/lm/ids_104_cns_injury/herniation/herniation.htm CNS NEOPLASMS CNS NEOPLASMS

° Secondary (metastatic) ° Most common – breast/lung ° Multiple / well demarcated

° Primary ° Gliomas, meningiomas, neuromas, pituitary, lymphoma, neuroendocrine

Generalised – raised ICP / seizures

Specific – focal neurology/local mass effect/paraneoplastic effect PRIMARY CNS NEOPLASMS

° Primary brain tumours ° Brain parenchyma, spinal cord or meninges ° Clinical effect depends on location and tumour type ° Rarely metastasise outside CNS

° Gliomas ° Astrocystomas (60%) ° Most common, slow growing, aggressive with time ° Oligodendrogliomas ° Slow growing. Calcification. Epilepsy ° Ependymomas ° Lining of ventricles. Hydrocephalus PRIMARY CNS NEOPLASMS

° Meningiomas ° Derived from arachnoid cells ° Most common adjacent to sinuses and typically in adults ° Slow growing – principle mass effects / skull erosion ° Raised ICP +/- focal neurology

° Primary CNS Lymphoma ° Associated with HIV / AIDS and non-Hodgkins B-cell

° Primary Neuroepithelial neoplasms ° Primitive small cells, classically affecting the cerebellum ° Children / <20yrs with raised ICP and cerebellar signs NEURODEGENERATIVE DISORDERS

° Broad spectrum conditions characterised by: ° Accumulation of abnormal proteins ° Neuronal damage

° Multiple cognitive deficits ° Memory impairment ° Loss of executive function DEMENTIA ° Aphasia (laguage) ° Apraxia (motor planning) ° Agnosia (recognition) DEMENTIA

° “Development of multiple cognitive deficits that include memory impairment and at least one of the following cognitive disturbances: aphasia, apraxia, agnosia or a disturbance in executive functioning. The cognitive deficit must be sufficiently severe to cause impairment in the occupational or social functioning and must represent a decline from a previously higher level of functioning”

° 30% of those >80yrs ° 7% of population aged 65-80yrs NEURODEGENERATION –THE BASICS

° Axonal damage ° Direct insult, neuronal death, axonal transection ° Primary damage Ï Wallerian degeneration

° Demyelination ° Myelin provided by oligodendrocytes ° Primary – genetic defects of myelin ° Secondary – inflammation, toxic/metabolic factors

° Neuronal inclusions ° Nuclear / cytoplasmic inclusions seen in physiological and pathological conditions NEURODEGENERATION –THE BASICS

Small spherical nuclear inclusions in liver Marinesco Bodies insufficiency Hirano bodies Rod like lipofuscins in ageing brains Bunina bodies Pathological inclusions of MND PD + Lewy body dementia Lewy bodies α-synuclein /ubiquitin plaques Pick’s bodies Pick’s disease Ageing, AD and progressive supra-nuclear palsy Neurofibrillary tangles Major antigenic component is phosphrylated tau Bielschowsky’d staining (β-amyloid, ubiquitin, Senile plaques phosphorylated tau) Neuritic or diffuse NEURODEGENERATIVE DISORDERS

° Alzheimer’s dementia

° Vascular / multi-infarct dementia

° Lewy body dementia

° Pick’s disease

° Huntingdon’s disease

° Others ALZHEIMER’S DISEASE

° 1907 Alois Alzheimer ° 50-75% dementia (5/1000 people) - leading cause of disability ° 20% those >80yrs ° Most cases sporadic, <10% inherited (pre-senilin gene) ° Definitive diagnosis only as post mortem

° Key features ° Severe brain atrophy – hippocampus, amygdala, frontal lobe ° Formation of senile plaques/neurofibrillary tangles Ï neuronal loss with reactive astrocytosis ° Amyloid plaques (β-amyloid) ° Neurofibrillary tangles (paired helical filaments) ° Dystrophic neuritis (phosphorylated tau) ALZHEIMER’S DISEASE VASCULAR/MULTI -INFARCT DEMENTIA

° Very common ° Arteriopaths ° 25% of dementia ° Cumulative affect of multiple small CVA’s ° Sudden onset and step-wise progression LEWY BODY DEMENTIA

° 3rd most common cause of dementia ° 15-25% of cases ° Characterised by ° Fluctuating cognitive impairment ° Detailed visual hallucinations ° Parksonism ° Rapid onset and progression

° Overlap with AD and PD ° Lewy bodies in cortical grey matter and subcortical nuclei ° Neurofibrillary sparing of hippocampus ° α-synuclein /ubiquitin plaques PICK’S DISEASE

° Arnold Pick 1892 ° Rare cause of dementia in young patients ° Autosomal inheritance ° Tau plaque deposition Ï spherical aggregations (Pick bodies) ° Characterised by ° Severe temporal / frontal lobe atrophy ° Difficulty in speech, behavioural change, impaired regulation social conduct HUNTINGDON’S DISEASE

° Autosomal dominant mutation of Huntingtin gene ° Chromosome 4 Ï CAG repeat ° Symptoms develop 30-40yrs

