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Colorectal and anal cancer Flashcards

1
Q

NZGG Family History Categories for Colorectal Cancer

A
  • Category 1: individuals w slight increase in risk of CRC
    • 1x first-degree relative diagnosed at ≥55
  • Category 2: individuals w moderate increase in risk of CRC
    • 1x first-degree relative diagnosed at ≤54 OR
    • 2x first-degree relatives on same side of family dx at any age
  • Category 3: individuals w a potentially high risk of CRC - one or more of
    • fhx of FAP, Lynch/HNPCC or other familial CRC syndromes
    • 1x first-degree relative plus two or more first- or second-degree relatives all on same side of family w a dx of CRC at any age
    • 2x first-degree relatives, or 1x first-degree relative plus one or more second degree relatives, all on same side of family w dx of CRC and one such relative
      • was dx at ≤54yrs OR
      • developed multiple bowel cas OR
      • developed an extracolonic tumour suggestive ofLynch
    • ≥1x first- or second-degree family member dx w CRC in assoc w multiple bowel polyps
    • a personal hx or 1x first-degree relative w CRC dx under the age of 50, particularly where colorectal tumour IHC has revealed loss of protein expressoin for one of MMR genes
    • a personal hx or one first-degree relative w multiple colonic polyps
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2
Q

Bowel screening for family history categories

A
  • slight increase risk (1x 1st degree relative with cancer >55) - no specific surveillance
  • moderately increased risk (1x 1st degree relative <55 or 2x 1st degree relatives on same side of family dx at any age) - start screenign q5yrly from 50 or 10yrs before earliest age at which CRC was diagnosed, whichever comes first)
  • high risk - refer to geneitcs for plan
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3
Q

What is the distribution of colorectal cancer?

A

1/3 rectum, 20% right, 30% left, 10% transverse

in 4-5% there is a synchronous lesion

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4
Q

What are the risk factors for colorectal cancer?

A
  • personal history of polyps - majority of colorectal cancers arise from polyps
  • familial syndrome with increased risk of CRC
  • but any family history increases risk
  • diet and lifestyle
    • decreased risk with dietary fibre, non-starchy vegetables
    • increased risk with obesity, red meat, processed meat, alcohol, animal fat, sugar
    • smoking
  • predisposing conditions
    • UC & Crohn’s
    • previous gastric surgery controversial
    • ureterosigmoidostomy - but now usu use ileal conduit
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5
Q

Describe the spread of colorectal cancer

A
  • direct
  • lymphatic
    • paracolic nodes along main colonic vessels –> nodes assoc w either cephalad or caudal vessels –> para-aortic glands in advanced disease
    • in contrast to rectal disease, rare for a colonic cancer that has not breached muscle wall to exhibit LN mets (15%)
    • in rectum, drainage is via mesorectal nodes
  • blood-borne spread
    • most common site = liver via portal venous system; up to 37% pts may have occult liver mets at time of op & ~50% will develop at some stage
    • lung next common - 10% at some stage
    • others ovary, adrenal, bone, brain, kidney
  • transcoelomic spread
    • spread throughout peritoneum either via subperitoneal lymphatics OR by virtue of viable cells being shed from serosal surface of a tumour, giving rise to malignant ascites
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6
Q

What is the role of EUS in assessing rectal ca?

A

Used in some centres to assist with assessment of early rectal cancer as it is reasonably accurate in distinguishig T1 from T2 tumours; may be helpful in selecting pts who may be suitable for local excision, but highly operator dependent. Less good at N stage, not able to assess extrarectal disease.

Rectal wall is indicated by 3 white lines & 2 hypoechoic lines; innermost line represents interface between water-filled balloon & transducer; transducer rotates 360 degrees to give an image of rectum

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7
Q

What is the role of MRI in staging rectal cancer?

A
  • stage local extent and predict status of resection margin
  • can reliably assess whether CRM is at risk of tumour involvement - accurately predicts both T stage and CRM clearance of 1mm from resection margin
    • plus extramural depth of penetration accurately predicted to within 0.5mm in 95% so possible to classify tumours pre-op into mrT3a (extramural tumour extension <5mm) and mrT3b (extramural tumour extension >5mm) subgroups & thus consider neoadj in advanced tumours - controversial
    • T stage accuracy quite variable but it is distance to CRM that is most powerful predictor of local recurrence, rather than T stage
  • can assess nodal involvement - though sens & spec remains problematic
  • can assess extramural vascular invasion

2 major prognostic metrics related to radial tumour growth that can be determined by pretreatment local imaging

  • distance of growth beyond muscularis propria & distance to CRM
  • distinction between a clinical T3 and T4a tumour in rectum requires careful assessment of the location of the peritoneal surface of the rectum relative to the site of tumour involvement
    • for rectal cancers below the level of the peritoneal reflection (typically at level of seminal vesicles or vaginal fornix), tumour within the mesorectal fat is evidence of T3 disease, and the tumour must extend to the mesorectal fascia to be T4
    • by contrast, anterior surface of rectum = covered by serosa (peritoneum) at and above peritoneal reflection; this coverge extends laterally around the rectum as we move superiorly toward sigmoid colon
      • for tumours extending above peritoneal reflection, presence of gross tumour in pericolonic fat represents T4a disease if present in a serosally covered surface, and T3 disease if present in the uncovered surface
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8
Q

Prognostic factors in colorectal cancer

A
  • staging (TNM)
  • CEA
  • LVI and PNI
  • histological grade
  • specific histologic subtypes eg mucinous & signet ring cell usu more aggressive/worse prognosis
  • CRM, prox and distal margin status
  • in rectal cancer, the completeness of the mesorectal excision
  • pathologic response to neoadj treatment (tumour regression grade)
  • molecular risk markers for some somatic & germline mutations eg MSI, KRAS, BRAF, NRAS - can help in both prognosis & treatment planning
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9
Q

