Histopathology Flashcards
1
Q
What is the most common childhood cancer?
A
Leukaemias (30%). For comparison in adults, leukaemia makes up ~4% of malignancies
2
Q
What is a Wilms tumour?
A
A nephroblastoma (kindey tumour). 5% of childhood cancers. Note that cases of any ‘blastoma’ cancers e.g. retinoblastoma, neuroblastoma are rarely seen beyond the age of ~15 years
3
Q
What is the general difference between the genetic and environmental influences for childhood vs adult cancers?
A
Childhood cancers are often the result of DNA changes in cells very early in life (some even before birth). Unlike many cancers in adults, childhood cancers are not strongly linked to lifestyle or environmental risk factors (because they didn’t have time to build up)
4
Q
Do childhood cancers respond well to chemotherapy?
A
Yes they tend to respond better to treatments such as chemotherapy than adults do. This is because in children the cells are often proliferating more, so when you give them chemotherapy you tend to hit more cells. Nowadays blastomas tend to have a survival rate of up to 80% and leukaemia’s 90%.
5
Q
What is Hirschsprung’s disease?
A
A congenital developmental abnormality with an absence of ganglion cells in the distal rectum. Due to failure of neural crest cell migration during development of the enteric nervous system. Progresses from the distal end, but can involve the whole gut.
6
Q
Some further facts about Hirschsprung’s disease…
A
Nowadays children can survive this disease with TPN (IV feeding). In a normal gut there will be normal peristalsis, in Hirschsprung’s disease the anus and rectum can narrow (which is where the diseased part is), so it is basically mechanical stenosis: due to the absence of ganglion cells, the parasympathetic fibres are firing and the muscle is constricting and not allowing any faeces past
7
Q
How might Hirschsprung’s disease present?
A
Most cases diagnosed first 48 hrs after birth: delayed meconium passage, abdominal distension, bilious vomiting
8
Q
What do you see histologically in Hirschsprung’s disease?
A
In the submucosa you will see large nerve trunks (to try and compensate for the absence of ganglion cells)
9
Q
How might coeliac disease present?
A
Great spectrum. Young children- failure to thrive, malabsorption, diarrhoea, abdominal distension. Older children- abdominal pain. Long term complications in adults- osteoporosis (due to malnourishment), intestinal T lymphoma
10
Q
Which antibodies might be raised in the blood in coeliac disease?
A
Anti-gliadin antibodies (AGA) and anti-tissue-transglutaminase antibodies (TGA).
11
Q
What features might you see histologically in coeliac disease?
A
Villous atrophy, increased intraepithelial lymphocytes, increased lamina propria inflammatory cells
12
Q
Which classification system is used for coeliac disease?
A
MARSH classification- provides a standard for coeliac disease histological classification and allows clinicians to understand the severity of disease
13
Q
Tell me the key facts about autosomal recessive polycystic kidney disease…
A
Most cases result in stillbirth or early neonatal death. It gives an abnormal kidney function in utero. The life-limiting problem is usually the immature lungs at birth. It is the most severe type of PKD. Associated with gene PKHD1 which encodes the protein fibrocystin
14
Q
Tell me briefly about adult polycystic kidney disease
A
It is autosomal dominant. It is the most common cystic renal disease. Responsible for 5-10% of chronic renal failure requiring dialysis. Cysts only involve a portion of nephron, so renal function is maintained until 40s-50s. Patients tend to present in 30s-50s.
15
Q
The perinatal autopsy involves external and internal examination, what is involved in the external examination?
A
Note: (often have translucent skin). Body weight, head circumference, crown heel and crown rump lengths, foot length, apparent gestation, maceration (aseptic decay in the mother before any formalin fixation- if baby born dead), dysmorphic features, other abnormalities, fractures of long bones and ribs e.g in osteogenesis imperfecta
16
Q
What is involved in the internal examination (perinatal autopsy)
A
Comment on cranial, thoracic and abdominal cavities. Systemic description of major organs and tissues. Weights of all major organs on digital balance. Comment on skeleton
17
Q
What are some of the perinatal autopsy special investigations?
A
X-ray: mandatory for suspected skeletal dysplasia and multiple malformations. Bacteriology, virology, karyotype if clinically indicated. Storage of fibroblasts/ frozen tissue/ DNA if clinically indicated. Biochemistry and haematology if clinically indicated
18
Q
What are the main causes of perinatal deaths?
A
Prematurity- the main cause of early neonatal deaths (62%)
Spontaneous preterm delivery and hypertensive disorders- most common obstetric events leading to perinatal deaths e.g. pre-eclampsia (29%). Death associated with foetal abnormalities (only 12%).
19
Q
What are the 5 most common chromosomal disorders in foetuses?
A
Trisomy 21 Trisomy 18 (Edward’s syndrome) Trisomy 13 (Patau’s syndrome) Triploidy Turners syndrome (45, XO)
20
Q
Of the 5 most common chromosomal disorders in foetuses, which 2 are the only viable ones?
A
Trisomy 21 and Turner’s syndrome
21
Q
Tell me about babies of diabetic mothers
A
Increased somatic size (macrosomia). Increased incidence of perinatal death. Prone to hypoxic complications during childbirth because they are bigger (leading to e.g. cerebral palsy), increased freq of malformation, baby may be producing insulin for the mother, so once they are born they are at risk of hypoglycaemia.
22
Q
What is often the autopsy finding in pre-eclampsia?
A
IUGR (intra-uterine growth restriction) and asymmetrical growth restriction. Clinically- maternal ugh BP and proteinuria
23
Q
What is foetal hydrops?
A
Generalised oedema of the foetus involving the lungs, abdomen and soft tissues. Many causes.
24
Q
What might be some findings in oligohydramnios (when there is hardly any fluid in the amniotic cavity)?
A
Wrinkled glove like skin and potter facies with triangular looking epicanthal folds
25
How might pre-eclampsia cause IUGR?
In the normal placenta you shouldn’t have any muscular wall in the feeding vessels, whereas in pre-eclampsia they stay muscularised and this can cause them to constrict, causing less continuous blood flow to the baby, causing the baby to have intermittent hypoxia and even continuous hypoxia.
26
What might you see in a placenta from a mum who had pre-eclampsia?
The spiral arteries of the placenta narrow because of the presence of abnormal smooth muscle, hence you could see the resulting fresh infarcts
27
What is acute chorioamnionitis?
Acute inflammation of the foetal membranes. Can cause stillbirth or usually pre-term delivery. Common after PROM. Ascending infection- the infection usually ascends from the cervix.
28
What are three developmental disorders of the skeleton?
Osteogenesis imperfecta, achondroplasia and osteopetrosis
29
Describe bone structure in simple terms
Cortex- compact bone consisting of a parallel arrangement of osteons.
Cancellous medullary bone composed of sponge like trabecular bone
30
Describe the structure of the growth plate
Well ordered columns of Chondroctyes in the growth plate hypertrophy as they pass towards the zone of bone formation. As the cells hypertrophy, they become calcified and these calcified cells are then converted to bone. Failure to calcify the chondrocytes leads to failure of bone growth
31
What type of ossification is primarily responsible for the growth in the length of bone?
Endochondral ossification
32
Tell me about achondroplasia
It is the most common developmental abnormality of bone, characterised by short limbs (all bones with endochondral ossification are affected). Trident hands. 75% of cases are sporadic, 25% are inherited as autosomal dominant trait (mutation in FGFR3).
33
Tell me about intramembranous ossification
In fibrous connective tissue, which occurs in the growth of flat bones such as the skull and ribs and also in appositional growth (growth in thickness) of the long bones
34
Tell me about endochondral ossification
In cartilage growth, which occurs at the epiphyseal growth plates at the ends of long bones, which results in lengthening of the bone. The growth plates are active throughout childhood and fuse ~16 years
35
Tell me the key facts about osteogenesis imperfecta
Aka. Brittle bones. Abnormality in the synthesis of type 1 collagen (about 90% of the organic matrix of bone). Extreme fragility of the skeleton as a result of defective organic matrix of the bone which leads to defective mineralisation. So the bone will bend and fracture in different areas. ‘Blue sclera sign’ - sign of the mild/moderate form. May also have developmental abnormalities of teeth/maxilla and mandible as well as symptoms affecting the auditory system.
36
Tell me the key facts about osteopetrosis
Defect in the osteoclastic arm of the ‘bone forming unit’. So patients will keep producing new bone but not resorting old bone, leads to a ‘cotton white appearance’ of the bone and cannot discriminate between cortex and cancellous bone (everything the same degree of radio-opacity). Little/no space left for bone marrow = disappearance of the marrow cavity and compromised haematopoiesis- pancytopenia, compensatory splenomegaly
37
Tell me some key facts about osteomyelitis
More common in children (in developing bones). This is because the susceptibility to acute osteomyelitis is related to the nature of the blood supply to the long bones.
38
Tell me some key facts about osteoporosis
Loss of bone MASS, but the bone is totally normal (i.e. mineralised as it should be etc). The cancellous bone mass is particularly reduced (typically found at the core of vertebral bones in the spine and at the ends of long bones and tends to bear most of the weight). Most important cause is post-menopausal osteoporosis.
39
Tell me some key facts about osteomalacia and rickets
Metabolic bone diseases caused by inadequate mineralisation of existing organic bone matrix, bones are therefore less calcified and are softer. Lack of activated vitamin D is the most common problem. Rickets in children and osteomalacia in adults.
