Week 6 Flashcards

Question

Pathology as a clinical discipline

Answer 1

Specimens from living people Approx 70% of hospital diagnoses based on pathology “tests” -majority are simple tests (eg blood samples) -others are more complex and invasive (eg biopsies, surgical resection, specimens, molecular biology tests) Information also important for prognosis and treatment

Answer 2

Clinical presentation and natural history Terms used to classify neoplasms and their clinical relevance Treatment options

Answer 3

Behaviour- benign or malignant Tissue of origin/differentiation Histological subtypes Knowledge of gross features helpful in distinction between benign and malignant lumps (clinical examination, radiology) Benign= smooth, well circumscribed, mobile Malignant= irregular, poorly defined, may be fixed to adjacent tissues

Answer 4

Commonest benign breast neoplasm Mostly occurs in young women <30 Smooth well circumscribed lumps, highly mobile on palpation (“breast mice”)

Answer 5

Commonest malignant breast neoplasm Commonest cause of cancer death in women Mostly occur in older women (75%>50 years) Irregular, poorly circumscribed lumps, rarely mobile on palpation (due to invasion of surrounding structures)

Answer 6

Caecum/ascending colon: often polypoid, rarely cause bowel obstruction, insidious presentation- eg anaemia, weight loss Sigmoid colon: often stenosing, frequently cause bowel obstruction, typically present with alteration in bowel habit

Answer 7

Biopsies: -endoscopic biopsies (upper and lower GIT, bronchus) -needle biopsies (radiologically guided) -punch biopsies (skin) Cytology specimens (cells-individuals or small groups) -smears (eg cervical) -endoscopic brushings -body fluid (eg sputum, urine, effusion fluids) -fine needle aspiration specimens Surgical resection specimens Frozen section specimens (intraoperative)

Answer 8

Mainly taken to confirm a diagnosis of malignancy and identify histological type Information used to plan further treatment -eg surgical resection versus non surgical approaches -decisions relating to therapeutic options are frequently made in multidisciplinary team meetings

Answer 9

Tumour heterogeneity Targeting the lesion accurately: -small lesions -inaccessible (or potentially dangerous sites) -surrounding stromal reaction (pancreatic cancer)

Answer 10

Diagnostic material obtained using less invasive methods -bladder cancer- urine cytology versus cystoscopy -fine needles used to aspirate material for cytology are much thinner than those needed to obtain biopsy material —may provide access to sites not suitable for biopsy (eg pancreas) Smaller tissue samples provided (individual cells or groups of cells rather than tissue cores) -interpretation may be more difficult than larger specimens obtained using biopsy)

Answer 11

Surgical resection is generally indicated to be a definitive (curative) treatment for cancer. In some cases it may be used in a palliative manner Pathological assessments are used to: -confirm the diagnosis of malignancy -determine the aggressiveness of a tumour (histological grade) -assess the extent of spread (histological stage) -examine completeness of excision This information may be used as the basis for determining further treatment (eg adjuvant chemotherapy) Other pathological assessments can sometimes be used to identify more specific therapeutic options

Answer 12

Size Shape (well circumscribed or irregular) Extent of local spread Proximity to surgical resection margins Identification of lymph nodes (important for staging) Other macroscopic features where relevant (eg colour, haemorrhage, necrosis)

Answer 13

Confirms (or establishes) a diagnosis of cancer Other features that are assessed microscopically include the following: -histological type (glandular, squamous) -degree of differentiation (histological grade) -frequency of mitoses -local invasion —presence: is important in determining a diagnosis of malignancy (eg capsular invasion in follicular carcinoma of the thyroid gland or hepatocellular carcinoma) —extent is important in staging Vascular invasion Examination of lymph nodes (for metastases)

Answer 14

Well differentiated tumour showing capsular and vascular invasion Presence of capsular or vascular invasion confirms diagnosis of malignancy Presence of vascular invasion up stages tumour from T1 to T2

Answer 15

Describe core data that should be provided in histopathology reports Uniform approach to handling resection specimens: -prognostic information -accurate data for cancer registration -feedback on the quality of resection -selecting patients for adjuvant therapy (including clinical trials) -auditing effectiveness of pre-operative staging procedures

Answer 16

Well differentiated: closely resembles tissue of origin, may also be classified as low grade, grade 1, more favourable outcome Undifferentiated/anaplastic: Anaplastic= no resemblance to any normal tissues in site of origin, may also be classified as high grade Grade III, poor prognosis

Answer 17

Staging is a measure of the extent of spread of a tumour most important factor predicting prognosis in most tumours TNM. T(1-4), N(0-3), M(0-1)

Answer 18

Immunohistochemistry: -a method of detecting the presence of specific proteins in cells or tissues, an antibody for each antigen Molecular pathology: gene mutation analysis; FISH; deletion of specific translocations -to support the diagnosis (specific translocations in sarcomas (myxoid liposarcomas, synovial sarcoma, Ewing’s tumour) -to predict response to targeted drugs (KIT in GIST; EGFR2 in breast adenocarcinoma; RAS in colorectal adenocarcinomas)