WHO Principles for the Introduction of Population Screening

A
  • the condition should be an important health problem
  • there should be a recognised latent or early symptomatic stage
  • the natural history of the condition, including development from latent to declared disease, should be adequately understood
  • there should be an accepted treatment for patients with recognised disease
  • there should be a suitable test or examination that has a high level of accuracy
  • the test should be acceptable to the population
  • there should be an agreed policy on whom to treat as patients
  • facilities for diagnosis and treatment should be available
  • the cost of screening (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole
  • screening should be a continuing process and not a ‘once and for all’ project
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10
Q

Notes on CRC screening

A
  • CRC = suitable candidate for screening; prognosis after tumour much better in early stage disease & the polyp-carcinoma sequence offers an opportunity to prevent ca by treating premalignant disease
  • ideal screening test should detect majority of tumours w/o large number of false +ve (ie high sens & spec)
  • screen-detected tumours are much more likely to be at an early stage than symptomatic disease but this doesn’t prove screening is beneficial; 3 biases involved in screening issues
    • selection bias - people who accept screening tend to be particularly health consciuos & therefore atypical of population as a whole
    • length bias - screening tends to detect a disproportionate number of cancers that are slow growing & therefore have a good prognosis
    • lead-time bias - results from the time between the date of detection of a cancer by screening & the date when it would have been diagnosed had the subject not been screened; as survival is measured from time of dx, screening advances teh date at which dx is made, thus lengthening the survival time w/o necessarily altering date of death
    • bc of these biases, effectiveness can be assessed only by comparing disease-specific mortality in a population offered screening w that in an identical population not offered screening - has to be done in context of a well-designed RCT
  • in CRC, 3 trials using FOB have reported mortality data
    • Minnesota - 33% reduction in CRC-specific mortality w annual FOB testing & a significant 21% reduction in a group offered biennial screening
    • Nottingham - trial of biennial FOB testing - 15% reduction in cumulative mortality
    • Denmark - almost identical trial - 18% reduction in mortality
  • NB 2 types of test - FOB and FIT
    • FOB (faecal occult blood) - a guaiac-based test that detects peroxidase-like activity of haematin in faeces
      • false +ves: ingestion of animal Hb or vegetables containing peroxidase
      • sens only 50-70% bc of intermittent nature of bleeding from tumours
    • FIT (faecal immunological testing)
      • isn’t affected by dietary peroxidase or animal Hb & therefore more accurate than the indirect guaiac test
      • FIT is the test of choice for the majority of programmes worldwide due to high sensitivity, specificity, convenience, ease of use (requires only one sample) and cost-effectiveness
      • in RCTs, annual and biennial gFOBT was found to reduce bowel ca mortality by 13-33%, but gFOBT is v non-specific; FIT has a greater sensitivity for detecting advanced adenomas and bowle cancer cf gFOBT
      • a screening programme evaluation of biennial FIT compared w gFOBT reported increased uptake, similar clinical outcomes and good analytical reproducibility, and supported the use of FIT as a first-line screening test
      • in NZ, the threshold of ‘positive’ has been set at 40ug Hb/gram dried faeces (or 200ng Hb/mL buffer solution) - projected to result in 7% of pts receiving a positive test (at 62%), but not overwhelming colonoscopy services; expected that about 70% will have polyps and 10% a bowel cancer
      • offered for ages 60-72, every 2yrs
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11
Q

Work up/preparation for colorectal ca

A
  • history and exam
    • symptoms
    • continence
    • personal/fhx polyps & previous cancers/cancers at other sites
    • other risk factors for CRC
    • PR - extent & position, mobility/fixity, sphincter assessment, accurate measurement of tumour distance from anal verge & dentate line
    • rigid sigi for rectal ca - measure height
  • Investigations
    • colonoscopy - r/o synchronous lesions (CTC only detects polypoid lesions down to 6mm)
    • CT CAP
    • endorectal USS used in some centres to assist with assessment of early rectal ca (reasonably accurate at differentiating T1 from T2, less good at N stage)
    • PET-CT has limited role - when surgical resection of mets being considered to exclude occult disease
    • MRI in rectal ca
  • Consider treatment approach
    • colon ca: usu surgery first
    • rectal ca:
      • traditional approach = surgery +/- preceded by neoadjuvant
        • consider whether neoadjuvant indicated
        • short course vs long course
        • operate 10-12 weeks later - APR or sphincter-sparing
      • organ preservation (TNT) = not yet standard of care
  • Preparation for surgery
    • check iron studies & Hb +/- iron infusion or transfusion
    • bowel prep + antibiotoics
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12
Q

Classify the molecular pathways involved in colorectal cancer

A
  1. Chromosomal instability pathway - 60% of pts w CRC
    - ‘gain of function’ phenotypes via either activation of growth promoting pathways or inactivation of tumour suppression
    - can be inherited (FAP) or sporadic
    - characterised by gross chromosomal abnormalities incl deletions, insertions & loss of heterozygosity
    - molecular events involved include: early APC gene mutations, subsequent activating mutations in oncogene KRAS, DCC, mutations resulting in inactivation of tumour suppressor gene Tp53
  2. Mismatch repair pathway/Lynch pathway
    - dysfunction of DNA MMR genes resulting from germline mutation in one of several different DNA MMR genes, most commonly MLH1 or MSH2; also MSH6, PMS1 or PMS2
    - when mutations in these genes are present, get microsatellite instability (microsatellites being normally occurring repeated sequences of 1-6 DNA base pairs; when unstable they become repeated dozens to hundreds of times)
    - often located in prox colon, large local tumour, typical absence of metastatic disease, poor tumour differentiation
  3. Hypermethylation pathway - 35% pts w CRC
    - most common initiating mutation in this pathway is in BRAF gene (usu V600E codon) which leads to inhibition of normal colon cell apoptosis; other common initiating mutation is KRAS
    - results in high frequency of methylation of some CpG islands (CpG island hypermethylation phenotype [CIMP]-positive) - this is an epigenetic altreation
    - this defect may result in hypermethylation of the promotor region of MMR enzymes eg MLH1 (a DNA repair gene) & silencing of gene expression - will result in MSI-H cancer if there is a further gene mutation or methylation
    - sporadic CRCs w high degree of MSI & BRAF mutations are a clinically distinct subgroup considered to develop from serrated polyps; don’t carry the favourable prognosis of MSI-H tumours w/o BRAF mutation
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13
Q

What are the criteria for local excision of a rectal tumour?