40
What is the classical x-ray finding in osteomalacia?
Looser’s zones - they are microfractures which develop due to structural weakness at the sites of bone turnover
41
How is rickets and osteomalacia treated?
By providing active vitamin D with supplements (and calcium if necessary)
42
What name(s) is given to the bone disease resulting from the hyperparathyroid state on bone?
Osteitis fibrosa cystica or Von Recklinghausen’s disease of the bone (essentially ‘holes’ in the bone, scattered all over the skeleton).
43
Tell me briefly about Paget’s disease of bone
Moments of increased bone production and moment of increased bone resorption (essentially increased bone turnover). Increased skull size/ head circumference (patient’s may complain that their hat doesn’t fit). Histologically bone has a ‘mosaic’ pattern which is pathognomonic for Paget’s disease. Patients often have bone pain and may suffer from fractures, but it also puts them at increased risk of osteosarcomas. Unknown pathogenesis.
44
What is the most common type of bone tumour?
Metastasis
45
What are the (general) different types of primary bone tumour?
Haemopoietic (plasma cell tumours and leukaemia)
Mesenchymal origin (benign/ malignant tumours producing bone/ cartilage/ fibrous tissue)
Mononuclear/ macrophagic family (i.e. giant cell tumour)
46
What are the benign and malignant bone forming tumours of mesenchymal origin?
Benign- osteoid osteoma. Osteoblastoma. Both of these tumours can be extremely painful, but respond well to NSAIDs.
Malignant- osteosarcoma. In the elderly is more likely to be associated with previous Paget’s disease.
47
Tell me briefly about osteosarcomas
They tend to grow on the metaphysis and most commonly they are intramedullary- starting with the cancellous bone and then it can grow towards the periphery of the bone and start to erode to cortex and lift the periosteum. In fact there can be a periosteal reaction (intramembranous ossification underneath the periosteum) which can form the classic sunburst appearance seen on x-ray
48
What about the subtype of osteosarcoma called high-grade intramedullary osteosarcoma?
Typically occur in the teenage years with a peak ~15 yrs. they are particularly common around the knee. >50% of the tumours arising in the distal femur or the proximal tibia
49
Name some benign cartilage forming tumours
Enchondroma
| Osteochrondroma - chrondromyxoid fibroma and chondroblastoma
50
What is Ollier’s disease?
= multiple enchondromas (enchondromas are tumours within the bone in the medullary cavity). Remember the picture of the hands in my notes. The tumours deform and expand the bone and can turn malignant (i.e. form a chondrosarcoma).
51
What is the buzzword to remember with osteochondromas?
‘Mushroom like’ formations of bone, with an irregular cartilaginous cap of top
52
What is the name given to malignant tumours of cartilage?
Chondrosarcoma.
They are classified according to site. Can be very aggressive if they grow in the pelvis or shoulders where they have more space to grow internally. 15% arise from osteochondromas.
53
What are the primary immune system organs?
The thymus and bone marrow. Remember that the bone marrow is where the B-cells stay to mature, whereas the T-cells go to the thymus to mature
54
What happens once the B and T-cells are mature?
They exit the primary immune organs (thymus and bone marrow) and take up residence in the secondary immune organs in the body, which are areas of concentrated immune cells i.e. the lymph nodes, spleen, GI system (and other epithelial surfaces where they reside as extra-nodal lymphoid aggregates such as the Peyer’s patches and appendix).
55
Are most lymphomas B or T-cell ?
They are mostly B-cell lymphomas
56
Tell me briefly about immunoglobulin gene rearrangement in B-cells.
B lymphoblasts undergo rearrangement of the immunoglobulin gene (in the bone marrow) to increase the diversity of the immunoglobulins they produce. When they mature (after undergoing the immunoglobulin gene rearrangement) naive cells exit the bone marrow and enter the blood and secondary lymphoid organs where they express their immunoglobulin on their surface as a receptor (B-cell receptor).
57
How can we utilise the fact that immunoglobulin gene rearrangement should produce gene segments of different length in every cell in the normal polyclonal population?
Because we can look at the gene segments using PCR (doing clonality studies) and if the majority of the population in the lymphoid cell population have the same length of this gene, then it means it’s a clonal population and therefore a neoplasm/ lymphoma
58
Outline the process of B-cell activation in the lymph nodes
The B cells sit in the secondary B-lymphoid follicles as naive (meaning they haven’t encountered an antigen yet). When the B-cells get stimulated in the follicle (which is a process depends on T-cell help and is antigen dependent) the B-cells enter the germinal centre from the mantle zone (in the unstimulated form). In the germinal centre they undergo rapid proliferation (in dark zone and referred to as ‘centroblasts’. Then they go into the light zone where they undergo affinity maturation (referred to as ‘centrocytes’). They then exit the germinal centre as plasma cells or memory cells.
59
Where does the process previously described of B-cell activation and proliferation etc occur?
Usually happens in the lymph nodes, but there is extra nodal tissue in which this process can also occur. One of the largest extra-nodal lymphoid organs is the Peyer’s patches in the small bowel and they function in a similar way as the lymph node.
60
Which antibody type is the usually excreted one?
IgA
61
What is mucosa associated lymphoid tissue (MALT)?
The largest secondary lymphoid organ committed to local immunity. First and best described in the Peyer’s patches in the ileum.
62
What are the tertiary immune system (organs)?
The tertiary immune system is areas of the body where under normal circumstances there aren’t many immune cells, but if there is immune stimulation they can easily acquire lymphoid cells and almost become like extra-nodal lymphoid tissue. Typically, this may include the skin.
63
What is the usual presentation for T-cell acute lymphoblastic lymphoma?
They often present wit a mediastinal mass (they will usually get bone marrow involvement at some point), but it’s usually a mediastinal mass which is the first presenting site because the immature T-cells mature in the thymus.
64
Are the majority of malignant lymphomas nodal or extra-nodal?
The majority (60%) are nodal, with 40% being extranodal
65
Viruses can be a very important driving factor for many types of lymphoma, can you give some examples?
EBV- Burkitt lymphoma (EBV is associated with a proportion of Burkitt lymphomas, especially the endemic subtype and HIV-associated subtype). Also associated with Hodgkin lymphoma and post-transplant and AIDS-related lymphoma.
HTLV1- associated with T cell NHL (non-Hodgkin lymphoma).
Hepatitis C- associated with low grade B cell NHL
Human herpes virus 8 or Kaposi sarcoma virus- associated with plasma cell malignancy
66
At every stage of B-cell maturation and activation (described previously) you can get lymphomas which are sort of the counterpart of that normal stage. Give the examples.
Neoplasms of the precursor B-cells- gives rise to BLL (B-cell lymphoblastic leukaemia/ lymphoma) which is very aggressive.
When B-cells are in the naive stage before they enter the germinal centre- gives rise to mantle cell lymphoma.
From the germinal centre you can get very aggressive lymphomas, the most common being the DLBCL (diffuse large B-cell lymphoma) - composed of cells that look like cells from the germinal centre (e.g. centroblasts). But from the germinal centre can also get Hodgkin lymphoma, Burkitt lymphoma and follicular lymphoma.
After the germinal centre there are memory B-cells which give rise to marginal zone lymphomas and MALT lymphomas. The long-lived plasma cells give rise to plasma cell myeloma (which is a pure plasma cell neoplasm).
67
Are follicular lymphomas high/low grade?
They are lower grade/ more indolent and try to reproduce the normal architecture.
68
Which cellular marker do we look for to inform us about cellular proliferation with regards to lymphomas?
KI-67. Process called the KI-67 immunisation. It will highlight the nuclei of every cell that is actively dividing. Remember that how many lymphoma cells in a particular lymphoma are actually dividing can give us an indication of how aggressive it is (because in aggressive lymphomas almost all the cells will be dividing at the same time). So e.g. in follicular lymphoma which is more indolent there is low KI-67 staining.
69
In which condition might you see a classic ‘pepper-pot’ skull and why?
Plasma cell myeloma - they have got plasma cell deposits in the skull causing small lytic lesions throughout the skull
70
What name is given to the light chains of a myeloma which are excreted in the urine?
Bence jones protein
71
Tell me briefly about Hodgkin lymphoma
It is a very particular type of lymphoma. Bimodal age distinction (peak in children/young adults and a peak in the elderly). Characteristic clinical B symptoms (weight loss, fever, night sweats). Nodal disease (almost never arises from an extra-nodal site unless it is very advanced disease and has spread). Role of EBV virus in 35% of cases.
72
What are the malignant cells in Hodgkin lymphoma referred to?
Reed Sternberg cells. They are believed to be derived from the B-cells from the germinal centre. Typical morphology where the malignant cells only make up about 1-5% of the tumour (see in a background of inflammatory infiltrate).
73
Hodgkin lymphoma typically causes a very nodular appearance of the lymph node where you get lots of pale nodules, what are these described as?
Fish flesh appearance
74
What do Reed Sternberg cells look like?
Very large binucleate cells with prominent nucleoli (which make them look like owl eyes). They can be single nuclei as well, or multiple nuclei. (Note that when they are single nucleate we call then Hodgkin cells).
75
There are various diagnostic methods for diagnosing lymphoma including morphology, immunohistochemistry, flow cytometry and molecular techniques such as PCR and FISH. Which is the most important diagnostic method?
Morphology (actually looking at the cells) as looking at the tumour under the microscope is then what determines all the subsequent investigations
76
What is the most important stain/marker used to determine whether the lymphoma is a B-cell lymphoma?