° Insidious and progressive ° Chorea Ï irritability Ï dementia Ï fits Ï death (15yrs)

° Cerebral atrophy with loss of corpus striatum ° GABA-nergic + cholinergic neurons ° Huntingtin protein inclusions PARKINSONISM

° Parkinsonism ° Tremor + rigidity + bradykinesia/hypokinesia

° Causes of Parkinsonism ° Idiopathic Parkinson’s Disease ° Multiple cerebral infarcts ° Parkinson’s plus syndromes – PAP, MSA, CBD, Lewy body dementia ° Post-encephalopathy ° Drug induced – neuroleptics, metoclopramide ° Toxin induced – MPTP, copper (Wilson’s Disease) ° Trauma – pugilistic encephalopathy PARKINSON’S DISEASE

° James Parkinson 1817 “Essay on Shaking Palsy”

° Degeneration of dopaminergic neurons in substantia nigra Ï reduced striatal dopamine + Lewy bodies ° 2nd most common neurodegenrative disease ° 95% sporadic ° Mean age onset 65yrs ° 1.6% of population (3.5% 85-90yrs)

° Parkinsonism ° Response to L-DOPA ° Autonomic features ° Psychiatric features MULTIPLE SCLEROSIS

° 1868 Charcot ° Principle cause of neuro-disability in the young

° “Inflammatory demyelinating disease of the CNS associated with dissemination in time and place.” ° 20-40yrs, F>M ° 15-20x increased risk in 1 st degree relative ° Focal symptoms Ï progressive physical/cognitive disability

° Histology ° Scattered plaques of demyelination ° Focal myelin breakdown and astrocytic scarring MULTIPLE SCLEROSIS MULTIPLE SCLEROSIS EMQ – CNS & MENINGITIS

° 42yr from East Africa complains of weeks of meningitis symptoms ° A 3yr old girl with incomplete vaccinations gets rapidly ill over a few days – CSF grows G-ve coccobacilli ° 73yr old male presents with neck stiffness and a high fever, his LP grows G+ve cocci ° 18yr old student presents with text-book meningitis symptoms – his CSF grows diplococci

A. Eschericha coli G. Poliovirus B. Haemophilus influenzae H. Protozoal meningitis C. Meningioma I. Streptococcus pneumoniae D. Migraine J. Subarachoid haemorrhage E. Mycobacterium tuberculosis K. Subdural haemorrhage F. Neisseria meningitis L. Viral meningitis EMQ – CNS & MENINGITIS

° 42yr from East Africa complains of weeks of meningitis symptoms -E ° A 3yr old girl with incomplete vaccinations gets rapidly ill over a few days – CSF grows G-ve coccobacilli -B ° 73yr old male presents with neck stiffness and a high fever, his LP grows G+ve cocci -I ° 18yr old student presents with text-book meningitis symptoms – his CSF grows diplococci -F

A. Eschericha coli G. Poliovirus B. Haemophilus influenzae H. Protozoal meningitis C. Meningioma I. Streptococcus pneumoniae D. Migraine J. Subarachoid haemorrhage E. Mycobacterium tuberculosis K. Subdural haemorrhage F. Neisseria meningitis L. Viral meningitis BREAST DISEASE

“Whoever thought up the word 'mammogram'? Every time I hear it, I think I'm supposed to put my breast in an envelope and send it to someone” - Jan King BREASTS –THE BASICS

° Principle function is production and expression of milk ° Lobules – secretory unit ° Acini (myoepithelial) embedded within loose connective tissue ° Terminal ductal lobular unit ° Extra-lobular ducts ° Join to form sub-segmental ducts Ï segmental ducts Ï lactiferous and sinus ° 15-20 lactiferous ducts each draining a different segment of breast THE SPECTRUM OF BREAST DISEASE

The Probable Pathological Causes of Breast Lesions

Probable Pathological Cause Clinical Presentation <25yrs 25-35yrs 35-55yrs >55yrs Mobile Lump Fibroadenoma Fibroadenoma Phyllodes tumour Phyllodes tumour

Fibrocystic change Poorly defined lump Uncommon Sclerosing Fibrocystic change Uncommon adenosis

Uncommon Firm lump +/- tethering Carcinoma Carcinoma Fat necrosis Clear Uncommon Uncommon Duct ectasia Duct Duct papilloma Discharge Bloody Uncommon Uncommon In situ carcinoma In situ carcinoma Nipple ulceration / Paget’s Disease Paget’s Disease Nipple Nipple adenoma eczema Nipple adenoma Nipple adenoma INFLAMMATORY CONDITIONS OF THE BREAST

° Infection ° Complication of lactation ° Acute pyogenic mastitis

° Mammary duct ectasia ° 2nd half of reproductive life ° Blood stained discharge and ductal fibrosis

° Fat necrosis ° Trauma PROLIFERATIVE DISORDERS OF THE BREAST

° Proliferative conditions of the breast ° Increase infrequency towards menopause ° Present as diffuse, granular and ill-defined swelling

° Fibrocystic Change ° Most common proliferative condition ° Adenosis and fibrosis ° formation ° metaplasia ° Epithelial hyperplasia ° Radial scar formation