A
  • Superficial T0 or T1 rectal ca
  • Tumour <3cm
  • Tumour involves <30% bowel lumen circumference
  • Tumour mobile & nonfixed
  • Able to achieve clear margins w local excision
  • Favourable histo characteristics based on biopsy (ie well-to-moderately differentiated cancer, no LVI or PNI)
  • No evidence of nodal mets
  • Pts compliant w aggressive postop surveillance
  • *before attempting local excision on a low polyp, should consider if procedure will impact future TME procedures if one required; a local excision can disrupt tissue planes in low rectum near sphincter such that APR is required instead of sphincter-saving procedures eg LAR
  • pts w more advance disease (eg T2 or higher) may also be tx w local excision after counselling if medically comorbid & can’t have transabdo surgery, refuse transabdo surgery or short life expectancy due to metastatic disease
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14
Q

What margins do you need for a local excision of a rectal tumour?

A

Full thickness excision, ideally w ≥10mm grossly normal circumferential margin w depth down to perirectal fat providing minimum 2mm deep margin

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15
Q

Who should have a completion radical resection with TME after a local excision of a rectal tumour?

A
  • Deeper T stage (T2 or greater)
  • Inadequate margins
  • Poor differentiation
  • Submucosal invasion depth >1mm or deep submucosal (SM2/3) invasion
  • Tumour budding
  • LVI or PNI
  • ?? piecemeal disection
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16
Q

Who gets adjuvant therapy in CRC and what is used?

A

The benefits of adjuvant chemotherapy have been most clearly demonstrated in patients with Stage III colorectal cancer (positive nodes, Duke’s C). Benefit in stage II disease is controversial.

FOLFOX is most commonly used. CAPOX/XELOX may be used where 5-FU infusions are to be avoided, may be more toxic.

Current thought is that patients with Stage II disease and high risk features may benefit from FOLFOX.

  • Presentation with perforation or large T4 or obstruction
  • LVI or PNI
  • High grade/poorly differentiated (incl signet ring and mucinous tumours)
  • Elevated CEA
  • <12 nodes in specimen
  • Genetic microassay - for pts w T3pMMR tumours & no high-risk clinicopathologic features, use of 12-gene recurrence score assay is an option for those who consider that a difference in a predicted 5yr recurrence risk of 21 vs 11%, corresponding to estimabed 6% vs 3% absolute reduction in mortality, would change their decision to take or not take adj therapy

Patients with stage II disease without high-risk features who have MSI-unstable tumours have a favourable prognosis and not likely to derive signif benefit from adj fluoropyrimidine-based therapy alone - suggest observation alone. Best approach for pts w stage II MSI-H/dMMR tumours that have high-risk features is uncertain - individualise

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17
Q

Surgery after radical chemoradiotherapy for anal SCC is required in which 4 instances?

A
  1. Residual tumour
  2. Complications of radical chemoradiotherapy
  3. Incontinence or fistula after tumour resolution
  4. Recurrence of tumour
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18
Q

What are the sites of injury of the autonomic nerves of the pelvis and their consequences?

A
  1. Ligation of the IMA
    • The pre-aortic sympathetic fibres may be damaged
  2. Mobilisation of the sigmoid mesocolon
    • The superior hypogastric plexus is at risk
  3. Posterior rectal mobilisation
    • The inferior hypogastric plexus and pelvic splanchnic nerves are at risk
  4. Anterior rectal dissection
    • The terminal branches of the PNS, SNS, or mixed autonomics to the pelvic viscera are at risk

Damage to the SNS = ejaculatory failure or retrograde ejaculation

Damage to the PNS = erectile impotence, urinary retention, vaginal dryness.

  • Pelvic autonomic nerves responsible for normal urinary & sexual function (particularly in male)
  • Presacral nerves lie like a wishbone, joined at sacral promontory & parting as they run distally on both pelvic side walls, & are responsible for ejaculation in male
    • Nerves can be identified at start of posterior dissection & preserved in most cases
  • Nervi erigentes lie anterolaterally in angle between the seminal vesicles and prostate – responsible for male erection
    • Attempts to control bleeding by diathermy, clamping or suturing in this area may result in erectile failure, even when injury has been unilateral
    • Previously, these neural structures thought to be ‘lateral ligaments’ where middle rectal a enters- traditionally many surgeons recommended clamping at this level; but a significant middle rectal artery is uncommon & usually can be isolated & sealed by light application of diathermy – clamping here may damage neural bundles & no longer advocated
  • When a posterior situated tumour & no evidence of disease in ant mesorectum on MRI, most surgeons would dissect immediately posterior to Denonvilliers’ fascia/septum to avoid potentially undue nerve injury
    • But in an anterior tumour, Denonviliier’s fascia/septum should be removed as acts as a barrier to tumour penetration; in these circumstances, nerves are at higher risk
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19
Q

What is (Low) Anterior Resection Syndrome?

How is it quantified?

How can it be treated?

A

Low anterior resection syndrome is a constellation of symptoms, such as fecal incontinence or urgency, frequent or fragmented bowel movements, emptying difficulties, and increased intestinal gas, that occur after a sphincter-sparing resection (ie, anterior resection) of the rectum.

Severity can be quantified using the LARS questionnaire or the MSKCC Bowel Function Instrument.

LARS can be treated with medications, transanal irrigation, pelvic floor rehabilitation, neurostimulation, or surgery. The choice of treatment(s) is based upon the variety, severity, and duration of symptoms.

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20
Q

In what ways can rectal cancer be staged?

A
  1. Duke’s Stage
    • Dukes A - Confined to wall
    • Duke’s B - Beyond wall
    • Duke’s C - Nodes
    • Duke’s D - Metastases
  2. Astler-Coller Stage
    • Stage A: Limited to mucosa
    • Stage B1: Extending into muscularis propria but not penetrating through it; nodes not involved
    • Stage B2: Penetrating through muscularis propria; nodes not involved
    • Stage C1: Extending into muscularis propria but not penetrating through it. Nodes involved
    • Stage C2: Penetrating through muscularis propria. Nodes involved
    • Stage D: Distant metastatic spread
  3. TNM staging
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21
Q

What are the indications for neoadjuvant chemoradiotherapy in rectal cancer?