CD20 (it is a surface antigen of the B-cells)
77
What chromosomal translocation is seen in Burkitt’s lymphoma?
T(8,14)
78
What method might we use to look at whether the chromosomes are translocated or not?
FISH
79
What are the layers of the GI tract?
Mucosa: epithelium, lamina propria, muscularis mucosa
Submucosa
Muscularis propria- circular muscle and longitudinal muscle
Serosa/ adventitia
80
What is the distance between the top front incisors and the GOJ (gastro-oesophageal junction)?
40cm (and the length of the oesophagus is fairly equal between different people of different heights- this measurement is useful to know especially when you are mapping out Barrett’s).
81
What is the histological lining of the oesophagus?
Non-keratinised stratified squamous epithelium
82
Give some of the risk factors for reflux oesophagitis
Hiatus hernia, peptic ulcer, smoking and alcohol, excessive vomiting, pregnancy, diabetes, surgery of/around GOJ
83
What is the histological trio that forms the hallmark of reflux oesophagitis?
Basal hyperplasia
Increased numbers of lymphocytes and eosinophils in the epithelium
Vascular papillae (bits of stroma that stick upwards into the squamous epithelium).
84
What are the complications of reflux oesophagitis?
Stricture (due to the chronic inflammation and fibrosis)- causing dysphagia
Barrett’s oesophagus
Neoplasia (Barrett’s predisposes to neoplasia)
85
Tell me about eosinophilic oesophagitis
Aetiology unknown. ? An allergic reaction. Presence of eosinophils. Classic presentation of dysphasia with a normal looking oesophagus at OGD or sometimes it may have a corrugation or ‘feline’ appearance. Biopsy look for: lots of eosinophils (clusters of eosinophils can be called eosinophilic ‘micro-abscesses’, the eosinophils start to degranulate, and you also get basal hyperplasia. Treatment is steroid based
86
What is achlasia
It is a rare condition of unknown aetiology (?autoimmune). You get targeted inflammatory destruction of the myenteric ganglion cells. (they are neural structures which regulate peristalsis in the oesophagus). Tends to affect the lower oesophagus and you tend to get a lack of relaxation (essentially a stricture formation).
87
What is a complication of achalasia and what is the implication of this?
Because you get a build up of content within the squamous epithelium-lined oesophagus (and the oesophagus doesn’t like chemical insult) it becomes inflamed, so long term complication is squamous cell carcinoma. Therefore patients with known achalasia get surveillance endoscopies.
88
Name the infections of the oesophagus (in order of commonality if possible)
Candida
Herpes simplex virus
Trypanosomiasis
(Candida and herpes are linked to immunosuppression)
89
Tell me briefly about Candida infection of the oesophagus
Looks like cottage cheese lining the inside of the oesophagus
Histologically you get spores and so-called pseudohyphae
The patient is treated with anti-fungals
90
Tell me briefly about herpes simplex virus (HSV) infection of the oesophagus
Because herpes is a virus, you don’t see it down the microscope, you see changes to the nucleus (cytopathic changes) of the cells which include: multinucleation and nuclear inclusion. Once this is suspected, can use an immunostain which should light up and confirm the diagnosis.
91
What type of people do you see HSV oesophagitis in?
Immunosuppressed individuals (people don’t get HSV oesophagitis unless they are immunosuppressed).
92
Tell me about Chagas disease.
It is rare, caused by the parasite Trypansoma cruzi. Transmitted in the faeces of ‘blood sucking’ reduviid bug via its bite. The parasite likes muscle (cardiac muscle)- causing cardiomyopathy. It also likes smooth muscle of the GI tract and you can get benign strictures forming e.g. of the oesophagus, so its a form of achalasia known as pseudo-achalasia.
93
Tell me about Barrett’s oesophagus
Definition: metaplastic replacement of oesophageal lining by glandular mucosa (columnar epithelium). Aetiology: reflux of gastric (acid) and duodenal (bile) contents into the oesophagus. Endoscopically squamous epithelium is white and glandular mucosa looks pink/red (projecting out in star like shape)
94
What is the length of Barrett’s (hint: not looking for a value)
The distance between the SCJ and the GOJ
SCJ = squamocolumnar junction - junction between the normal squamous epithelium and abnormal columnar epithelium
GOJ = gastrooesophageal junction
In most people the SCJ is at the same level as the GOJ (because it is where the stomach starts)
95
What type of Barrett’s is most likely to turn into a neoplasia? Options are: gastric cardia, gastric body, pancreatic and intestinal. (Note, this is how we subdivide the epithelium histologically)
Intestinal
96
What are the two types of oesophageal carcinoma and which is more common?
Adenocarcinoma (80%) and squamous cell carcinoma (20%)
97
Does the cardia have any specialised glands? Where does? What can this tell you?
The cardia has similar mucosa to the antrum and the pylorus (there are no specialised glands). The specialised glands are only present in the body and the fundus, so it is possible to tell roughly where a gastric biopsy has been taken (in relation to the stomach) when looking at the biopsy histology.
98
Tell me about chemical/ reactive gastritis.
It is now the commonest form of ‘chronic’ gastritis. Bile reflux, drugs- aspirin and other NSAIDs, alcohol. Histologically we look for: foveolar hyperplasia (foveal cell hyperplasia) and lamina propria changes - look for oedema and dilated blood vessels. Tx- remove the insult causing it.
99
Tell me briefly about autoimmune/ atrophic gastritis
E.g. pernicious anaemia. Typically Caucasian older women who get autoimmune gastritis. You get destruction of the body mucosa, and whenever the stomach destroys its mucosa (which normally produces acid) you get a condition called achlorhydria, where you lose the acidic environment in the stomach and you replace the lost mucosa with intestinal mucosa (intestinal metaplasia) and this can turn neoplastic.
100
What are the diseases called by H.pylori?
Gastritis (reddening of the gastric epithelium with some erosions which appear white)
Ulcer
MALT lymphoma
Carcinoma
101
What are foveolar cells?
Also known as surface mucous cells, they are mucus-producing cells
102
How is H.pylori considered protective against Barrett’s?
As helicobacter becomes pangastric it destroys acid production (so you get achlorhydria) and as Barrett’s is caused by reflux of acid, it has been said that helicobacter causing achlorhydria therefore protects against Barrett’s.
103
Tell me about MALT lymphoma caused by H.pylori
Lymphoid aggregates form due to H.pylori and if lymphocytes are stimulated enough times to proliferate, there is always the risk of lymphoma (remember that all chronic inflammatory conditions potentially can predispose to lymphoma). H.pylori can therefore predispose to MALT lymphoma. Many of these lymphomas can be treated effectively with antibiotics (because you knock out H.pylori which reduces the drive for lymphocytes to proliferate) and in most cases this cures the MALT lymphoma.
104
How can H.pylori cause carcinoma?
Helicobacter causes superficial gastritis, followed by atrophic gastritis (causing achlorhydria), so you then get intestinal metaplasia and this can predispose to dysplasia, which can evolve into carcinoma. Helicobacter tends to colonise the distal stomach first, so most cancers which develop in H.pylori infected patients tend to occur distally.
105
Name the various gastric neoplasia’s
Adenocarcinoma
Lymphoma
Neuro-endocrine tumour
GIST (gastrointestinal stromal tumour)
106
Tell me about adenocarcinoma of the stomach
Particularly common in Japan, Korea and Chile. M:F= 3:1 Risk factors: diet (high salt, low diary products) and helicobacter and intestinal metaplasia. We can subdivide into: intestinal-type carcinomas or diffuse-type carcinomas. Diffuse-type carcinomas of the stomach rarely express HER-2, whereas one third of intestinal-type gastric cancers express HER-2. Herceptin (transtuzumab) is licensed for use in advanced gastric cancer.
107
Tell me about GIST
Gastrointestinal stromal tumour. Rare. Stomach > small intestine > oesophagus and large bowel. Mutations in tyrosine kinase genes. Management is therefore surgery +/- TKI (tyrosine kinase inhibitors) e.g. imatinib. Patients are genotyped to look for GIST mutations
108
What is the mucosa of the small intestine? (Histological lining)
Lined by simple columnar epithelium. Presence of villi and crypts
109
Tell me about coeliac disease (histopathology)
May see flat mucosa if really severe. Reduction in the normal villus height to crypt depth ratio from 5:1 to <3:1. (So the villus should normally be >3 times as tall as the crypt length, and any reduction is called villus atrophy/blunting). Also see: crypt hyperplasia, increased intraepithelial lymphocytes, infiltration of the lamina propria by plasma cells and lymphocytes
110
What are some of the complications of coeliac disease?
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Refractory sprue (non-responsive to gluten restriction)- can be due to the lymphocytes causing coeliac disease becoming clonal i.e. constant stimulation even though gluten has been withdrawn.
Ulcerative jejunitis (usually a sign the patient is starting to develop lymphoma. Neoplasia: enteropathy-associated T-cell lymphoma (EATL) and small intestinal adenocarcinoma.
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111
Tell me about giardiasis in relation to the intestine.
Giardia lamblia. Commonest small intestine protozoal infection worldwide (but rare in the UK). Contaminated water (person to person) spread by faecal-oral transmission. Immunocompromised patients more likely to be infected. Histology: small intestinal mucosa may be normal or inflamed. Giardia organisms histologically can look like small flecks.
