BM422 - Block B (cervical screening programme)

what is the main objective of the cervical (or any) screening programme?

reduce morbidity and mortality of cancer by detecting and treating precancerous abnormalities

what 8 factors dictate a good/effective screening programme? what are these factors based on? (hint: people)

disease should be common

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early stages should be known/recognisable

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mortality should be known so that effectiveness can be measured

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test must be available, cheap, safe, reliable, and acceptable to the populaiton

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there should be an agreed policy on who should be referred for further diagnostic testing (i.e., HPV+/- in cervical screen)

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treatment should be well established

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should be cost effective

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evaluation must be ongoing and evidence-based changes made

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based on Wilson and Junger Screening Principles

what are the main arguments against screening programmes? (3)

false negatives/positives

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can be harmful (e.g., can lead to harmful overtreatment) (e.g., in young woman > can affect fertility)

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public perception (they may find it embarrassing)

who is the NSD? how does the NSD achieve their goal? (what do they actually do)

national services division

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responsible for commissioning and performance of cervical screening programme on behalf of NHS Scotland

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develop systems, guidelines, policies, quality assurance, and statistics

what is the SCCRS? who manages it?

scottish cervical call recall system

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scotland-wide database accessible over secure NHS network

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records all patient history (i.e., previous results/diagnoses)

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handles call/recall of all women between the ages of 25 and 64 registered with a GP

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the NSD

what services does the SCCRS offer to medical personnel? (6)

- smear test request and reporting

- clinical information (instantly available)

- notification of smear test result to patient

- direct referral to colposcopy/gynaecology

- virology results

- HPV vaccine status of patient

what cervical screening programme is currently in place?

primary HPV testing with reflex cytology on HPV positive samples

what patient pathways exist in the context of cervical screening? (4)

1. primary screening

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2. test of cure

for those who have previously been treated for CIN

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3. cytology surveillance

for low/high-grade disease

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4. conservative management

for low-grade disease

how does specificity compare between cytology and HPV testing?

HPV testing not as specific as cytology for diagnosis (since it is just determining HPV infection - not degree/type of CIN)

in terms of HPV status and cytology, what type of patient would be particularly difficult to treat? what may happen with these patients?

HPV positive (especially for high risk) with negative cytology

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these patients will have a 1 year recall instead of 3/5

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they may be genotyped to determine if the HPV strain is high or low risk

summarise the cervical smear process?

speculum examination of cervix

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small cervical broom inserted into cervical os and rotated 360 degrees 5 times

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broom then placed in Preservcyt solution (ThinPrep)

what is the function of the hologic tomcat?

aliquots 1mL samples from the ThinPrep vial (input) into Aptima sample tubes (output)

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prints and places barcode onto Aptima sample tube (from SCCRS)

what is the function of the hologic panther?

performs HPV assay on prepared Aptima sample tubes

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tubes contain 1mL of patient sample + an aptima medium

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also load a HPV assay kit, calibrators, and controls for each batch

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first result of the day takes 3.5 hours to generate - subsequent batches will only take 5 minutes for a result

how many samples are run per batch on a hologic panther? how long does it take for results to generate?

240 per batch

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first batch of the day will take 3.5 hours but subsequent batches will only take 5 minutes

in what sense is the hologic panther random access?

you can load samples in any order/at any point without any batch constraints

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can add/remove samples without disrupting another sample

what is the purpose of the Aptima HPV Assay?

targets 14 HR-HPV subtypes that pose the largest threat to women (includes 16, 18, 31, 33, 45)

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detects mRNA (for E6/E7) which indicates both the presence and activity of HPV

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does not target low risk strains

what is meant by integrated HR-HPV?