A

Threatened CRM

T3/T4 disease (though T3a/b potentially can avoid if mid/high)

Nodal involvement (controversial unless threatening CRM)

EMVI

Low rectal tumours (mesorectum fizzles out)

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22
Q

How is malignancy in a pedunculated colonic polyp classified?

A

Haggitt’s Levels.

Risk of LN metastases of 1-3 = <1%

Risk of LN metastases of level 4 = 12-25%

Concerning histology:

  • LVI
  • Resection margin less than 2mm
  • Poorly differentiated lesions
  • Piecemeal resection
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23
Q

What are the histological sub-types of anal SCC?

A
  • Squamous cell
  • Basaloid/cloacogenic
  • Muco-epidermoid cancers

Basaloid tumours form arise in the transitional zone.

The different morphological subtypes of anal SCC do not appear to have different prognoses.

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24
Q

How is malignancy in a sessile polyp classified?

A

Kikuchi classification:

SM one third - 1-3% node mets

SM two thirds - 8%

SM three thirds - 23%

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25
Q

What are the criteria for local excision of a rectal tumour with TAE or TAMIS?

A
  • Superficial Tis or T1 disease
  • Tumour less than 3cm in diameter
  • Tumour involves less than 30% diameter
  • Tumour is mobile / non-fixed
  • Favourable histological features
  • Node negative on all imaging modalities
  • Patient compliant with intensive follow up.
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26
Q

Describe what constitutes the various AJCC rectal cancer stages and what are the 5 year survivals in each?

A
  • Stage I - Small tumour, node negative - 93%
  • Stage II - Large tumour, node negative - 60-80%
  • Stage III - Any tumour, node positive - 30-60%
  • Stage IV - Mets - 8%
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27
Q

How is “on-table colonic lavage” performed?

A
  1. Mobilise large colon; bring down splenic flexure
  2. Excise tumour with oncological resection
  3. Transect appendix at half-way and insert 12-14Fr Foley into caecum and inflate balloon
  4. Vicryl tie to secure Foley
  5. Place additional side square drape
  6. Exteriorise bowel and place end into sterile camera-drape and secure with artery forceps; place distal end of camera drape into bucket on floor
  7. Lavage with 6-8L of warmed normal saline
  8. By now, any devascularised bowel will have demarcated; resect as required and anastomose.
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28
Q

What is the mean doubling time for a colonic tumour?

A

130 days

Hence, approximately 5-10 years until it reaches a size to cause symptoms.

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29
Q

Summarise the evidence base around anastamosis technique in right hemicolectomy.

A
  1. Considering mechanical colorectal anastomosis, level 1a evidence indicates that stapling and hand-sewn anastomoses give equal results with regard to clinical AL.
  2. A single-layer continuous suture technique by an inverting technique with slowly absorbable monofilament material seems preferable on the basis of level 1b evidence.
  3. Large cohort studies that are available, describing low rates of AL for the used anastomotic technique, might indicate that dedicated, high-volume colorectal surgery has a role in lowering the incidence of AL because of a surgeon’s familiarity with a certain technique.
30
Q

What is the effect of colonoscopy screening programmes on colorectal cancer mortality?

What is the NNS?

A

3 large RCTs (Denmark, UK, Minnesota) have suggested a 20% reduction in relative risk.

Number needed to screen is ~800-1250

31
Q

What are the principles of rectal cancer surgery?

A
  • TME
    • optimal therapy for low or mid-rectal cancer
    • TME for upper rectal ca = debatable & now considered unnecessary for oncological reasons; extent of mesorectal spread distally been reported to be up to 3-4cm below distal mragin of tumour - so mesorectal celarance of 5cm below lower edge of tumour by mesorectal transection = sufficient and probably results in less leak and better post-op function
  • proximal margin 5cm
  • distal margin: 5cm for upper rectal cancers; for cancers above distal mesorectal margin, minimum 2cm; for cancer at or below distal mesorectal margin, 1cm neg distal margin in conjunction w a TME may be acceptable, espec in setting of neoadj
    • failure to achieve 1-2cm gross neg distal margin = convert to APR
    • NB for v low tumours the mesorectum has tapered out and is no longer an issue; in these cases distal muscle tube excision is the issue
  • vascular ligation
    • recommended to take IMA 1-2cm distally from origin to reduce autonomic nerve injury (high ligation) or below origin of asc left colic (low tie technique)
      • ligation of IMA at aorta w resection of associated LNs (high tie) may be indicated in selected pts when clinically suspicious LNs are present at level of IMA or to provide mobilisation to afford adequate length for a tension-free anastomosis
      • low tie had no worse outcomes in blood loss, operative times, defecatory function, postop complicaitons incl leaks, LN yield or survival & better preserved genitourinary & sexual function
    • general opinion has always supported using desc colon instead of sigmoid when anastomosing to anal canal for two reasons - 1) sigmoid generates fairly high pressures which could lead to poor function and 2) marginal artery may be minimal/absent in sigmoid which is thus pronen to ischaemia if used for anastomosis
    • but desc colon won’t generally reach unless splenic flexure mobilised and there is a high tie of IMA as left colic is too short & won’t allow desc colon to reach - hence low anastomosis will almost always need a high ligation but for technical rather than cancer-specific reasons
    • HAR can usually use high or low tie
  • LN dissection
    • benchmark of 12 LNs
    • lateral pelvic LN dissection
      • while TME addresses main route of reectum, distal anorectal segment is additionally drained by int iliac route via middle rectal & pudendal vessels; progression of advanced rectal ca along lateral rectal pedicles may lead to lateral spread of disease, affecting LNs of pelvic side wall
      • lateral (or extended) pelvic LN dissection removes nodal compartment along common iliac, int iliac & obturator arteries
        • whether to routinely perform this differs by geography
          • Japanese - recommend it for T3/T4 low rectal ca below peritoneal reflection
          • Western - do ipsilateral pelvic LN dissection if clinically positive lateral pelvic lymph nodes only
          • LPLD controversial particularly in XRT setting (XRT may treat)
          • controversy around MRI acccuracy for detection

APR: Low rectal ca defined as ‘adenocarcinoma with its lower edge at, or below, the origin of the levators on the pelvic sidewall; usu corresponds to a tumour within 6cm of anal verge. Cancers at this level commonly involve levators adn sphincter complex & concept of Extra Levator AbdominoPerineal Excision (ELAPE has been a significant advance in improving outcomes in these pts w high risk tumours) - reduces both CRM positivity & tumour perforation rates thus reducing local recurrence and improving survival

32
Q

Describe the typical histology seen in Lynch Syndrome Colorectal Cancer

A

(LaMPS)

  • Lymphoid aggregates
  • Mucinous pattern
  • Poorly differentiated
  • Signet ring differentiation
33
Q

What type of bowel screening tests are there?