Answer 19

Prognostic markers: -markers of cell turnover (eg Ki-67 labelling index) -may be used to determine tumours of low or high metastatic potential —eg pancreatic endocrine neoplasms (also applies to other endocrine neoplasms) —most cases well differentiated (low grade) by conventional histological criteria and behaviour difficult to predict -Ki 67 labelling index <2% low metastatic potential -Ki 67 labelling index >20% high metastatic potential Also used to determine prognosis (and sometimes treatment options) in tumours already known to be malignant. Often correlates with other histological features (mitotic activity, degree of differentiation)

Answer 20

Expression of specific antigenic markers used to identify tumours that are likely to be amenable to specific therapies targeting the antigens expressed -breast carcinomas expressing the growth factor HER2 can be treated with herceptin -breast carcinomas expressing oestrogen receptor may be amenable to hormone therapy -metastatic colonic (and gastric) adenocarcinomas showing deficient/loss of mismatch repair proteins can be treated with immunotherapy

Answer 21

Diagnostic: -translocations in sarcomas and lymphomas -B and T cell clonality -KIT/PDGFRA gene mutation in GIST Prognostic: -1p 19q LOH in gliomas: better prognosis -mismatch repair protein alterations in colorectal cancer: better prognosis -immunoscore: prognostic/predictive in colon cancer -oncotype, prosigna, endopredict in breast cancer Predictive

Answer 22

Targeted treatments; -HER2 amplification in breast, oesophageal/gastric and lung cancer – RAS mutation prior to anti EGFR1 antibody in metastatic colorectal ADC: negative predictive marker – EGFR1 mutation prior to anti EGFR1 small molecules in NSCLC (tissue or/and plasma) – KRAS G12C in lung cancer – KIT/PDGFRA mutation in GIST and melanoma – BRAF mutation in melanomas and lung cancer prior to targeted therapy – ALK, ROS1, RET translocation in lung cancer – MET exon 14 skipping mutation in lung cancer – NTRK translocation testing in any solid tumour – PIK3CA mutation in breast carcinoma – FGFR2 rearrangement and IDH1/2 mutations in cholangiocarcinoma – MMR testing in upper GI cancer – PD-L1 expression prior to check point inhibitor therapy: lung, head and neck, melanoma, bladder, breast, oesophageal, gastric, cervical carcinoma

Answer 23

Optimal pathology report of a cancer -histology: nature of tumour and sub typing through immune profile -immunohistochemistry single test, IVD protocols, quantification on digitalised slides -DNA analysis in FFPE and plasma single mutation, NGS -FISH partial automation of interpretation on digitalised slides

Answer 24

Many important decisions relating to the diagnosis and treatment of malignant neoplasms now take place in the setting of MDT meetings Core members: -histopathologists -radiologists -surgeons -oncologists -other health care professionals (eg specialist nurses) The presence of recognised MDT meetings and regular attendance by core members is now a requirement in order for a hospital to be recognised as a cancer treatment centre Regularly monitored by cancer peer review teams

Answer 25

Original descriptions by Cragie, Virchow, Bennett 1840 First description of Philadelphia chromosome- 1960 Chronic myeloid leukaemia other landmark discoveries : -Janet Rowley et al: a new consistent abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and giemsa staining Historical treatment options: -1964= hydroxyurea -combination therapy -1975=bone marrow transplantation -1983=interferon alpha -2001= imatinib

Answer 26

1-2/100000 Scotland 0.9/100000 (2008) Increases with age Virtually none below 8 years old (rare in children)

Answer 27

Excess of myeloid cells Primary polycythaemia- too many red cells Primary thrombocythaemia- too many platelets Idiopathic myelofibrosis- too much marrow fibrosis Chronic myeloid leukaemia CML- too many neutrophils They’re all related in a way all can transform into something else

Answer 28

A type of myeloproliferative disease: -accumulation of myeloid progenitors -high white blood cell count -large spleen Can transform into acute leukaemia Previously treated with: -myelosuppressive therapy (hydroxycarbamide) -transplantation

Answer 29

Many mature granulocytes Basophils Blast cell

Answer 30

Almost every patient with CML will have a Philadelphia chromosome 90% The Ph chromosome: t(9;22) translocation

Answer 31

One is BCR lies on C22 Other is ABL lies on C9 You get fusion of part of BCR gene onto next part of the ABL gene So end up with BCR-ABL fusion gene ABL is tyrosine kinase- converts ATP to ADP to phosphorylated other proteins In normal cell ABL will not always be expressed However by fusing it with BCR it becomes constructively active inside WBC

Answer 32

Fusion creates new gene and thus new protein You can see the gene being joined together using FISH- fluorescent in situ hybridisation You can label the genes by using fluorescent probes BCR::ABL is found in normal people as well

Answer 33

You get various different fusions depending on where they are joined together. Therefore have various different lengths They’re also associated with slightly different kinds leukaemia P190BCR-ABL P210BCR-ABL P230BCR-ABL