° Gynaecomastia BENIGN NEOPLASTIC DISORDERS OF THE BREAST

° Connective tissue and epithelial tissue ° Fibroadenoma ° Duct papilloma ° Adenoma ° Benign connective tissue tumours

° Fibroadenoma ° “Breast mouse”

° Duct papilloma ° Solitary lesion of large ducts – most common cause of a palpable lump and nipple discharge MALIGNANT NEOPLASTIC DISORDERS OF THE BREAST

° Breast ° Most common female cancer – 20% ° 1:9 women will develop ° Leading cause of death 35-55yrs

° Principle risk factors ° Female sex ° Increasing age ° Environment ° Family history ° Lifestyle ° Oestrogen exposure MALIGNANT NEOPLASTIC DISORDERS OF THE BREAST

° Typical presentation ° Lump, discharge skin changes, pain, metastases

° Triple assessment ° Clinical (S1-5) ° Radiological (M1-5) ° Pathological (C1-5 / B1-5)

° NHS national screening programme MALIGNANT NEOPLASTIC DISORDERS OF THE BREAST NON-INVASIVE CARCINOMA OF THE BREAST

° Carcinoma in situ ° Cancer which has not breached the basement membrane

° in situ (DCIS) ° Pre and post-menopasual women ° Unilateral and unifocal ° Behaviour related to grade and morphological subtyoe

° in situ (LCIS) ° Predominantly pre-menopausal women ° Multi-focal and bilateral INVASIVE CARCINOMA OF THE BREAST

° Invasive carcinoma ° Pre and post-menopausal women ° Spread via direct invasion, lymphatic/haematogenous spread

° Histological subtypes ° Infiltrating ductal - 75% ° Infiltrating lobular - 10% ° Other – mucinous, tubular, medullary, papillary

° 75% 5yr survival ° Nottingham Prognostic Index ° >90% if <5cm vs 6% if >5cm PAGET ’S DISEASE OF THE NIPPLE

° Paget’s Disease of the nipple ° 2% of breast cancer ° Erosion of the nipple ° Underlying ductal carcinoma <40mm from nipple ° Typically unilateral and associated with underlying mass CONNECTIVE TISSUE DISORDERS CONNECTIVE TISSUE DISEASE

° Multi-system diseases ° Defined by clinical, pathological and serological criteria ° Autoimmune basis

° Systemic Lupus Erythematosus ° Scleroderma ° Polymyositis / Dermatomyositis ° Vasculitis ° Sarcoidosis ° Amyloidosis SYSTEMIC LUPUS ERYTHEMATOSUS

° Multi-system autoimmune disease ° Auto-antigens – ANA (90%), dsDNA (60%), RhF (40%), anti-Ro, anti-La, anti-SM, antiRNP, anti-phospholipid ° Polyclonal β-cell Ab generation and immune complex formation ° 0.2% of population, W>M

° Diagnosis - >4 of 11 criteria:

Malar rash Discoid rash Photosensitivity Oral ulcers Non-erosive arthritis Serositis Renal disorder CNS disorder Haematological disorder Immunological disorder Anti-nuclear Ab (ANA) SYSTEMIC LUPUS ERYTHEMATOSUS SCLERODERMA –SYSTEMIC SCLEROSIS

° Sceleroderma + vascular disease ° Limited vs diffuse

° Limited Systemic Sclerosis (CREST) ° Calcinosis, raynaud’s, oesophageal/gut dysmotility, sclerodactyly, telangiectasia ° Skin involvement limited to face, hands and feet ° 70-80& anti-centromere

° Diffuse Systemic Sclerosis ° Diffuse skin involvement and organ fibrosis ° Anti-topoisomerase-1 (Scl70) (40%), anti-RNA polymerase (20%) SCLERODERMA –SYSTEMIC SCLEROSIS POLYMYOSITIS / DERMATOMYOSITIS

° Insidious, progressive & symmetrical proximal muscle weakness associated with myalgia and arthralgia ° 5 variants Proximal ° Common diagnostic criteria limb/anterior neck weakness ° Polymyositis = >4 criteria Oesophgeal/respirat ory muscle weakness

+ve muscle biopsy ° Dermatomyositis = >3 criteria + skin rash (T/B cell infiltrate + ° Gottron’s sign / Heliotrope rash / Shawl sign muscle fibre atrophy)

° Anti-Jo Ab Elevated enzymes (CK) +ve EMG POLYMYOSITIS / DERMATOMYOSITIS VASCULITIS

° Inflammatory disorder Vessel Type Disease of vessel walls Giant Cell Arteritis Larger arteries ° Organ vessels Takaysu’s Arteritis

° Categorised according to Medium Polyarteritis Nodosa target vessel size arteries Kawasaki’s Disease Wegener’s Granulomatosis ° Immune complex Churg-Strauss Syndrome mediated Small arterioles Microscopic Polyarteritis ° Anti-DNA, ANCA / capillaries Henoch-Schonlein Purpura Cryoglobulinaemia ° Secondary or primary Arteries + veins Buerger’s Disease SARCOIDOSIS