112
What are the types of small intestine neoplasia?
Adenomas- duodenal (FAP)- adenomas are the most common type of neoplasia in the large bowel but they are very rare in the small bowel (so if adenomas are found in the small bowel you start to wonder whether the patient might have FAP which is a genetic condition caused by an APC gene mutation).
Adenocarcinoma- rare so consider predisposing factors: coeliac disease, Crohn’s disease, FAP
Lymphoma- B-cell lymphoma (e.g. Burkitt’s lymphoma in ileum). T-cell lymphomas e.g. EATL.
GIST
Neuroendocrine tumours
113
Tell me about (neuro)endocrine tumours
Most common in the appendix and small intestine. Used to call the entities in the gut ‘carcinoids’. Typically, NETs of the small bowel are very small, but can give rise to big metastases in the mesentery and the liver.
114
What is the commonest cause of hypothyroidism?
Hashimoto’s thyroiditis. (Atrophic process)
115
Tell me more about Hashimoto’s thyroiditis
Autoimmune: anti-thyroid peroxidase antibodies (anti-TPO).
Lymphocytic destruction of the thyroid (aka. Chronic lymphocytic thyroiditis).
F:M = 10:1.
116
Other than Hashimoto’s what are the causes of hypothyroidism?
Removal of the thyroid, radioiodine treatment (iatrogenic causes)
117
What are the clinical signs and symptoms of hypothyroidism?
Myxoedema (the clinical syndrome of under active thyroid):
| Weight gain, constipation, cold intolerance, tiredness, depression, thin hair, weak heartbeat, slow reflexes
118
What neoplasm is someone with Hashimoto’s thyroiditis prone to?
Lymphoma (thyroid lymphoma)- because they have got a chronic, proliferative and destructive lymphoid infiltrate occurring in the thyroid
119
What is the most common cause of hyperthyroidism?
Grave’s disease (85% of cases)
120
Other than Grave’s disease, what can cause hyperthyroidism?
```
Hyperfunctional MNG (multinodular goitre)
Hyperfunctional adenoma (benign follicular tumour)
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121
What are some of the symptoms of hyperthyroidism?
Sweating, heat intolerance, weight loss despite increased appetite, diarrhoea, tachycardia, arrhythmia (often AF), tremor, anxiety, hyperactivity, brisk reflexes. Exophthalmos (in Grave’s)
122
Tell me about Grave’s disease
F:M = 10:1
Autoimmune
Thyroid stimulating antibodies (TSH receptor autoantibodies)
Symmetrical enlargement of the thyroid (diffuse toxic goitre)
Exophthalmos- deposition of connective tissue behind the eyeball, causing the eye to protrude.
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Tell me about multi-nodular goitre (MNG)
Usually euthyroid. We don’t really understand why it occurs. Large goitre may cause tracheal compression or dysphagia.
124
Tell me about follicular adenomas of the thyroid
Benign tumour, usually euthyroid. Rarely hyperfunctional (‘toxic’ nodule). Tx: thyroid lobectomy
125
What are the 4 types of carcinoma of the thyroid?
Papillary (most common)
Follicular
Anaplastic
Medullary
126
Which of the thyroid carcinomas have a good prognosis and which have a bad prognosis?
Papillary and follicular carcinomas have a very good prognosis and are well differentiated. Anaplastic and medullary carcinomas have a very poor prognosis and are poorly differentiated.
127
For all of the thyroid carcinomas, where do they originate and is there an implication for a tumour marker?
Papillary, follicular and anaplastic carcinomas all come from the follicular epithelium. However, medullary thyroid carcinomas come from the parafollicular cells (called C-cells). Remember that C-cells secrete calcitonin so can measure this in the blood as a tumour marker
128
How do papillary vs follicular thyroid carcinomas like to spread?
Papillary carcinoma of the thyroid —> spread by lymphatics
| Follicular carcinoma of the thyroid —> spread by blood, often to the bone
129
What diagnostic tests are there for thyroid pathology?
Hyper/hypothyroidism - thyroid function tests, autoantibodies.
Thyroid enlargement/ nodules - ultrasound
Thyroid nodules - FNA cytology, excision if indicated: thyroid lobectomy or total thyroidectomy - for histology
130
Quick question- how many parathyroid glands are there?
4. = 2 sit near the inferior pole on either side and 2 sit near the superior pole on either side
131
Is PTH secreted in response to low or high calcium levels?
In response to low serum calcium levels
132
What is the most common cause of an under active parathyroid gland?
Accidental surgical damage (e.g. in thyroid surgery)
133
What is Chvostek sign?
A clinical sign of nerve hyper-excitability (tetany) seen in hypocalcaemia. It refers to an abnormal reaction to the stimulation of the facial nerve.
134
Primary hyperparathyroidism can be due to adenoma, hyperplasia and carcinoma. With adenoma and hyperplasia how many glands are affected and which is more common?
Adenoma is the most common cause (85-95% of cases) which affects 1 of the 4 glands. Hyperplasia (5-15% of cases) affects all 4 glands.
135
What are the symptoms of hypercalcaemia?
Painful bones, renal stones, abdominal groans and psychiatric moans
136
What are the causes of secondary hyperparathyroidism? Indicate which is the most common.
Chronic renal failure is the most common cause.
Less common causes: vitamin D or calcium deficiency, malabsorption, low serum magnesium, tissue resistance to vitamin D, pseudohypoparathyroidism (genetic resistance to PTH)
137
What is produced in the adrenal cortex and the adrenal medulla?
Adrenal cortex produces 3 types of steroids:
Glucocorticoids: mainly cortisol. Mineralocorticoids: mainly aldosterone. Sex steroids: oestrogen’s and androgens.
Adrenal medulla produces catecholamines: mainly adrenaline
138
Tell me about Addison’s disease
Primary adrenocortical insufficiency. Autoimmune destruction (main cause). Small print causes include: tuberculosis, removal (of adrenal glands), metastatic cancer, AIDS, congenital hypoplasia
139
What are the causes of secondary adrenocortical insufficiency?
Disorders of the hypothalamus or pituitary- reduced output of ACHT
Treatment with steroids long term
140
What are the symptoms of an under active adrenal cortex (Addison’s disease). Note: the symptoms are due to low levels of glucocorticoids and mineralocorticoids.
Weakness, tiredness, GI disturbance, nausea, vomiting, weight loss, diarrhoea, hyperpigmentation of skin, potassium retention and sodium loss (hypotension).
141
What is an acute adrenal crisis with respect to Addison’s disease?
Precipitated by infection, trauma or surgical procedures. Causes vomiting, abdominal pain, hypotension and coma. Rapidly fatal unless treated promptly with corticosteroids.
142
What are the clinical features of an overactive adrenal cortex (Cushing’s syndrome)?
Central obesity, abdominal striae, moon facies, thin skin, easy bruising, hypertension, glucose intolerance.
143
What is the most common cause of Cushing’s syndrome? (Note the use of the word SYNDROME)
Most commonly iatrogenic due to glucocorticoid administration
144
What is Cushing’s disease?
A pituitary adenoma causing ACTH-dependent excess cortisol
145
Briefly describe the embryogenesis of the genital tract in males and females
Up until about the 6th week of embryogenesis the genital tract is at an indifferent stage. In male embryo with XY the production of anti-mullerian hormone results in proliferation of the Wolffian duct (aka. The mesonephric duct). In females with XX the Müllerian duct develops (aka. The paramesonephric duct).
146
What is the most important neoplasia of the uterine cervix that we are trying to avoid?
Squamous cell carcinoma
147
What is the purpose of the cervical screening programme?
To try and detect pre-malignant changes
148
Briefly describe the uterine cervix histology (in terms of transformation zone etc).
At birth the non-keratinising stratified squamous epithelium of the vagina also lines the part of the cervix which is exposed to the vagina, and then within the external os of the cervix the lining changes from a stratified squamous to a single layer of columnar lining (squamous-columnar junction). At around puberty under the influence of sex hormones, the size and shape of the cervix changes- it bulges out such that tissue that is covered by the columnar epithelium becomes exposed to the acidic environment of the vagina and as a protective mechanism (metaplastic phenomenon) you then get squamous epithelium growing over the exposed columnar lined tissue. The area that was once columnar epithelium but is now squamous epithelium is called the transformation zone. It is in this transformation zone that one can get dysplastic or pre-malignant changes and with regards to the cervix it is most likely due to HPV infection.
149
What are the characteristic low risk and high risk HPV subtypes that affect the female genital tract?
Low risk = HPV 6 and 11 - cause warts
| High risk = HPV 16 and 18- more likely to cause pre-malignant and malignant changes.
150
High risk HPVs produce a number of viral-derived proteins, what are these and what tumour suppressor genes do they interact with?
E6 and E7.
E6 has an effect on the p53 tumour suppressor gene and E7 interacts with the function of the retinoblastoma tumour suppressor gene.
151
Tell me more about HPV infection
If the virus isn’t cleared this can cause increased proliferation and the epithelium can then become dysplastic (graded 1-3: mild, moderate and severe dysplasia/ dyskaryosis)- and this is also known as cervical intra-epithelial neoplasia. CIN 3 is where severe dysplasia is synonymous to carcinoma-in-situ. If these atypical cells breach the basement membrane then this is when it is called squamous cell carcinoma.
152
What are the epithelial cells called when they have been infected with HPV and what do they look like?