Which is used in NZ bowel screening from 60-74yo?

A
  1. FIT - Fecal immunochemical test - specific antibodies to detect human blood in the stool
  2. (gFOBT) Guaiac-based fecal occult blood test - guaiac reagent-impregnated paper blue as the result of a peroxidase reaction. Requires dietary restriction.

NZ uses FIT

34
Q

What investigations would you do for anal SCC (and AIN)?

A
  • consider HIV testing
  • female pts - make sure cervical screening up to date
  • detailed EUA - optimum assessment of tumour in terms of size, involvement of adjacent structures & nodal involvement + biopsies
    • AIN: if suspected, EUA w excision of discrete lesions which are small enough not to risk anal stenosis, biopsy of larger suspicious areas & anal mapping (clock face biopsies w a skin punch) to exclude field change
    • anal & genital papillomavirus-assoc lesions may be identified clinically by naked eye or w high-res anoscopy w application of acetic acid to epithelium - ‘aceto-white’ lesion
    • high grade AIN may be characterised by hyperkeratosis or changes in pigmentation of epithelium - thus carcinoma in situ may appear white, red or brown, the pigmentation commonly being irregular
      • lesions may be flat or raised but ulceration suggestive of invasive disease
  • biopsy or FNA groin nodes if radical block dissection considered - may not be reuqired if PET/CT that shows avid uptake
  • tumours markers not useful
  • MRI pelvis & CT CAP for staging
  • FDG PET/CT been suggested for staging & may help w planning of rad & improved assessment of locoregional LN involvement
  • ?endoanal USS may be useful in small tumours as more info usu available from MRI
35
Q

Discuss the advantages and disadvantages of laparoscopic surgery in colorectal cancer.

A

Advantages (as per Cochrane review):

  • Reduced blood loss
  • Earlier recovery
  • Reduced pain
  • Improved pulmonary function
  • Reduced rates of incisional hernia
  • (2016 meta-analyisis - fewer early and late postop bowel obstruction)

Disadvantages:

  • Longer operating time; ~30-60 minutes longer
  • Some evidence to suggest not cost effective
  • Major concerns regarding rectal cancer TME
  • Significant learning curve
  • High conversion rate in obese, previous surgery, advanced disease

Meta-analyses of RCT demonstrate faster recovery with no detrimental impact on recurrence or survival for lap compared to open colectomy for the treatment of colon cancer.

Laparoscopic rectal cancer surgery has been compared with open surgery in 5 RCTs with conflicting results. Local data (the ALaCaRT trial) demonstrated that lap. surgery fails to achieve non-inferiority compared to open. Although 2yr recurrence rates & DFS rates weren’t different between lap & open groups, the event rates were low at 2yrs & longer f/u data required to be conclusive.

36
Q

What are the principles of a colonic resection for colon cancer?

A

Complete mesocolic excision - analogous to TME in rectal ca; 3 principles

  • dissection in embryologically defined mesocolic plane
    • improved survival
  • central ligation of the vascular pedicle (CVL)
    • debate about how much this contributes to onc outcome and confers increased periop risk in certain situations (aka D3 resection)
    • survival benefit in T3 or T4 disease in both node pos and node neg pts - perhaps due to removal of undetected micrometastatic disease within mesnetery, but difficult to accurately predict T stage to know which operation to do
    • such ligation of IMA on aorta often described, but unless N3 nodes dictate, ligation 1cm from origin of IMA preferred in order to avoid damage to hypogastric plexus, thus minimising urinary & sexual dysfunctino
    • similarly, damage to autonomic nerves of SMA may result in severe diarrhoea; some prefer to dissect ileocolic artery to origin on SMA by displacing bowel & mesentery folly to left & upwards but Japaene data suggest lymphatic drainage from right colon limited to front of SMV & resection behind vein not recommended
  • resection of an adequate length of colon on either sode of the tumour
    • 5cm for colon
    • for rectum, 2cm distal margin sufficient (distal spread 1-2% when distal margin 2cm); in ultralow, cancer free margin of 1cm can be accepted

Some debate about the utility of CME & its relative contributions to cure of the different elements

Practical guidance on extent of resection (see separate document for operative stuff from sabiston)

  • R hemi for tumour of caecum, R colon or R transverse
    • Ileocolic vein taken at or within 1cm of junction w SMV
    • R colic w or w/o R branch of middle colic artery taken close to or at its origin
  • Tumour of transverse colon
    • Companion says when Japanese guidelines on extent of longitudinal resection can’t be fulfilled by either R hemi or segmental left colectomy, middle colic is transected at its origin, preserving rest of colon
    • “although extended R hemi advocated for transverse colon ca by many, more difficult operation w likely greater morbidity”
  • Tumour of splenic flexure – segmental left colectomy done
    • Divide origin of left branch of middle colic & that of the ascending left colic
    • All nodal tissue taken from left aspect of middle colic & left side of IMA
    • 5cm of bowel away from lesion on other side of each vessel is included in the resection – satisfactory from onc perspective & preferred to an extended R hemi as function is preserved
  • tumour of left colon ca distal to ascending left colic – left hemicolectomy
    • with CVL & anastomosis of prox descending colon to rectum at 15cm from anal verge
    • involves mobilization of splenic flexure, incl left half of transverse, w division of IMV at inf border of panc to allow anastomosis to rectum w/o tension
    • in v rare circumstance that there is a large desc left colic arising from middle colic it is preserved, as division of this may result in ischaemia of distal colon
  • distal sigmoid cancer – resection performed as described above for left hemi but taking 5cm distal to cancer & performing an anastomosis to the rectum
37
Q