° Multi-system granulomatous disorder of unknown aetiology ° 20-40yrs, 10x more common in afro-caribbeans ° Associated with HLA-DRB1 ° 20-40% incidental discovery

° Clinical features ° Pulmonary disease – 90% with abnormal CXR ° Non-pulmonary features

° Prognosis ° 60% resolve in 2yrs, 20% respond to steroids, 20% progress SARCOIDOSIS AMYLOIDOSIS

° Group of disorders characterised by extra-cellular deposition of proteins in abnormal fibrillar form that are resistant to degradation ° AL amyloid (primary amyloidosis) ° AA amyloid (secondary amyloidosis) ° Alzheimer’s, T2DM, haemodialysis related

° Amyloid deposition – all organs ° Median survival 1-2yrs

° Congo red stain ° Red-green birefringence under polarised light GASTROINTESTINAL TRACT DISEASE

“… half the unhappiness in the world proceeds from little stoppages; from a duct choked up, from food pressing in the wrong place, from a vexed duodenum, or an agitated pylorus” - Sydney Smith 1855 EMQ - DYSPEPSIA

° 56yr with RA presents with epigastric pain and vomiting. Campylobacter like organism test negative. Endoscopy – areas of mucosal damage, no polymorphs seen on histology

° A 70 year old man presents to A&E extremely unwell, in shock, with a board like abdomen. Erect CXR – Free air under the diaphragm

° A 30 year old man presents with acute epigastric pain and vomiting. He may have taken an overdose of bleach. Endoscopy biopsy – neutrophilic infiltration

A. Posterior duodenal ulcer E. Gastric erosions B. Anterior duodenal ulcer F. Acute gastritis C. Gastric ulcer G. Chronic gastritis D. GORD EMQ - DYSPEPSIA

° 56yr with RA presents with epigastric pain and vomiting. Campylobacter like organism test negative. Endoscopy – areas of mucosal damage, no polymorphs seen on histology -G

° A 70 year old man presents to A&E extremely unwell, in shock, with a board like abdomen. Erect CXR – Free air under the diaphragm -B

° A 30 year old man presents with acute epigastric pain and vomiting. He may have taken an overdose of bleach. Endoscopy biopsy – neutrophilic infiltration -F

A. Posterior duodenal ulcer E. Gastric erosions B. Anterior duodenal ulcer F. Acute gastritis C. Gastric ulcer G. Chronic gastritis D. GORD GI TRACT –THE BASICS THE OESOPHAGUS

° Connects pharynx to stomach ° 25cm long ° Carriage of food and prevention of regurgitation ° Stratified squamous Ï columnar at z-line OESOPHAGITIS BARRETT ’S OESOPHAGITIS BARRETT ’S OESOPHAGITIS OESOPHAGEAL NEOPLASMS

° Principle signs/symptoms ° Dysphagia, odynophagia, regurgitation, weight loss

° Risk Factors: ° Age >60yrs ° M>F ° GORD, smoking, EtOH ° HPV infection

° Overall prognosis poor – 5yr survival <5% OESOPHAGEAL NEOPLASMS

° ° 30-40% primary oesophageal ° Distal 1/3 oesophagus ° Barrett’s oesophagitis

° ° May present anywhere in oesophagus ° Proximal 1/3 – 20% ° Middle 1/3 – 50% ° Distal 1/3 30% ° 50% present with LN involvement ° Smoking, alcohol, achalasia ACHALASIA

° Dysmotility disorder of the oesophagus ° Degeneration of Auerbach plexus ° Incomplete relaxation and lack of peristalsis ° Dysphagia Ï hypertrophy Ï squamous cell carcinoma

° Classical bird’s beak appearance HIATUS HERNIA THE STOMACH GASTRITIS

° Inflammation of the gastric mucosa ° Acute ° Chronic ° Associated with MALT

° Chronic gastritis Ï metaplasia Ï dysplasia Ï cancer ° 2-4% risk of malignancy HELICOBACTER PYLORI

° Micro-aerophilic gram –ve bacterium

° Infection of gastric mucosa ° Predilication for anturm ° Stimulates increased gastrin production ° Faeco-oral / oro-oral transmission ° 50% world population ° 80% duodenal ulcers ° 20% gastric ulcers

° Eradication therapy ° Abx + high dose PPI PEPTIC ULCER DISEASE

° Ulcer = breach of the mucosa extending through the muscularis mucosa into the sub-mucosa or deeper ° Typically solitary and <4cm ° Principle sites ° 1st part duodenum ° Antrum/lesser curve of stomach

° Complications ° Bleeding – 15-20% ° Perforation – 5% ° Obstruction – 2% ° Malignant transformation – rare ° Pyloric stenosis Ï gastric outlet obstruction PEPTIC ULCER DISEASE EMQ – UPPER GI MALIGNANCY

° A man who is H. Pylori positive is found to have a malignancy during an endoscopy. He is told that 70-80% of people which this cancer are cured by triple therapy.

° A 35 year old Irish woman presents with chronic anaemia and steatorrhea. Biopsy of the jejunum shows villous atrophy, lymphocytic infiltration and crypt hyperplasia

° A 69 year old gentleman presents with weight loss and chronic anaemia. An upper GI endoscopy reveals a gastric ulcer and biopsy shows characteristic “signet ring” cells.