The cells are known as Koilocyte’s. When cells have become infected with HPV you get: nuclear enlargement, nuclei pleomorphism and a characteristic perinuclear halo.
153
What is involved in the NHS cervical screening programme?
For women aged 25-64 years. The screening starts off with a cervical smear- we can look for abnormal changes (and when it comes to cytology we talk about dyskaryosis (as this is what the smear is - cells that have been exfoliated off the surface). Contrast this to the term dysplasia used in histology (biopsies). Broadly speaking the degree of dyskaryosis (mild, moderate or severe) would equate to mild, moderate and severe dysplasia. With the smear test they can also do PCR for high and low risk HPV.
154
In the context of cervical smears, what is meant by CIN 1, 2 and 3?
In CIN 1 there are abnormal cells (predominantly in the lower third) but there is still good maturation towards the surface.
In CIN 2 about 2/3rds of the surface is occupied by abnormal cells and in CIN 3 more or less the entire thickness of the squamous epithelium is occupied by abnormal cells
155
What is the other carcinoma you can get of the cervix? (Other than squamous cell)?
You can also get adenocarcinoma of the cervix (the deeper part of the cervix towards the body of the uterus is lined by columnar glandular type epithelium, and this too under the influence of HPV can become malignant).
156
What is adenomyositis?
The uterine cavity is lined by endometrium and then the bulk of the uterine wall is myometrium which is smooth muscle. In adenomyositis you can get islands of endometrial tissue embedded deep within the myometrial tissue.
157
What are the symptoms/signs of adenomyositis?
Slight discomfort in the pelvis, a slightly uniformly enlarged uterus and cyclical pain related to the menstraul period- this is due to these islands of endometrial tissue within the myometrium causing hypertrophy of the small muscle cells in the immediate vicinity.
158
Tell me about endometriosis
When the endometrial tissue is outside the uterus, usually affects pelvic organs but very occasionally can be further away from the pelvic organs such as above the diaphragm is involve the pleura/lungs (but quite unusual). The common sites are the ovaries, peritoneal lining of the pelvic side wall, uterus ligaments and Fallopian tubes. These areas respond to hormones in the same way as the normal endometrial lining of the uterus, so they will expand in the proliferative phase of the menstraul cycle and then shed at the end of the secretory phase.
159
What is the buzz word/ what might you classically see in endometriosis?
A ‘chocolate cyst’- the breakdown products of blood can appear like a chocolatey material (esp. in the ovaries where it often forms in cystic areas). Most chocolate cysts are the cause of endometrioma.
160
What type of cancer may endometriosis predispose to?
An increased risk of ovarian cancer (endometrioid carcinoma of the ovary).
161
What is the most common type of uterine cancer?
Adenocarcinoma (derived from the glands which comprise the endometrium).
162
What is a key sign of potential endometrial carcinoma of the uterus?
Post menopausal bleeding
163
What are the risk factors for developing endometrial carcinoma? (Tell me about the two types)
Two types of endometrial carcinoma: one type is associated with oestrogen excess and there is another group of patients who get a different type of endometrial carcinoma- they are usually much more elderly patients with a background of atrophic endometrium.
Risk factors: obesity, nulliparous with non-ovulatory cycles, diabetes, hypertension, infertility.
164
What is the staging system for endometrial carcinomas?
FIGO staging.
Stage I = confined to corpus uteri (uterine body)
Stage II = invading cervix, not beyond uterus
Stage III = beyond uterus, not beyond true pelvis
Stage IV = beyond true pelvis +/- bladder +/- rectum
165
What is a uterine fibroid?
Fibroid (leiomyoma)
The most common tumour of the uterus is a benign tumour (leiomyoma- benign smooth muscle tumour) colloquially known as a ‘fibroid’.
166
What do fibroids/ leiomyoma’s look like?
Characteristic fairly firm, cream coloured surface.
They can be subdivided into their anatomical location within the body of the uterus: subserosal, intramural or submucosal.
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Tell me about ectopic pregnancy
1% of all pregnancies (90% in Fallopian tubes)
But also: ovaries, abdominal cavity and uterine section of oviducts. Risk of rupture and fatal haemorrhage in Fallopian tube implantation. Aetiology: (abnormal anatomy of Fallopian tubes e.g. scarring or fibrosis)- could be due to: previous surgery, chronic scalpingitis/ PID (could be due to chlamydia).
168
Are more ovarian tumours primary or metastases?
Only ~5% are metastasis. Most tumours of the ovary are primary
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In relation to ovarian tumours, what is a Krukenberg tumour?
Metastasis to the ovary from a signet ring cell carcinoma (particularly of the stomach) by transcoelomic spread (along the peritoneal cavity)
170
Which layers can ovarian tumours be derived from?
Can be derived from the surface epithelium of the ovary, from the germ cells which reside within the ovary, or from the stromal cells which make up the rest of the cells in the ovary.
171
What is the most common germ cell tumour and in women is this type of tumour more commonly malignant or benign?
A teratoma is the most common kind, and most teratomas in females are benign
172
From which layer are the vast majority of ovarian tumours derived?
Surface epithelial cell tumours
173
Which age range do germ cell tumours of the ovary tend to affect?
0-25 year olds
174
Tell me about Crohn’s disease
Tends to be a disease of Caucasian populations. Maximal incidence in young adults is 15-30 years but there is a second smaller peak in the age of diagnosis at around 50 years. Any portion of the GI tract can be affected. At presentation most common sites of involvement: terminal ileum, ileocaecal valve and caecum. Discontinuous or ‘skip’ lessons on colonoscopy or barium studies are characteristic
175
What is the pathology of Crohn’s disease on macroscopic examination?
Central part of bowel thickened and rubbery looking.
‘Cobblestone’ appearance
Ulcer on mucosal surface- starts off superficial but as disease advances can deepen, causing crevices into the deeper smooth muscle layer of the bowel wall- very often these ulcers can both be transverse across the width of the bowel and also linear along the length of the bowel.
Very often you get hypertrophy of the smooth muscle and fibrosis in the submucosa which can contribute to narrowing of the lumen and stricture formation. Another tell-tale sign of Crohn’s disease is mesenteric fat wrapping
176
Summarise the histopathology of Crohn’s disease
Transmural inflammation
Non-necrotising granulomas (in UC these are extremely uncommon)
Crypt abscesses
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What are the complications of Crohn’s disease?
Inflammatory disease (perianal fistulas and abscesses)
Malabsorption (generalised but particularly vitamin B12 and bile salts)
Small bowel adenocarcinoma
Bowel perforation is not common
Adhesions can potentially cause intestinal obstruction
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What is the treatment for Crohn’s disease?
5-ASA aka. Mesalazine (an anti-inflammatory drug)
Steroids
Immunosuppressive agents
Monoclonal antibodies against TNF alpha (e.g. Infliximab)
Surgery (sometimes the only option for fibrosing strictures)
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What are the macroscopic features of UC?
One area of ulceration, starts in the rectum and progresses from distal to proximal. Sometimes you can get ‘backwash ileitis’ but its quite uncommon so generally UC is just a disease of the colon. Usually a large area of ulceration and can get some surviving areas of non-ulcerated mucosa WITHIN IT which form pseudo polyps. Mucosal surface can become atrophic (you lose the normal mucosal fold arrangement)
180
What are the histological features of UC?
Crypt abscesses. Crypt architectural distortion. A large number of mixed inflammatory cells in the mucosa/ lamina propria
181
Tell me about toxic megacolon as a complication of UC
Sometimes the inflammatory cells and mediators can cause paralysis of the motor function of the muscularis propria so that it is not able to undergo peristalsis anymore. This causes the bowel to dilate and the bowel wall gets thinner and thinner and more fragile. Characterised by: high fever, tachycardia, diarrhoea
182
What are the other complications of UC?
Perforation, massive haemorrhage, colon cancer (correlation with colonic involvement and duration of disease)
183
What are the treatments for UC?
5-ASA
Steroids
Immunosuppressive drugs
Surgery
184
Tell me about inflammatory pseudopolyps
Seen in UC and Crohn’s disease
Macroscopically can look like adenomas (so they tend to be biopsied)
Microscopically: inflammatory tissue, hyperplastic mucosa
185
Tell me about hamartomatous polyps (examples)
Juvenile polyps: most common paediatric GI polyps
| Peutz-Jegher’s: GI polyps, pigementation of oral mucosa, lips, palms genitalia
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Tell me more about juvenile polyps
A type of hamartomatous polyp. Can either occur sporadically or as part of juvenile polyposis syndrome. In juvenile polyposis syndrome SMAD4 is the most common mutation.
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Tell me about peutz jegher’s polyps
Seen in Peutz-Jegher’s syndrome
Autosomal dominant
Loss of function mutations in the STK11 gene is the most common genetic abnormality. Occur throughout the GI tract- small bowel more common than large bowel. Potential colon cancers can occur with these polyps- people with this syndrome also have increased risk of malignancy elsewhere in the body.
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Tell me about adenomas as a type of neoplastic polyp
Glandular epithelial tumours. All are dysplastic, dysregulated proliferation, failure to fully differentiate, pre-malignant.
Classified into: tubular, tubulovillous and villous
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What is the most common type of polyp in the GI tract?
Hyperplastic !!!
They are benign with no malignant potential unless they are mixed (hyperplastic-adenomatous polyps). Should be biopsied anyway to check
190
What is important to remember about flat/depressed adenoms
They have a high malignant potential (even if small). Associated with familial colon cancer syndromes (HNPCC or FAP)
191
What is the malignant potential of adenoms proportional to?