Answer 34

Variable Asymptomatic Hyperviscosity- from high WBC Specific symptoms: -bleeding -anaemia, tiredness -infection (recurrent) as WBC may not function properly

Answer 35

Common symptoms and signs: -fatigue -weight loss -sweating -haemorrhage- eg easy bruising, discrete ecchymoses -splenomegaly Blood values: -Hb 7.9g/dL (anaemia) -WBC 467 x10^9/L (very high) -PIts 600 x10^9/L Massive splenomegaly: can result in rare symptoms -splenic infarction -leucostasis -gout -retinal haemorrhages -priapism -fever

Answer 36

Blood count and film -elevated white cell count -low platelets and haemoglobin -film Biochemistry: -abnormal liver function can occur -impaired renal function- raised urate -raised lactate dehydrogenase LDH Need to exclude other causes eg bacterial infection, other malignancies

Answer 37

Blood counts Blood film morphology Bone marrow diagnosis Cytogenetics Molecular diagnostics

Answer 38

Clinical Blood tests Blood film morphology Bone marrow diagnosis Cytogenetics Molecular diagnostics (new)- FISH and QPCR

Answer 39

Here is the 9-22 translocation so we have the diagnosis We also confirm this via FISH

Answer 40

PCR is used when you have a bit of DNA that you want to find out it’s sequence eg see if there is BCR-ABL present The easiest way of doing that is by putting one primer on BCR and one on ABL where you think the break point will be Heat up DNA, anneal the primer, polymerase it, cool, join together Every time you double the product see if there’s a BCR-ABL fusion

Answer 41

When we treat the patient want to know how much of the gene is around QPCR tells you how much of the gene is there Each time the gene is copied the reporter fluorophore is released giving a signal The intensity of the signal rises exponentially Compare with a known gene ABL to know how much BCR-ABL you have

Answer 42

Acute treatment: -reduce WBC —hydroxycarbamide weak chemo —leukapheresis, removes WBCs. For very high WBC and life threatening complications -prevent hyperuricaemia —gout —renal failure —allopurinal to treat this —IV fluids stop renal failure -analgesia for pain relief splenomegaly Chronic treatment: -tyrosine kinase inhibitors: imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib -interferon: 10-20% -allogenic transplantation

Answer 43

Potent inhibition of Abl-K, c-kit and PDGF-R Salts are soluble in water Oral bio available Not mutagenic CGP57148: a phenylamino pyrimidine derivative Imatinib mesylate fits into the ATP binding pocket of BCR-ABL protein

Answer 44

Imatinib binds to ATP binding pocket of BCR-ABL prevents phosphorylation of target molecules. So get no downstream signalling and no cell proliferation and survival Maintains BCR-ABL in inactive state BCR-ABL is a tyrosine kinase The kinase domain of abl activates a substrate protein eg PI3kinase by phosphorylation. This activated substrate initiates a signalling cascade leading to cell proliferation and survival

Answer 45

Randomised controlled trial for imatinib RCT is the gold standard for testing the efficacy of new drugs in patients It typically compares the new drug against standard treatment RCT compared imatinib to IFNalpha . 553 patients in each arm, there was cross over Results: progression free survival on imatinib is better than previous therapy

Answer 46

Baseline- risk stratify long term score (ELTS) Haematological: normal blood counts at 1 month Molecular : BCR::ABL -<10% 3 months -<1% 6 months (complete cytogenetic response) -<0.1% 12 months (major molecular response) <0.1% any time onward

Answer 47

BCR-ABL transcript numbers expressed as log reduction in patients responding to treatment

Answer 48

If you have gotten down to that level your life expectancy is the same as anyone else

Answer 49

Kinase domain mutations occur in 30-50% of cases of acquired resistance. Mutations fall into 4clusters Resistance manifests itself through different mechanisms causing -changes to the stability of the BCR-ABL conformation -reduction in binding efficiency of imatinib

Answer 50

Nilotinib Dasatinib Bosutinib Ponatinib. T315I activity Asciminib. Allosteric inhibitor- not the ATP pocket Next generation nilotinib is more effective than imatinib for newly diagnosed chronic myeloid leukaemia

Answer 51

Progression to the accelerated phase or blast crisis 14 patients: 12 patients 4.8% receiving imatinib 2 patients 0.7% receiving 300mg of nilotinib 3 patients (1.3%) receiving 400mg of nilotinib

Answer 52

High dose (myeloablative) chemotherapy or chemo-radiotherapy for recipient- kills leukaemic cells and existing marrow components= conditioning Re-infusion of haematopoeitic stem cells -autologous cells (collected if marrow not involved) -allogeneic from HLA-matched donor (sibling or unrelated) Pre-engraftment and post transplant -extreme vulnerability to complications of infection, bleeding etc immunosuppressed Establishing a chimera= donor haematopoiesis/immune cells, recipient tissues, you are yourself but blood is from someone else

Answer 53

Works well chances of survival reasonably good for young patients But only around 30% patients rate eligible for HSCT because: -age -morbidity -donor availability

Week 6 Flashcards

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