Management of anastomotic leak

A
38
Q

Indications for adjuvant radiotherapy for colon cancer

A

Generally not done - high risk of radiation enteritis affecting adjacent SB. UTD offers to pts w estimated risk of local recurrence ≥30%: asc or desc colon primary w either T4b disease or positive resection margin (these structures anatomically ‘immobile’ & anatomic constraints caused by close proximity of these bowel segments to retroperitoneal tissues may preclude wide resection, increasing risk of residual disease & local failure cf mid sigmoid/mid transverse

39
Q

What is in:

XELOX/CAPOX

FOLFOX

FOLFIRI

5-FUFA

A

XELOX/CAPOX = oxaliplatin + capecitabine (xeoloda)

FOLFOX = fluorouracil, leucovorin (folinic acid) + oxaliplatin

FOLFIRI = folinic acid, fluorouracil + iriniotecan

5-FUFA = fluorouracil + leucovorin (folinic acid)

40
Q

What is used for adjuvant chemo in colon cancer

A

Should be started within 8wks of surgery if at all possible

  • Oxaliplatin-based chemo (rather than fluoropyrimidine-based regimen alone) recommended for fit pts w resected stage III disease, <70yrs and likely to tolerate oxaliplatin, and if tumours are MMR deficient or microsatellite unstable
    • survival benefit for adding oxaliplatin in stage III disease
    • benefits less well established in >70yrs
    • in dMMR cancers, fluoropyrimidines alone are ineffective for adjuvant therapy
  • Originally the fluoropyrimidine bit was IV 5FU, but oral capecitabine is as effective (toxicity profiles differ; capecitabine causes more hand-foot syndrome; 5FU causes more stomatitis and neutropenia)

What is given:

  • FOLFOX (oxaliplatin, leucovorin, short-term infusional FU) = standard & is preferred when 6mo adjuvant therapy is chosen
    • 14 day cycle. Oxaliplatin + leucovorin on day 1 as 2hr infusion, FU as slow IV push on day 1 then infusion over 46hrs w ambulatory pump for outpatient treatment
  • CAPOX/XELOX (oxaliplatin + oral capecitabine) = may be more toxic but selected over FOLFOX if shorter choice of adjuvant therapy (eg 3mo) chosen or if ambulatory infusion pump not feasible
    • may be able to give CAPOX w/o central line but signif no of pts get pain w oxaliplatin through peripheral vein & many centres routinely use central line for it
    • 21 day cycle. Oxaliplatin as 2hr infusion day 1, then BD capecitabine days 1-14
  • NB optimal duration of oxaliplatin-based chemo evolving; standard is 6mo for high risk cancers (T4N2) which is superior to 3mo, but small improvement in 5yr OS w additional 3mo & need to balance against increased neuropathy; for low risk cancers (T1-3N1) 3mo may be ok

Things not recommended:

  • irinotecan - no benefit
  • bevacizumab - humanised monoclonal antibody targeting VEGF - doesn’t improve outcomes for stage II/III disease (but adding it to FOLFOX or FOLFIRI improves outcomes in metastatic CRC though side effects)
  • cetuximab - mouse/human chimeric monoclonal antibody that targets EGFR - benefit in metastatic CRC in pts w wild-type RAS/BRAF; no benefit in adjuvant setting
41
Q

What are the acute and long-term toxicity associated with fluroprimidine and oxaliplatin chemotherapy?

A
  • fluorpyrimidine:
    • lethargy, mucositis, diarrhoea, hand-foot syndrome
    • common but usu reversible: watery eyes, minor nose bleeds, taste alterations
    • risk of neutropenic sepsis low but <1% pts deficient in enzyme dihydropyrimiidine dehydrogenase & severe toxicity may be seen within first 3wks of treatment
  • addition of oxaliplatin
    • increased risk of diarrhoea & neutropenia
    • but most signif = neurotoxicity: paraesthesia & cold sensitivity of extremities & larynx/uppr oesoph during treatment, w peripheral sensory neuropathy either during or after, w incidence & severity reducing over time
42
Q

Describe the anatomic vascula landmarks for colorectal resection

A
  • ileocolic pedicle originates from superior mesenteric vessels just caudal to D2
  • middle colic vessels originate from superior mesenteric vessels at level of inferior margin of pancreas
  • IMV can be easily identified at level of ligament of Treitz
  • IMA originates from aorta, 2-3cm caudal from area where IMV is identified; its origin is surrounded by mesenteric & hypogastric nervous plexus
  • left colic originates ~2cm distally to origin of IMA
43
Q

What factors are considered when selecting a surgical treatment for rectal cancer

A
  • Distance of ca from anal verge (ie low, mid or upper rectal ca + distance from lower border of tumour to top of anorectal ring (which informs surgical decision making for sphincter preservation
    • Low = 4-8cm form anal verge, mid 8-12cm, upper 12-15cm (anal canal 0-4cm from anal verge)
    • But surgical decision making most dependent upon distance from lower border of tumour to top of anorectal ring (ie top of sphincter complex) rather than anal verge
  • Presence of invasion into lateral pelvic walls and/or other intra-abdominal organs
  • Size of ca
  • Presence of regional LN mets
  • Pt’s pelvic anatomy
  • Pt’s presurgical anorectal sphincter function
  • Whether or not pt can tolerate transabdo surgery
44
Q

Who should have a defunctioning stoma after resection and anastomosis for rectal cancer?