HPV that has integrated into the host cell genome (serious/transition between transient infection and CIN)

can the aptima HPV assay tell you which strain of HPV the person is infected with?

yes and no

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it can tell if the strain is HPV 16 or HPV 18/45 (grouped) but other than that it would just be a positive/negative result for any of the other 14 strains

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result could also be fail is sample was inadequate or something else went wrong with the machine itself

what issue exists with screening for HPV prior to cytology?

detection of transient infection leading to overtreatment (= why cytology and patient history are also important considerations)

what is meant by routine and non routine pathways?

routine = for everyone (i.e., the primary screening)

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non-routine = depends on outcome of primary screen

once HPV testing is complete, what happens next? (both for HPV positive and HPV negative) (+ what physically happens to samples of for each)

all results are sent to the SCCRS

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patients on the primary screening pathway with a negative test do not require further intervention - they are recalled in 3/5 years

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vials are discarded after 10 days

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patients on a non-routine pathway or patients with a positive test require cytology

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vials are identified and processed for cytology

what is the function of the hologic thinprep 5000 (T5000)?

scans tubes and labels them with patient information

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fully automated process in which a monolayer of cells is produced

summarise the constituents of a papanicolaou stain? (6)

haematoxylin = stains nucleus blue

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light green SF = stains cytoplasm of active cells blue

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orange G = orange cytoplasmic dye (keratin filament)

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eosin Y = stains cytoplasm pink (+ RBCs)

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bismarck brown Y = stains acid mucins (=mucus, tends to coat surface of certain epithelial cells)

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phloxine = enhances cytoplasm staining (red)

in essence, what does a papanicolaou stain aim to achieve?

a stain for the nucleus (important feature in dysplasia)

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two main stains for cytoplasm to differentiate between cell types (mature/superficial and immature/active)

what imaging system is associated with the cervical screening process?

slides are reviewed on a thinprep imager review scope linked by a server to the processor

what does the thinprep imager review scope do? (it directs the screener to what)

it identified 22 fields of view (areas) in which the darkest nuclei are located (based on computational calculation)

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means screener is not pouring over entire slide - just most significant zones

what are the two possible outcomes of cytological evaluation?

no abnormal cells

>>> smear is reported as negative, passed for rapid review and final reporting

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abnormal cells

>>> slide is screened in full, passed to a checker for further review, then a cytopathologist for final reporting

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all information is saved within SCCRS server

how many cytology reporting categories exist? name a few?

11

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unsatisfactory

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negative

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borderline change (squamous or epithelial)

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low grade dyskaryosis (~CIN I)

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high-grade dyskaryosis (moderate/severe/?invasive)

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glandular abnormality (CGIN)

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adenocarcinoma

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endometrial or other (i.e., non cervical cell)

as a component of the papanicolaou stain, what is the difference between light green and fast green?

light green = likely to fade

fast green = less likely to fade

what would be the main histological difference between low grade and high grade dyskaryosis?

low grade you'd see a mix of mature/immature cells (pink/blue) with a characteristic halo around the nucleus (nucleus may be gritty)

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high grade is mostly immature cells (blue) with huge nuclear variation (some huge, some small, some close, some far, some gritty) (more severe = more smudgy around nucleus (content leakage))

will smears/slides always be evidently high or low grade dyskaryosis?

no - usually it is a combination - you look for what is dominant

what is a tadpole cell?

bizarre morphology observed in abnormal keratinising squamous cells (indicates cellular abnormality)

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often implicated in invasive squamous carcinoma

in an ideal world, would keratinised/keratinising cells be observed in a cervical smear?

no - the ectocervix is not supposed to be keratinised (i.e., tough)

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the vaginal canal is partially keratinised (in low oestrogen conditions) so these cells could have come from the vaginal canal if present in small amounts

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if present in large amounts may suggest abnormality of ectocervix (keratinising dysplasia/possible squamous carcinoma)

can glandular cells keratinise?

no - it is typically an end stage for squamous cells only (basically death of cell via replacement cellular contents (including nucleus) with keratin)

in summary, what features are histologically seen in dyskaryosis?

bizarre shapes (usually in high grade)

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marked variation in size/shape (high grade)