A. Transitional cell carcinoma D. Leiomyosarcoma B. Squamous cell carcinoma E. MALT lymphoma C. Adenocarcinoma F. T-cell lymphoma EMQ – UPPER GI MALIGNANCY

° A man who is H. Pylori positive is found to have a malignancy during an endoscopy. He is told that 70-80% of people which this cancer are cured by triple therapy -E

° A 35 year old Irish woman presents with chronic anaemia and steatorrhea. Biopsy of the jejunum shows villous atrophy, lymphocytic infiltration and crypt hyperplasia -F

° A 69 year old gentleman presents with weight loss and chronic anaemia. An upper GI endoscopy reveals a gastric ulcer and biopsy shows characteristic “signet ring” cells. -C

A. Transitional cell carcinoma D. Leiomyosarcoma B. Squamous cell carcinoma E. MALT lymphoma C. Adenocarcinoma F. T-cell lymphoma GASTRIC MALIGNANCY

° Adenocarcinoma ° Intestinal ° Inflammation Ï metaplasia Ï dysplasia Ï neoplasia ° H.pylori related ° Diffuse ° Normal mucosa ° Signet ring cells ° Highly infiltrative and aggressive () GASTRIC MALIGNANCY

° Lymphoma ° MALT ° H.pylori – marginal cell lymphoma

° Leimyomas/leimyosarcomas ° Benign/mlignant tumour of muscle

° Stromal tumours ° Connective tissue origin PERNICIOUS ANAEMIA

° Autoimmune disease ° 90% anti-parietal cell Ab ° 50% anti-IF Ab ° Atrophic gastritis + intrinsic factor deficiency

° Vitamin B12 deficiency ° Macrocytic anaemia ° Neuropathy – sub-acute combined degeneration of the spinal cord COELIAC DISEASE

° Prototypic non-infectious cause of malabsroption ° 1/2000 in the UK

° Gluten sensitivity Ï enterocyte damage and villous atrophy Ï reduced absorptive capacity ° Gliadin water soluble cereal protein Ï T-cell cross-reaction with enterocytes

° Auto-Ab’s implicated ° Anti-tTG (tissue transglutaminase) ° Anti-AGA (gliadin) ° Anti-EMA (endomysium) COELIAC DISEASE

° Complications ° 10-15% risk of GI lymphoma (EALT) ° Increased risk GI malignancy COELIAC DISEASE LOWER GI TRACT –THE BASICS LOWER GI TRACT –THE BASICS

° Congenital or acquired ° Acquired – mechanical, functional, vascular, inflammatory, neoplastic, iatrogenic

° Manifestations of lower GI Tract Disease ° Obstruction – pain ° Disturbance of function – altered bowel habit ° Bleeding – anaemia/malaena ° Systemic manifestations ° Perforation / fistula formation INFLAMMATORY BOWEL DISEASE

° Colitis ° Acute – infection, drugs, chemo/radiotherapy, ischaemic ° Chronic – IBD, TB

° “Excess wall-based inflammatory activity leading to relapsing and remitting disease.” ° Crohn’s Disease ° Ulcerative colitis ° Diarrhoea +/- blood +/- mucus ° Fever ° Abdominal pain/distension ° Anaemia ° Weight loss ° Extra-intestinal manifestations ° 10% of cases intermediate colitis – no distinction made INFLAMMATORY BOWEL DISEASE

Susceptibility genes Environmental - infection

IBD

UC CD

Phenotypic genes

Disease specific genes Environmental influences CROHN’S DISEASE

° Any part of GI tract ° Transmural granulomatous skip lesions ° 10-20yrs, mainly Western populations ° Terminal ileum (50%) > ileo-caecal junction > GI tract ° More common in smokers

° Key pathological features ° Transmural inflammatory skip lesions ° Non-caseating granuloma formation ° Deep fissuring ulcers ° Tendency for fistulation + peri-anal disease (50%) ° Fat wrapping of bowel Ï bowel wall thickening, abscess formation CROHN’S DISEASE

° Extra-intestinal manifestations: ° Erythema nodusum ° Pyoderma gangrenosum ° Iritis/conjunctivitis/scleritis/uveitis ° Large joint arthritis ° Seronegative spondyloarthritis ° Myositis

° Complications ° Abscess ° Fistula formation (10%) ° Obstruction – strictures ° 50-80% require at some point CROHN’S DISEASE ULCERATIVE COLITIS

° Mucosal inflammation spreading continuously and proximally from the rectum ° Relapsing remitting, 20-25yrs ° 50% rectum, 30% left sided colitis, 20% pancolitis ° Backwash ilietis – incompetent ilio-caecal valve ° More common in non-smokers ° Systemic manifestations rarer than in Crohn’s disease

° Pathology ° Hyperaemic/haemorrhagic granular colonic mucosa + inflammatory pseudopolyps ° Crypt abscesses ULCERATIVE COLITIS