A
  • pts who benefit most are those with low anastomosis within 5-8cm of anal verge, male sex or preop rad, also consider if immunosuppressive thereapy eg steroids
  • defunctioning stoma reduces rates of both clinically relevant leaks & reoperations
  • some say defunctioning stoma should be considered in all pts who have had a TME for rectal cancer
  • risk of leak = higher the lower the anastomosis
45
Q

What are the predictors of local recurrence for rectal cancer

A
  • Size of primary
  • Involvement of CRM = main determinant
    • defined as tumour within 1mm of margin of resected specimen; can also be involved due to metastatic disease
  • distal location of tumour/nearness to anal verge
  • extramural vascular invasion
  • tumour differentiation
  • nodal status - debated; some have found LN involvement not assoc w higher local recurrence provided optimal TME performed
  • extent of extramural spread
  • peritoneal involvement by tumour
46
Q

Complications of preop radiotherapy for rectal cancer

A

Early: perineal wound breakdown, diarrhoea, proctitis, UTI, SBO, leucopenia, venous thrombosis

Also shown to have adverse effects on anal function & on function and integrity of coloanal anastomosis w or w/o formation of a colonic pouch

Preop chemorad has less acute toxicicty than postop

Late: anorectal dysfunction (faecal incontinence, poorer resting/squeeze pressures, increased risk of sexual dysfunction, sarcal insufficiency fractures (3% at 3yrs)

47
Q

Follow-up after anterior resection

A
  • Clinical rv in OPC: PR and rigid sigi (not first visit)
    • at 2 wks post op for histo
    • at 3 mths post op
    • then q6monthly out to 2yrs
    • then annually out to 35yrs
  • complete colonoscopy within 3mo if not done pre-op
  • first surveillance colonoscopy at 1yr then annually after that; extend to 2-5yrly stratified by risk (CHECK)
  • CT at 12 & 24mo
  • CEA q3mo out to 2yrs then q6mo
48
Q

Discuss neoadjuvant therapy in rectal cancer and the evidence behind it

A
  1. Neoadjuvant therapy has been demonstrated to offer better outcomes than adjuvant therapy
  2. Improved surgical technique with TME must account for some of the improvements in LR
  3. Refined multi-modal care & newer chemo regimens are also improving DFS
  • 1997 Swedish Trial
    • surgery vs neoadjuvant rad then surgery
    • lower LR rates with neoadj rad
  • 2001 Dutch TME trial:
    • TME alone vs TME + neoadj short course rad
    • even with TME, there was a reduction in LR with neoadj rad
  • 2004 German Rectal Cancer Study:
    • TME; neoadjuvant vs adjuvant chemorad (long course)
    • neoadj had more favourable long-term toxicity profile & fewer local recurrences than postop therapy; overall survival appears similar
    • more patients in the preop treatment group were able to undergo sphincter-sparing procedures
  • 2013 TROG (Trans-Tasman Radiation Oncology Group)
    • short course vs long course rad
    • no significant difference in OS or complications
    • higher rate of PCR in long course
49
Q

What are the indications for neoadjuvant therapy in rectal cancer?

What is used?

A
  • T3 or T4 on pretreatment staging
  • Threatened CRM (by tumour or nodes)
    • NB T3 not the same as threatened CRM - could have T3 in a really bulky part of mesorectum which is fine, vs T2/T3 straddling peritoneal reflection which threatens CRM
  • EMVI
  • Nodal disease
  • Tumours requiring APR (ie low)
    • b/c published results have shown poor surgical CRM in low tumours (mesorectum runs out)
    • High quality definitive evidence is lacking that preop therapy can consistently convert pts who need an APR to where a LAR is feasible

In my institution we use long course chemoradiotherapy, however we consider short course for logistical reasons and there are some advantages with regards to toxicity and resources. Also there is increasing evidence that short course radiotherapy may in fact have equivalent outcomes to long course chemoradiotherapy. Particularly in this COVID era with its associated resource implications, one could make a strong argument for using short course.

The use of preoperative therapy for a distal clinical T1N0 or T2N0 rectal cancer in an attempt to convert the operation from a needed APR into a LAR is controversial and not yet an accepted standard of care; however, if the pt is a poor surgical candidate or declines APR, initial RT or CRT may be chosen, followed by restaging w MRI or EUS.

The optimal management of cT3N0 (based on preop imaging) is unclear; some of these pts have a sufficiently favourable prognosis that some have questioned utility of upfront CRT for pts w cT3N0 tumours that don’t threaten the CRM, particularly those involving the upper rectum, given favourable low rates of local recurrence after TME alone in Dutch TME trial and others; however as many as 1/5 may be understaged by preop imaging & found to have involved LNs at surgery (and given the downstaging effect of CRT likely even larger number of these pts would have been found to have node-pos disease if had surgery initially). ESMO guidelines now suggest that T3 pts with a depth of invasion beyond muscularis propria ≤5mm are appropriate candidates for upfront surgery rather than neoadj, even if node positive, as long as levators not threatened, mesorectal fascia clear and no extranodal extension. Preop MRI can identify pts w cT3 tumours and <5mm of extramural invasion but T3 stage subclassification isn’t incorporated into TNM staging and isn’t validated as a prognostic factor; approach for these patients not yet standard.

NZ Bowel cancer quality improvement report: The current New Zealand guidelines for the management of early colorectal cancer8 recommend either preoperative short-course radiotherapy or preoperative long-course chemoradiation for people with rectal cancer who are at risk of local recurrence. Preoperative long-course chemoradiation is recommended for people who have a low rectal cancer or a threatened circumferential resection margin. Short-course radiotherapy is more convenient for patients, has fewer short-term side effects and uses fewer health resources, so it is should be considered for patients at increased risk of pelvic recurrence, who are not at risk of positive resection margins.