Villosity
Size
Degree of dysplasia
192
What is a leiomyoma (in terms of bowel polyps)
Benign smooth muscle tumour. In the bowel this is usually derived from the smooth muscle which makes up the muscularis mucosae.
193
What is the histological type of most colon cancers?
Almost all malignant tumours of the large bowel are carcinomas i.e. malignant tumours of epithelial origin, and strictly speaking they are adenocarcinomas because they are derived from glandular-type epithelium. The exception is carcinomas of the anal canal- part of the anal canal is lined by stratified squamous epithelium (so a malignant of this would be a squamous cell carcinoma)
194
What is the typical macroscopic appearance of a colon cancer?
Ulcerated lesion which has a raised, rolled edge
195
What do you see on biopsy of a colon cancer? And when do we call it a carcinoma?
Abnormal glandular shaped structures invading at least into the submucosa, possibly even deeper (so once something has invaded into the submucosa, that’s when we call it a carcinoma)
196
Where are the majority of colon cancers located?
Right colon 25%
Left colon 15%
Rectosigmoid 50% (relative stasis of bowel contents)
197
What are the characteristics of colon cancer in the right and left sides respectively?
Right side: polyposis (resembles a polyp), mass, discomfort/ anaemia, anaemia from chronic blood loss but blood not recognisable in the stool because has been digested and mixed in/ not recognised as blood.
Left side: annular (ring shaped), obstructing, bleeding/ mucus, colicky pain, change of bowel habit
198
What are the risk factors for colon cancer?
Westernised diet and lifestyle
Reduced stool bulk (low in fibre)
Increased fat intake
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Where is the most common site for metastasis of colon cancer?
The liver
200
What are the complications of colorectal carcinoma?
Obstruction, perforation, bleeding, pericolic abscess, fistulae, intussception (where a segment of bowel invaginates into the adjoining bowel lumen, causing bowel obstruction).
201
Reminder: what is the difference between grading and staging?
Grading refers to how well differentiated a tumour is (histologically), whereas staging refers to how far it has spread
202
What staging system can be used for colorectal carcinoma?
DUKES
203
Tell me about DUKES staging system for colorectal carcinoma
Dukes A- the cancer has spread into the tissues of the bowel wall, but not all the way through the muscularis propria.
Dukes B- the tumour has spread all the way through the muscularis propria in the fat.
Dukes C1- indicates the presence of large bowel tumour in lymph nodes whatever degree of penetration through the bowel wall
Dukes C2- as in dukes C1, with involvement of the apical node (when the highest node is positive for metastasis).
Dukes D- distant metastatic spread
204
Tell me about HNPCC
Also known as Lynch syndrome. Autosomal dominant. Carcinoma develops in younger. Right sided tumours. Multiple tumours of colorectum (may also develop cancer elsewhere in body e.g. endometrial). Abnormalities in 4 mismatch repair genes
205
What is the criteria called which is used to identify HNPCC?
Amsterdam criteria:
3 or more family members with colorectal cancer, at least 2 of which must be first degree relatives
The disease affects family members from at least two successive generations
One of the colorectal cancers must occur <50
FAP excluded
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Tell me about FAP
Relatively rare. Without intervention, virtually all people with this condition develop colon cancer. Characterised by multiple polyps throughout the entire colon (up to thousands). Polyps not present at birth but develop over time (patient is born with abnormal APC gene)
207
Measurement of what in blood can be useful when you’re monitoring a patient who’s had colon cancer?
CEA = cardioembryogenic antigen
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What is the gold standard way to diagnose colon cancer?
Cellular pathology
209
How does terminology in histopathology of the liver differ?
Often in histopathology we split things into malignant vs benign, however in the liver we split them into neoplastic (which includes malignant and benign lesions) vs medical
210
What are the benign liver diseases I need to know about?
Haemangioma
Liver cell adenoma (which can also be called hepatocellular adenoma)
Bile duct malformations
Focal nodular hyperplasia
211
What are the malignant liver diseases I need to know about?
Hepatocellular carcinoma (HCC)
Cholangiocarcinoma
Metastases
212
What is the most common primary hepatic tumour seen in the liver?
Haemangioma
213
Tell me more about haemangioma
Benign. A neoplastic proliferation of blood vessels (made up of a tangle of blood vessels). You look for lots of vascular channels which are packed quite closely together within the normal liver parenchyma. Usually an incidental finding. F>M. No known risk for malignant transformation. May (rarely) rupture and cause a large intra-abdominal bleed which is why large haemangioma may be removed despite there being no risk of malignant transformation.
214
Tell me about liver cell adenoma (aka. Hepatocellular adenoma)
Arises in normal liver (so doesn’t tend to occur in cirrhosis, so the background liver will look normal). 95% occur in women. Associated with oral contraceptive use (i.e. oestrogen). May contain HCC within them- sample the nodule well to exclude malignancy. Different subtypes- inflammatory, steatotic, beta-catenin activation and unclassified
215
Tell me about bile duct malformations
Common incidental finding, always benign. Not a tumour but can lead to bile duct adenoma. No clinical significance. Bile duct hamartoma vs bile duct adenoma. Hamartomas tend to have big dilated ducts, whereas adenomas tend to have lots of small ducts with smaller lumens who are closely compacted together. Normal round bile ducts become jagged and forked.
216
Tell me about focal nodular hyperplasia
Common benign mass, indolent course. No malignant transformation. Incidental. Macroscopically: CENTRAL SCAR - this is reassuring as you wouldn’t get a scar in a HCC for example
217
What is the most common primary MALIGNANT tumour of the liver?
Hepatocellular carcinoma (HCC)
218
What may HCC cause a massive rise in? (think of markers)
AFP (alpha fetoprotein)
219
What is the histology of HCC?
Trabeculae thickening
Nuclear pleomorphism of cells
Prominent cell nucleoli and mitotic figures
BILE PIGMENT is a classic feature which occurs in HCC (HCC is the only tumour which makes bile)
220
Tell me about fibrolamellar HCC as a subtype of HCC
Occurs in younger people, better prognosis. No underlying chronic liver disease. So often in regular HCC the background liver will be cirrhotic, whereas in fibrolamellar HCC the background liver looks normal. The other feature of fibrolamellar HCC is that you get large bands of fibrosis traversing through the tumour which is a classic feature. Collagen deposition may appear blue when stained.
221
Key point: what is the classic feature of fibrolamellar HCC?
Large bands of fibrosis traversing through the tumour
222
Tell me about cholangiocarcinoma
Adenocarcinoma arising from bile duct epithelial cells. Diagnosis of exclusion (rule out metastases)- there isn’t a specific immunohistochemical stain. Associated with PSC (primary sclerosis growth cholangitis). Poor prognosis.
223
What is the classic feature of metastatic liver disease?
Central necrosis (nodules outgrow blood supply)
224
What is the most common tumour in the liver?
Metastases
225
What are the most common primary sites for liver metastases?
Colon, breast, lung, pancreas
226
What are the medical liver diseases I need to know about?
Viral hepatitis, alcoholic/ non-alcoholic fatty liver disease, autoimmune hepatitis, chronic biliary disease (PBC, PSC), drug induced liver injury and inherited disorders (Wilson’s, haemochromatosis and alpha-1 anti-trypsin deficiency)
227
What do you classically see in viral hepatitis?
Infiltration of lymphocytes into the portal tract
228
Key points about hepatitis A
No carrier state. Faecal-oral transmission. Variable progression
229
Tell me the key facts about hepatitis B
Transmission via bodily fluids. May be acute or chronic disease. Risk of HCC, fulminant hepatic failure and cirrhosis
230
Key points about hepatitis C
Occurs via blood transmission. 50-80% develop chronic liver disease (20% of these develop cirrhosis). High risk of developing HCC.
231
Key points about hep D
Defective RNA virus that requires hep B infection for own replication. May cause acute/ fulminant hepatitis. Usually occurs in IVDUs
232
Key points about hepatitis E
Faecal oral transmission. May cause acute/ fulminant hepatitis
233
Tell me some key facts about autoimmune hepatitis
Inflammation starts at the portal tract (just like any other chronic hepatitis e.g. HBV, HCV). Inflammation is mainly by PLASMA CELLS. So plasma cells are classically seen in autoimmune hepatitis. Serology: high ALT, high IgG, ANA+
234
Tell me about PSC (primary sclerosing cholangitis)
M>F. Usually <40 years old. Possibly autoimmune - associated with IBD (particularly UC). Increased risk for cholangiocarcinoma which has a poor prognosis.
235
What is the histology seen in PSC?
There is a layer of (pink) fibrosis around the duct, whereas normally the hepatocytes would go right up to the edge of the duct epithelium. It can be described as ‘onion skinning’ because the fibrosis looks like layers of an onion. Onion skinning is a classic feature of PSC.
236
Tell me about PBC (primary biliary cirrhosis/ cholangitis)
F>M. Possibly autoimmune- associated with Sjogrens, thyroiditis, Raynaud’s and SLE. AMA positive (anti mitochondrial antibodies). Histologically: classic feature is granulomatous inflammation affecting the bile ducts.
237
Tell me about Wilson’s disease
Autosomal recessive. Causes accumulation of copper in tissue (liver, eyes -Kayser-Fleischer rings, brain). Tends to present in childhood and may cause psychosis because of the brain involvement. When the copper accumulates in the liver it leads to liver failure. Histologically: may see stipple gold material within the cells in the cytoplasm (this is the accumulation of copper).