° Complications ° Severe haemorrhage ° Toxic megacolon (>6cm) ° Adenocarcinoma – 20-30x increased risk ° 15% of those with pan-colitis will develop adenocarcinoma ° Flat, ill-defined polyps requiring screening ° 20% require surgery

PARAMETER MILD MODERATE SEVERE Motions/day <4 4-6 >6 Rectal bleeding Small Moderate Large Temperature (6am) Apyrexial 37.1 – 37.8°c >37.8°c HR <70 70-90 >90 Hb >11g/dL 10.5-11g/dL <10.5g/dL ESR <30mm/h >30mm/hr ULCERATIVE COLITIS COLORECTAL CARCINOMA

http://www.pathologyoutlines.com/topic/colontumoradenomacarcinoma.html INHERITED DISORDERS

° Peutz-Jeghers Syndrome ° Hamartomatous polyps + pigmentation ° Commonly presents as intussception during childhood ° 15% risk malignancy – co-existing

° Hereditary Non-Polyposis Colorectal Cancer (HNPCC) ° Rare, autosomal dominant – 3-5% colorectal cancer ° Early onset, high frequency tumours proximal to splenic flexure ° Poorly differentiated, mucinous ° Commonly associated with multiple synchronous colorectal cancers and extra-colonic cancers ° Endometrium, prostate, breast, stomach INHERITED DISORDERS

° Familial Adenomatous Polyposis (FAP) ° Autosomal dominant – APC tumour suppressor ° >100 colorectal adenomatous polyps (average >1000) ° >95% will develop adenocarcinoma in 10-15yrs

° Gardner’s Syndrome ° FAP + extra-intestinal manifestations BOWEL CANCER

° 98% colorectal malignancy = adenocarcinoma ° 60-80yrs ° If <50yrs consider familial syndrome ° Western diet, obesity, IBD ° Bleeding, change bowel habit, anaemia, weight loss, pain, fistula formation ° Grade defined by level of differentiation ° Dukes staging BOWEL CANCER QUIZ TIME HOW MUCH DID YOU PAY ATTENTION ?

HEPATOBILIARY & PANCREATIC DISORDERS

“It was my Uncle George who discovered that alcohol was a food well in advance of modern medical thought” - PG Woodhouse THE LIVER –THE BASICS

http://www.britannica.com/EBchecked/media/60419/Microscopic-structure-of-the-liver-Liver-cells-or-hepatocytes-have THE LIVER –THE BASICS

http://www.biologymad.com/master.html?http://www.biologymad.com/kidneys/kidneys.htm CIRRHOSIS

° “Potentially reversible fibrotic scarring of the liver” ° Whole liver involvement ° Fibrosis ° Nodules of regenerating hepatocytes ° Distortion of vascular architecture

° Principle causes ° EtOH, Hepatitis B/C, NAFLD/NASH, PBC, haemachromatosis, Wilson’s disease, A1AT, idiopathic (15%)

° Established cirrhosis – 35-65% 10yr mortality CIRRHOSIS HEPATITIS

° Acute vs chronic ° Acute – viral infection, drug reaction ° Histo: diffuse lobular injury (apotty necrosis), reactive changes in Kupffer cells and portal inflammation ° Chronic – viral infection, drug reaction, autoimmune ° Histo: portal inflammation and interface hepatitis – piecemeal necrosis AUTO-IMMUNE HEPATITIS

° Chronic hepatitis ° Anti-smooth muscle (anti-SM) + anti-nuclear (ANA) ° 1-2/100,000 ° 70% women ° May progress to cirrhosis ° Treatment successful in 60-80% PRIMARY BILIARY CIRRHOSIS & PRIMARY SCLEROSING CHOLANGITIS

° Primary Biliary Cirrhosis ° Autoimmune condition Ï inflammatory/granulomatous damage to bile ducts Ï bile duct loss ° Anti-mitochondrial Ab ° Fatigue, pruritis, jaundice, cholangitis, xanthoma, cirrhosis ° Associated with other autoimmune condition in 80% - RA/Sjogrens

° Primary Sclerosing Cholangitis ° Chronic inflammatory liver disease Ï peri-ductal bile duct fibrosis and bile duct loss ° Associated with UC (70%) and carries increased risk ° P-ANCA, beading of bile ducts on ERCP HAEMOCHROMATOSIS

° Excessive absorption/deposition dietary iron ° Irish, chromosome 6 ° Same clinical symptoms as iron overload – e.g. sickle cell, thalasseamia

° Presentation ° Malaise, cirrhosis, insulin resistance, erectile dysfunction, CCF, adrenal insufficiency, diabetes bronze ° Serum transferrin saturation >45% ° Serum ferritin >1000u/L

° Phlebotomy and treatment of end-organ damage WILSON’S DISEASE

° Autosomal recessive disorder of copper accumulation ° Copper important co-factor in many body processes ° Chromosome 13 Ï failure of copper excretion by hepatocytes

° Presentation ° Liver disease, neuropsychiatric symptoms, Kayser-Fleischer rings ° Abnormal LFT’s ° Low ceruloplasmin, raised serum/urine copper

° Treatment with copper chelation with penicillamine WILSON’S DISEASE HEPATIC TUMOURS