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tumour diathesis (specific to invasive carcinoma often)

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cytoplasmic keratinisation (suggestive of invasive carcinoma)

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low to high NC ratio

what is tumour diathesis?

presence of debris (i.e., random staining with no outline/nucleus)

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suggestive of invasive carcinoma

can invasive carcinoma status be diagnosed from a smear test result alone?

no

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that is why result is "?invasive"

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biopsy is required

in summary, what histological features suggest there may be invasive carcinoma? (2)

presence of keratinising/tadpole cells

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tumour diathesis

what is keratinisation?

terminal differentiation considered a controlled form of cell death

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loss of cellular material (organelles/cytoplasm/nucleus)

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replacement with keratin (makes cell hard/tough)

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common for external skin layer

how would a glandular abnormality appear in a pap stain?

nuclei are crowded (close to one another/overlapping)

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nuclear dissolution (karryorrhexis/pyknosis evident)

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like one big smudge as opposed to bunch of blueberries/honeycomb (=loss of architecture)

who are UKAS? (when do they visit)

united kingdom accreditation service

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certificating body mandated by scottish government

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visit every 4 years for full inspection and every 2 years for surveillance/monitoring purposed

why is it important for biomedical labs to have accreditation?

gives confidence that system follows best practice/achieves high standards

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gives assurance to quality of work

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assures users that you are a suitable supplier of the service

the SCSP has both internal and external quality assurance; what are some example of external auditors? (5)

NHS England cervical cytology EQA

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NEQAS molecular detection of HPV

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QCMD HPV EQA programme

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hologic technical EQA sscheme

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UKHSA technical EQA scheme

what contribution does the SCSP make directly to quality control/assurance?

they have a laboratory QA group that monitors programme performance

what are the four main IQC measures in place for the SCSP? what does each involve?

HPV IQC

>>> processing two known HPV+ and two known HPV- samples with each batch of samples

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HPV data trend analysis

>>> recording of data (number of samples processed + results from each)

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monthly environmental testing

>>> swabs taken from areas of the lab for HPV testing on the panther

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technical IQC

>>> assessment of staining each morning + after full staining machine change

what hologic machine automatically applies pap stain?

thinprep 5000 (T5000)

what are the 5 major goals of external quality assurance?

1. contribute towards establishment of/upholding a minimum of national standard

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2. promote consistency nationally

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3. facilitate education/professional development within the lab

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4. enhance the experience/confidence of staff in reporting

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5. assist in meeting accreditation standard

what is the invasive cancer audit?

systematic review of invasive cancer cases to monitor and improve screening programmes

what data is considered in the monitoring of screening programmes? (3)

data from invasive cancer audit (number of cases/types of cancer)

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data from QA meetings (turnaround, % of HPV+ samples, % of samples in cytology)

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data from NSD (test uptake, ages screened)

what 3 major changes have been made to NHSCSPs? (~trials)

ARTISTIC (=primary HPV testing)

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TOMBOLA (=managing borderline/low-grade abnormalities)

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STRATEGIC (=strategies to increase screening uptake)

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all = trials that were done and have now been implemented

who are the national HPV surveillance Scotland team?

a team set up to monitor the effectiveness of the cervical screening programme

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monitor HPV prevalence since 2009 (around time of vaccine introduction)

with regards to the success of the HPV vaccine; summarise the findings of the national HPV surveillance report of 2009?

vaccine had/has singificant effect on HPV16/18 incidence

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measured effect on other HR-HPVs (31/42/etc) suggesting cross protection

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herd immunity demonstrated

when is the next HPV surveillance report due? what is it looking to assess?

in 2029 (started 2024)

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monitor HPV prevalence to allow us to see the duration of protection by vaccine type

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monitor changes in herd protection following further/new vaccine introduction

what two improvements are currently being trialled with regards to cervical screening?

digital cytology

>>> viewing/sharing cytology images live

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self-sampling

>>> aimed at those who do not attend screening