238
Tell me about haemochromatosis
Excessive accumulation of iron. Usually deposited in liver, pancreas and heart. Primary: autosomal recessive or secondary. Presents earlier in males as menstruation delays iron accumulation in females. Leads to cirrhosis, increased risk of HCC.
239
Tell me about the histological stain used to detect haemochromatosis and what you see
Perls stain: stains for iron- blue flecks seen in the cytoplasm of the cells indicates iron.
240
Tell me about alpha 1 anti-trypsin deficiency
Autosomal recessive disease. Abnormal protein (alpha 1 anti-trypsin) accumulates in the liver, leading to fibrosis and cirrhosis (increased risk of HCC). May be associated with emphysema (lung problems). Biopsy: pink globules within the cytoplasm of hepatocytes due to DPS stain which highlights the alpha 1 anti-trypsin which is being accumulated abnormally within the liver.
241
Tell me about histopathology of cirrhosis
Diffuse nodulation of liver due to fibrous bands subdividing liver into regenerating nodules. Macroscopically: a cirrhotic liver can be seen to have lots of nodules (and not smooth), microscopically (nodules of hepatocytes which are divided into fibrous bands).
242
With regards to valvular heart disease which valves are more often involved (pathology)?
The left sided valves (mitral and aortic) because of the high pressure coming from the left side of the heart.
243
Which processes (degenerative, rheumatic heart disease, bacterial endocarditis) tend to cause stenosis/ regurgitation?
Degenerative valvular heart disease can cause stenosis or regurgitation.
Rheumatic heart disease tends to cause stenosis. Bacterial endocarditis tends to cause regurgitation
244
What is ischaemia? And what is meant by the terms relative and absolute ischaemia?
Ischaemia = not enough blood to an organ (reduced blood supply). Relative ischaemia is when demand increases but the blood vessels stay the same. Absolute ischaemia is when you block a coronary artery that supplies the myocardium
245
What is the vascular supply of the myocardium?
Predominant blood supply is from the coronary arteries which arise from the aorta and run along an epicardial route before penetrating the myocardium as intramural arteries. Coronary artery blood flow to the myocardium occurs during ventricular diastole when the microcirculation in the myocardium is not compressed by cardiac contraction
246
On which side of the heart do heart attacks tend to occur?
The left side (they hardly ever occur on the right side of the heart)
247
Tell me some differences between the right and left ventricles of the heart
The left ventricle is defined as having a smoother inner surface than the right and about 250g out the 350g weight of the heart is due to the left ventricle- it is most susceptible to IHD. The left ventricle is about 15mm thick. The right ventricle is about 4mm thick and only weighs at most around 70g.
248
How many cusps are there normally in the aortic valve?
3- (left, right and non-coronary)
| The left coronary artery comes off the left cusp and the right coronary artery comes off the right cusp.
249
Tell me about coronary artery anatomy
The part of the left coronary artery before it branches is called the ‘main stem’. The LAD continues down the heart and the circumflex artery circumnavigates around the top of the heart to the left. The branches which come off the LAD are called ‘diagonal’ vessels. The branches which come off the circumflex are called ‘obtuse marginal’. The right coronary artery is a single vessel and turns into the posterior descending artery (so it turns and then runs down the back of the heart)
250
What is important to know about the right coronary artery (RCA)?
In 9/10 individuals the RCA continues into the posterior descending artery at the back of the heart which supplies the posterior part of the LEFT ventricle at the back of the heart.
The RCA also supplies the SAN and AVN so if you block the RCA near where it begins this would prevent blood supply to the right ventricle, but more importantly it would prevent blood flow to the conducting system of the heart, so people with RCA occlusions tend to get conduction system problems e.g. arrhythmia’s.
251
What is meant by ‘right dominance’ and ‘left dominance’ in relation to the coronary arteries?
‘Right dominant heart’ is when the RCA supplies the left ventricle (in 9/10 of us). ‘Left dominant heart’ is when the RCA stops and doesn’t go into the posterior descending artery and instead the posterior descending artery is supplied the the circumflex artery
252
Which coronary arteries are most prone to coronary artery atheroma?
The epicardial coronary arteries (the vessels on the surface of the heart)
253
What is atherosclerosis?
Intimal thickening due to fibroelastic and cholesterol deposition.
254
What is arteriosclerosis and what does it encompass?
Arteriosclerosis is hardening of the arteries and encompasses:
Atherosclerosis (which is the most common cause of arteriosclerosis)
Arteriosclerosis (arterioles)- in certain areas of the body the arterioles are very vulnerable to a type of arteriosclerosis (often in the kidneys due to diabetes or HTN).
Medial sclerosis- calcifying sclerotic disease of the arteries (it doesn’t make them narrow but it makes them really hard)- so its a true hardening of the arteries which shows up on x-rays. Medial sclerosis only affects the tunica media which is the muscular layer.
255
What are the gross changes of myocardial infarction and their timescales?
None to occasional mottling (up to 12 hours)
Dark mottling (12-24 hours)
Central yellow tan with hyperaemic border (3-7 days)
Grey white scar (2-8 weeks)
256
All of the four heart valves are tricuspid except which?
The mitral valve which is bicuspid.
257
What is the most frequent of all the valvular abnormalities?
Calcific aortic stenosis
258
Rheumatic fever is an acute immunologically mediated disease that occurs a few weeks after an infective episode of what?
Group A (beta haemolytic) streptococcal pharyngitis
259
Chronic rheumatic valvular heart disease almost always affects which valve?
The mitral valve
260
Which valve is typically involved in infective endocarditis in IVDUs?
Tricuspid valve
261
Tell me about Sertoli cells
They facilitate spermatogenesis under the control of FSH
262
What are the various stages of sperm cell development?
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Spermatogonium
Primary spermatocyte
Secondary spermatocyte
Spermatid
Spermatozoon (mature)
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263
Tell me about Leydig cells
They make testosterone under the control of LH.
264
What ‘crystals’ help you to distinguish between Leydig cell tumours and other tumours?
Leydig cells have crystals in their cytoplasm called ‘crystals of Reinke’. If these crystals are found then you can confidently say that you are dealing with a Leydig cell tumour
265
What is the route from the seminiferous tubules to the urethra?
Seminiferous tubules -> rete testis -> efferent ductules -> epididymis -> vas deferens -> prostatic urethra
266
When is the peak incidence for testicular tumours?
15-34 years
267
What makes up the bulk of testicular tumours?
Germ cell tumours (90%)
268
What are the broad categories of testicular tumours? (Note: not asking for all the various types of germ cell tumour, in fact germ cell tumour is one of the categories).
Germ cell tumours (90%)
Sex-cord stromal tumours (include Leydig and Sertoli cell)
Mixed germ cell-sex cord stromal tumours
Primary tumours not specific to the testis (e.g. lymphomas)
Metastatic tumours
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Are germ cell tumours (GCT) of the testis usually benign or malignant?
They are usually malignant - remember that GCTs in the ovary can be benign or malignant but when it comes to the testis they are all malignant until proven otherwise.
270
How can GCTs of the testicle present?
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Painless unilateral enlargement of the testis
Secondary hydrocele
Symptoms for metastasis
Retroperitoneal mass
Gynaecomastia
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271
What are the risk factors for GCTs of the testis?
Cryptorchidism (undescended testis)
Genetic predisposition
Testicular dysgenesis (e.g. testicular feminisation (androgen insensitivity) and Klinefelter’s syndrome
Cytogenetic changes involving chromosome 12 and 1
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How do we classify GCTs?
In situ - intratubular germ cell neoplasia
Invasive- seminoma or non-seminomatous GCTs (include embryonal carcinoma, yolk sac tumour, choriocarcinoma, teratoma)
Mixed
273
What is the commonest type of testicular tumour?
Seminoma
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Some key factors about seminoma
Seminoma cells look like undifferentiated germ cells.
Excellent prognosis. Metastatic cases are sensitive to RADIOTHERAPY. Main subtypes include: classical seminoma (peak age 40) and spermatocytic seminoma (occurs in old age). However these subtypes are quite outdated.
275
What treatment are non seminomatous GCTs sensitive to?
Chemotherapy
276
Tell me about embryonal carcinoma
Mostly in 20-30 years ago group (so earlier age group than seminoma). Malignant cancer from embryonal germ cells showing epithelial differentiation. More aggressive than seminoma. The cells are anaplastic and arranged in glandular, alveolar, solid or papillary growth patterns. Usually associated with other GCT, pure form constitutes only 3% of GCT.
277
Tell me about yolk sac tumours
Malignant cancer from embryonal germ cells showing yolk sac differentiation. In children pure form, most common GCT in infants and children up to 3 years of age. Good prognosis. In adults associated with embryonal carcinoma.
278
What key histological terms do you have to remember for yolk sac tumour?
Schiller-Duval bodies. Raised serum levels of AFP (alpha fetoprotein) and the neoplastic cells are positive for AFP.
279
Tell me about choriocarcinoma
Malignant cancer from embryonal germ cells showing trophoblastic differentiation. Composed of both cyto and syncytiotrophoblasts. Highly malignant (quite often you see metastases at the time of diagnosis).
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What key histological terms do you have to remember for choriocarcinoma?