° Hepatic tumours ° Primary – HCC, hepatoblastoma, cholangiocarcinoma, haemangiosarcom ° Secondary – most common

° ° RFx: cirrhosis, viral hepatits, aflatoxin (aspergillus) ° Unifocal/multifocal/diffuse with marked venous invasion ° Resembles normal liver structure and capable of producing bile ° CT – hypervascular, pseudocapsule, mosaic pattern ° Tumour marker - AFP THE PANCREAS –THE BASCIS DIABETES MELLITUS

° 1-2% population Ï 5% NHS budget ° T1DM – insulin deficiency ° 20% of cases, presents <20yrs ° Ketoacidosis common ° Autoimmune destruction β-cells ° T2DM – insulin resistance ° 80% cases, presents >40yrs ° 90% cases obese, 11% Asian, 9% Afro-Caribbean ° No ketoacidosis ° β-cells insufficiency due to insulin resistance

° Classical diabetic syndrome ° Thirst, polyuria, tiredness, blurred vision ° Random glucose >15mM/L ° Fasting glucose >7mM/L DIABETES MELLITUS

° Multi-system disease: principle complications ° Nephropathy – most common cause CKD ° Neuropathy ° IHD ° PVD ° CVA ° Retinopathy – most common cause blindness 25-70yrs

° Secondary Diabetes ° Rare cause – 5% casues ° Pancreatic disease – chronic pancreatitis, haemochromatosis ° Endocrine antagonism – cushing’s/steroids, iselt cell tumours (/ METABOLIC SYNDROME –SYNDROME X

° A combination of medical disorders that increases CVD/diabetic risk affecting 20% of the population ° Fasting hyperglycaemia - >6mmol/L ° Increased BP - >140/90 ° Central obesity - >94cm men, >80cm women ° Decreased HDL - <1mmol/L ° Increased triglycerides >2mmol/L ACUTE PANCREATITIS

° Sudden onset destruction of pancreatic tissue ° 20/100,000/year ° EtOH, gallstones

° Inappropriate active of enzymes within pancreas Ï acute inflammation + necrosis + haemorrhage ° Epigastric pain radiating to back, N/V/D, SIRS, steatorrhoea, Grey- Turner’s sign, Cullen’s sign ° Serum amylase raised in 90% ° Lipase elevated in 4-8hrs ° Lipase >3x that of amylase suggestive of EtOH

° Severe pancreatitis mortality 10-20% CHRONIC PANCREATITIS

° Long standing inflammation of the pancreas Ï altered structure and function ° Alcoholism (70%), CF, gallstones, pancreas divisum ° Abdominal pain ° Steatorrhoea ° Secondary DM ° Malabsorption ° Lipase/amylase often normal ° Associated with cyst/pseudocyst formation ADENONCARCINOMA OF THE PANCREAS

° Ductal adenocarcinoma of the pancreas – 85% cancers ° 4/5000/year, 55-75yrs ° Smoking, poor diet, chronic pancreatitis, genetic (cationic trypsin) ° Sub-types – clear cell, mucinoos, signet ring, giant cell ° Genetic mutations – K-ras (>90%), p16 (>95%), p53 (50-70%)

° Presentation ° Weight loss, anorecia, back pain, painless jaundice, DM, Courvoiser’s sign, Trosseau’s syndrome ° CA 19-9 (>70%)

° Prognosis ° 15% cases suitable surgical resection ° <5% 5yr survival, 25% 1yr survival NEUROENDOCRINE TUMOURS

° Neuroendocrine tumours – 3-5% cancers ° Associated with MEN1 ° Usually affect body/tail ° Unpredictable behaviour ° 10% malignant, >50% metastasise

° Subtypes ° Insluinoma – hypoglycaemia ° – Zollinger-Ellison Syndrome ° Glucagonoma – DM ° Somatostainoma – gallstones/steatorrhoea GENITOURINARY TRACT DISEASE THE KIDNEY –THE BASCIS

° I million nephrons ° Principle functions ° Excretion of waste ° Acid-base balance ° Fluid/electrolyte balance ° Hormonal ° EPO, renin, Vit-D

° Filtration at glomerulus ° Glomerular disease Ï failure filtration CONGENITAL DISEASES OF THE KIDNEY

° Bilateral / unilateral agenesis

° Ectopic kidney

° Horseshoe kidney ° 1/1000 – fused at lower pole, found in lower abdomen/pelvis

° Adult Polycyctsic Kidney Disease ° Autosomal dominant (1/1000) Ï ESRF in 10% ° PKD1/2 ° Associated with liver and Berry aneurysms AKI VS CKD

AKI CRF

Sudden Progressive

Reversible Irreversible

Oliguria/Anuria Asymptomatic Ï Anuria

Hyperkalaemia/acidosis Multi-system disturbance ACUTE KIDNEY INJURY

° Rapid loss of glomerular filtration and tubular function ° Abnormal water/electrolyte balance ° Reduced GFR – rise in Ur/Cr ° Acidosis

° Pre-renal ° Renal ° Post-renal RENAL FAILURE

° Blood vessels / Glomerulus / Tubules / Interstitium RENAL FAILURE –BLOOD VESSELS

° Hypertension ° Thickening of vessel walls and luminal narrowing ° Chronic ischaemia Ï gradual loss of nephrons

° Atherosclerotic renal disease ° Renal artery stenosis ° Arteriopathy ° Ischaemic nephropathy (hypoperfusion) + RAA mediated HTN RENAL FAILURE –THE GLOMERULUS

° Glomerulus – site of ultrafiltration

° Glomerulonephritis – inflammation of glomeruli ° Primary – idiopathic ° Secondary – another disease process ° SLE, DM, amyloidosis, infections, vasculitis, malignancy, drugs (toxins)

° Response to injury ° Proliferative – nephritic syndrome ° Cellular elements of cellular tuft proliferate ° Structural – nephrotic syndrome ° Thickening/sclerosis of basement membrane ° Necrotising – AKI ° Necrosis of capillary wall and crescent formation NEPHRITIC SYNDROME

° Proliferative response to injury ° Proteinuria ° Haematuria ° Fluid overload

° Urine brown/coke coloured

° Common causes ° Adults – IgA nephropathy ° Children – post-streptococcal glomerulonephritis NEPHROTIC SYNDROME

° Structural response to injury ° Proteinuris (>3.5g/day) ° Hypoalbunaemia ° Oedema

° Associated with hyperlipidaemia, immunosuppression, hyercoagubility

° Manifestation of glomerular disease ° Adults – diabetic nephropathy, membranous GMN, focal/segmental glomerulosclerosis ° Children – minimal change disease RENAL FAILURE –THE TUBULES

° Acute Tubular Necrosis ° The most common cause of ARF ° Damage to tubular epithelium by ischaemia/toxins ° Reduction in GFR – tubular obstruction, leak, haemodynamic changes ° Will resolve is treated ° Oliguric – polyguric ° Morphology ° Loss of brush border ° Detachment from basement membrane ° Formation of intra-luminal cysts

° Others – rare! ° Excessive loss of substances – glucosuria, amioaciduria ° Inadequate excretion of substances – renal tubular acidosis RENAL FAILURE –THE INTERSTITIUM

° Intersitital nephritis ° Acute – Type 1 hypersensitivey ° NSAID’s, Abx ° Chronic – analgesia, chronic pyelophephritis (reflux nephritis) CKD

° Chronic kidney disease: ° 10-12% population ° DM (20%), glomerulonephritis (15%), HTN/vascular disease (15%), reflux nephropathy (10%), PCKD (10%)

Stage Description GFR (ml/min) Prevalence 1 Normal GFR >90 3.3% 2 Mild 60-89 3% 3 Moderate 30-59 4.3% 4 Severe 15-29 0.2% 5 ESRF <15 / dialysis 0.2% OUTFLOW DISEASE

° Stones

° Malignancy

° Prostate

° Retention

° Inflammation RENAL STONES

° Very common: 1-5% pop ° 90% stones radio-opaque

° Types ° Calcium oxalate – 75% ° Hard, irregular, radio-opaque (mulberry stones) ° Acid urine ° Triple phosphate – 15% ° White, soft ° Large staghorn calculi ° Alkali urine (proteus UTI) ° Urate – 7% ° Yellow, hard, smooth radiolucent ° Cysteine – 1% UROLOGICAL MALIGNANCY

° ° Adenocarcinoma – clear cell ° Rarely papillar/chromophobe sub-types ° Smoking

° Urothelial tumours ° Transitional cell carcinoma ° 90% ° Carcinogens – e.g. smoking, azo dyes ° Occur anywhere from renal pelvis to neck of bladder ° Squamous cell carcinoma ° 7% ° Chronic irritation – schistosomiasis, chronic UTI, chronic stones ° Others – adenocarcinoma, sarcoma, small cell carcinoma UROLOGICAL MALIGNANCY TESTICULAR TUMOURS

° Germ cell tumours – 90% ° Derived from maturing spermatozoa ° Seminomas - 30-40yrs, placental ALP, hCG ° Non-seminonmas - 20-30yrs, hCG, AFP ° Embryonal, teratomas, yolk sac, choriocarcinoma ° 90% 5yr survival

° Sex cord stromal (Sertoli/Leydig) – 10% ° Sertoli – oestrogens ° Leydig - androgens

° Others – lymphoma (diffuse B cell in elderly), secondary (AML in children) THE PROSTATE

° Benign Prostatic Hypertrophy (BPH) ° Benign nodular proliferation of musculofibrous/glandular prostate ° Reduced testosterone/oestrogen ratio – smooth and diffuse ° Obstructive + irritative symptoms ° α1-blockers, 5 α-reductase inhibitors, surgery

° Carcinoma of the prostate ° Most common cancer in men – 60% men >85yrs ° Asymptomatic Ï obstructive/irritative symptoms Ï disseminated disease ° Adenocarcinoma – hard and craggy ° Gleason staging system ° Prognosis dependent on stage – 1/2 = 75% 5yr, 2.5yrs once mets END OF PART 2 – ANY QUESTIONS ?