Raised serum HCG levels. Histologically look for area of haemorrhage, as this is often where there is choriocarcinoma
281
Tell me about teratomas of the testis
Malignant cancer from embryonal totipotent germ cells showing any type of germ cell layer differentiation. It can produce any type of cell. Can differentiate into any of the three germ cell layers: ectoderm, mesoderm or endoderm. These tumours can have: mature (adult type) tissue or immature (foetal type) tissue. Pre-pubertal diagnosis has a better prognosis than a post-pubertal diagnosis.
282
What is a mixed testicular tumour and what is a combined testicular tumour?
A mixed tumour is a mixture of the types of non-seminomatous GCT.
Combined tumours are if there is a mixture of non-seminomatous and seminomtous GCTs. (Treated as NSGCT)
283
What is the 1st line treatment for any type of GCT?
Orchidectomy - surgical removal of one or both testicles
284
What are the two main neoplastic differentials you should think about in an old man with enlarged testis?
Spermatocytic seminoma (now called spermatocytic tumour) and diffuse large B cell lymphoma
285
What are the zones of the prostate?
Divided into inner (periurethral) and outer (cortical) zone
The inner periurethral zone is where you get hyperplasia in BPH. The outer cortical zone is where carcinoma develops (so because it occurs in the outer zone, if a carcinoma causes urinary obstruction/ retention it is an advanced stage).
286
Tell me about BPH
Involves periurethral region of the prostate. Results in urinary retention. Caused by androgens (DHT)- enzymes in the prostate stromal cells called 5-alpha reductase transform androgens into DHT which is 10 times more potent. Increased weight. There is increase in both glandular and stromal component. No prominent nucleoli (hence not malignant).
287
What are the cells of the alveolar epithelium?
Type 1 pneumocytes (95%)
| Type 2 pneuomocytes - secrete surfactant (surfactant reduces the surface tension in the alveoli)
288
What cell type lines the pleura?
Mesothelial cells
289
What is pneumokoniosis?
Any of several, usually occupational diseases of the lungs such as asbestosis or silicosis, caused by prolonged inhalation of especially mineral or metallic dust particles
290
What is kartagener syndrome?
Aka. Primary ciliary dyskinesis (a ciliary defect)
291
What is meant by primary and secondary respiratory infections?
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Primary = with no underlying predisposing condition
Secondary= when local or systemic defences are weakened
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292
What is the term ‘pneumonitis’ usually used to refer to?
Usually used by doctors to refer to non-infectious causes of lung inflammation.
293
What are some differences between lobar and bronchopneumonia?
Anatomical distribution- in lobar pneumonia an entire lobe is involved, whereas in bronchopneumonia only patchy involvement is present surrounding the bronchi.
Age group- lobar pneumonia is a primary type which occurs in otherwise healthy young adults, whereas bronchopneumonia occurs at extremes of age.
Clinical circumstances- because lobar pneumonia involves a larger area it presents as an infection in terms of high-grade fever, cough, foul smelling sputum. Whereas in bronchopneumonia they can present as flu-like symptoms.
Causative agent- in lobar pneumonia as the person is immunocompetent they involve pathogenic organisms such as strep pneumonia. Whereas, in bronchopneumonia slightly ‘weaker’ organisms can cause infections such as haemophilus and klebsiella
Morphology: under the microscope they both show neutrophil leukocytic exudate. In lobar pneumonia the consolidation may cause the tissue to look more like the liver ‘hepatization’ so the stages of lobar pneumonia go as follows histologically: congestion, red hepatization, grey hepatization, resolution. In bronchopneumonia there are speckled areas of consolidation in the lung.
Prognosis: in lobar pneumonia because they present with clear signs and symptoms they are often diagnosed earlier, and if given the right antibiotics there is complete resolution. In bronchopneumonia patients may be missed at the diagnosis stage, so sometimes they don’t receive treatment in time and die as a result
294
What are the complications of lobar pneumonia if it is not treated appropriately?
Abscess formation
Empyema (pus within the pleural cavity)
Organisation of the exudate with fibrosis
Bacteraemic dissemination to other organs e.g. heart valves
295
What type of necrosis do you see in TB?
Caseous necrosis
296
Other than caseous necrosis what is the other characteristic feature of the granulomatous inflammation that occurs in TB?
Appearance of Langhans multinucleated giant cells
297
What is miliary TB?
When individuals do not have any resistance to the bacteria whatsoever, so the bacteria can grow anywhere and produce small millet like seeding of TB throughout the lung/ throughout the body. Can get miliary TB from either primary or secondary TB depending upon at which stage a person develops immunodeficiency.
298
What can help to differentiate TB from other infections?
Organisms- types M. Hominis and M. Bovis have a lipid cell wall which makes them very resistant compared to other types of bacteria and because of this their staining characteristics are different too. Uses a ZN stain, or on the basis of their characteristics is also called AFB staining. Other organisms tend to take around 2-3 days to culture and sensitivity, however if you send a sample for culture of TB organisms it can take 5-6 weeks.
299
What type of hypersensitivity is seen in TB?
Type 4 hypersensitivity. This is a delayed hypersensitivity (Th1 response) in which there is formation of granuloma. Can see localised collection of modified macrophages and some Langhans multinucleated giant cells (horseshoe shape arrangement of cells) and there is a central area of necrosis.
300
How does TB tend to present?
With a low-grade fever, night sweats, and other features of TB that may mimic cancer such as weight loss and loss of appetite.
301
Name some important oncogenes involved in lung cancer
C-myc (small cell lung cancer)
| K-ras (adenocarcinoma)
302
What are some important paraneoplastic effects of lung cancers to know about?
ACTH (Cushing’s syndrome) and ADH from small cell carcinoma
PTH from squamous cell carcinoma
Finger clubbing and hypertrophic pulmonary osteoarthropathy
303
How are small cell and non small cell carcinomas treated?
Small cell carcinoma = treated by chemotherapy
| Non small cell carcinoma = treated by surgical resection
304
What are the characteristics of the non small cell carcinomas (squamous cell carcinoma and adenocarcinoma)?
Squamous cell carcinoma (common in smokers, usually towards the hilum of the lung)- microscopically you may see either keratin or intercellular bridges. TTF-1 negative, usually positive for CK56 or p63.
Adenocarcinoma (produce gland like structures and tend to be at the periphery of the lung) TTF-1 positive.
305
What are the lung conditions that may affect the pleura?
Pleuritis (pleurisy)
Pneumothorax- air in the pleural cavity
Effusions- hydrothorax (watery fluid in the pleural cavity), haemothorax (blood in the pleural cavity), chylothorax (lymph in the pleural cavity).
Mesothelioma
306
Give some features of nephrotic syndrome
Massive proteinuria (albumin)
Hypoalbuminaemia
Oedema
Hyperlipidaemia/uria
307
Give some features of nephritic syndrome
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Variable proteinuria
Haematuria
Mild oedema
Oliguria
Azotaemia (high levels of nitrogen containing compounds in blood)
Hypertension
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308
What is the pathophysiology of nephrotic syndrome?
Loss of glomerular basal membrane sialoprotein -> loss of normal negative charge -> increased glomerular permeability -> massive proteinuria/ albuminuria.
Whole body: decrease proteinemia -> decrease plasma oncotic pressure -> fluid shift from vascular to interstitial oedema -> contraction of plasma volume
309
What are the causes of nephrotic syndrome?
Minimal change disease, focal segmental glomerulosclerosis, membranous glomerulonephritis, systemic disease (secondary to diabetes).
310
Tell me about minimal change disease
Commonest cause of nephrotic syndrome in childhood. No detectable immune deposit, but has an immune basis. Strong association with resp infection and immunisation. Diffuse effacement of foot processes, only seem under electron microscope and looks normal under light microscope hence ‘minimal change’. No inflammatory cells to be seen or any immune mediated damage (yet steroids work really well)
311
Tell me about FSGS (focal segmental glomerulosclerosis)
Primary or secondary. Scarring (sclerosis) of some parts of the glomeruli (hence segmental) only in certain parts of the kidney. This is rare but more severe and difficult to treat. Some (focal) glomeruli show partial (segmental) hyalinisation. Unknown pathogenesis. Poor prognosis.
312
Tell me about membranous glomerulonephritis
Deposition of anti-glomerular basal membrane antibodies in the glomerulus. Causes a thickened GBM and sub-epithelial deposits/ spikes. The most common form of autoimmune type of nephrotic syndrome. 85% idiopathic, 15% association with malignant tumours, SLE, drugs, chronic infection
313
Name some causes of nephritic syndrome
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Proliferative glomerulonephritis
Membranoproliferative glomerulonephritis (includes diffuse mesangioproliferative glomerulonephritis, crescenteric glomerulonephritis and lupus nephritis)
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314
Tell me about acute proliferative glomerulonephritis
The major cause of acute nephritis in childhood. Arises following a group A (beta-haemolytic) streptococcal infection. Histology: endocapillary hypercellularity with numerous neutrophils and closure of glomerular vessels. The glomeruli are increased in size and cellularity.
315
Tell me about membranoproliferative glomerulonephritis
Usually presents with a combined nephritic-nephrotic picture. Caused by deposits in the kidney glomerular mesangium and GBM thickening, activating complement and damaging glomeruli. Should not be confused with membranous glomerulonephritis in which the basement membrane is thickened but the mesangium not. When there are ‘cresents’ in the glomerulus it is a bad prognostic marker
316
What is the most common malignant renal cancer?
Renal cell carcinoma (80%).