50
Q

Role of TNT, watch and wait, organ preservation

A
  • UTD: for most pts w locally advanced rectal cancer who are at high risk for a margin-positive resection (ie T4 disease or an involved mesorectal fascia), as well as for those w clearly node-positive disease and a low-lying rectal tumour, they suggest TNT (ie oxaliplatin-based chemo combined w long-course CRT or short-course RT) rather than long or short course alone
    • TNT assoc w increased compliance w chemotherapy (bc of greater tolerability in the preop vs postop setting), improved local control and the ability to consider nonoperative treatment if the pt declines surgery
    • generally don’t suggest this strategy in pts w lower-risk locally advanced cancers (ie early cT3N0 disease w/o a threatened mesorectal fascia, espec involving the upper rectum, distal cT1-2N0 tumours) bc/ these pts may not need chemo at all
    • for cT3N0 disease that is low lying and would require either an APR or a v low coloanal anastomosis, the decision to pursue TNT for the primary goal of ORGAN PRESERVATION is a complex decision that requires careful explanations of the pros and cons w the patient
      • cannot be recommended as the standard of care currently until datasets become more mature
    • If TNT is chosen, and chemo is initiated first, recommend proceed cautiously w scans after 2mo of chemo and move directly to CRT if no response is seen; particularly important in setting of a tumour w deficient MMR/hMSI, a substnatial proportion of which may be resistant to neoadj chemo
      • during the chemo portion suggest oxaliplatin-based chemo rather than FU alone
    • while TNT is emerging as a new standard for the treatment of locally advanced rectal cancer, there are several controversial and unresolved issues, incl best way to sequence radiation and chemo, exact amount of chemo that is needed, and whether outcomes may be better with oxaliplatin and irinotecan-containing regimen (FOLFIRINOX) vs FOLFOX alone
      • preliminary data from OPRA trial suggest that at least for long-course RT, an increased interval from RT to surgery may be an important mechanism of benefit of TNT, lending support to administering RT first followed by chemo, but no trials directly comparing different sequences of therapy for eitehr long or short course
    • non-op mx for complete clinical responders to neoadj therapy remains controversial; despite lack of randomised trials, non-operative management is becoming an acceptable alternative for those pts who experience a clinical complete response to neoadj therapy, especially TNT
      • should be emphasised that mature data not yet available to ensure that survival outcomes are equivalent, and this is particularly important given the natural hx of rectal ca and the rate of late recurrences between 5-10yrs after resection
    • year 2020 consensus-based guidelines from NCCN state that for pts who achieve a cCR w no evidence of residual tumour on PR, MRI and direct endoscopic evaluation, an initial nonoperative approach may be considered w an experienced multidisciplinary team; however there is not uniform agreement on whether nonoperative approaches should be considered standard at this time. 2020 guidelines from ASCRS say pts w apparent clincial complete response to neoadj should typically be offered radical resection though ‘watch and wait’ can be considered for highly selected pts in the context of a protocolised setting
    • given the degree to which the risk of local and distant relapse has not been adequately characterised, any decision for nonop mx should involve a careful discussion w the pt as to their risk tolerance
  • Watch and wait
    • with standard neoadjuvant (either, some think more so w long course than short course though not good evidence for this), can get complete PATH response on subsequent histo- 10-15%
      • but with watch & wait which is based on complete CLINICAL response, up to 30% recur in the first 3yrs- so if don’t operate, need close surveillance
        • 95% of these had salvage therapy with sphincter preservation in 50%
  • TNT
    • 40-45% of complete clinical response
    • still need close surveillance as above
    • appealing both because
      • organ preservation - rectal cancer surgery is morbid; APR has permanent stoma, LAR get ULAR, chronic leak etc
      • MAY reduce risk of metastatic disease which is the holy grail in rectal cancer - everyone worries about local recurrence but risk of metastatic disease in rectal ca is 10-30% in 1st 3yrs
51
Q

What is the optimal time interval between CRT and surgery?

A

At least 5 RCTs have examined the time interval between CRT and surgery, only 2 of which have shown a higher pCR rate with longer cf shorter wait times; in neither trial did higher pCR rates with delayed surgery translate into better oncologic outcomes (survival, recurrence). A meta-analysis from 4 of these trials and 22 other nonrandomised series concluded:

  • compared w a standard 6-8wk interval from completion of neoadj RT to surgery, an interval of ≥8wks was assoc w greater odds of pCR and tumour downstaging but no differences in rates of complete (R0) resection, sphincter preservation or complication
  • the higher rate of a pCR translated into reduced distant metastases and overall recurrences, but not reduced local recurrences or overall survival
  • consensus-based guidelines are discordant
    • ESMO: no specific recommendation other than to state that in practice there is wide variation in timing of surgery (4-12wks) & that longer intervals may enhance pCR rates, but this risks repopulation, delays the use of postop chemo and risks subsequent mets
    • NCCN guidelines suggest surgery be performed 5-12wks after full-dose neoadj CRT
52
Q

Notes on local excision of rectal cancer

A
  • Local excision can be done thru both endoscopic & transanal means
    • Endoscopic – routine polypectomy, EMR, ESR
    • Surgical – standard transanal ecision, TAMIS or TEMS
  • Endoscopy
    • Use of this for transanal excision of large rectal lesions has expanded w availability of improved staging techniques, including endorectal & endoscopic ultrasound & MRI
    • PR is also accurate at staging lesions within reach of the finger; a lesion that is soft to the touch typically is benign – goes particularly for villous adenomas of the rectum
    • Villous adenomas of lower rectum = commonly amenable to a transanal excision or endoscopic excision – key is excision w a free margin to risk of local recurrence
    • Partial- or full-thickness for cancers) excision of lesions can be done; w partial-thickness for benign lesions, these techniques are made easier by submucosal injection of a solution to elevate the lesion off the underlying muscularis mucosa
    • Endoscopic submucosal dissection is used for lesions that are superficial – a hollow cap is placed over tip of endoscope & after submucosal injection has been done to lift lesion away from underlying muscularis, suction is applied to the colonoscope when the cap is positioned over the lesion; lesion is drawn into the cap by suction, the snare that fits around the cap then is tightened, cutting off the area of mucosa that has been aspirated into the cap, much like a routine polypectomy
      • Fairly large areas of mucosa can be safely removed
    • When lesions go deeper through muscle wall, can sometimes do ESR – submucosal injection performed to facilitate dissection of a lesion off the underlying colon wall after the margin has been scored
  • Surgical transanal resection of rectal lesions has long been popular as a form of sphincter-sparing surgery but become less so w advent of circular staplers & espec w minimally invasive techniques for resectional rectal surgery
    • Traditional criteria: small lesions (<2cm diameter), well differentiated cancers within reach of index fingers, and lesions that are mobile (not fixed); T1 lesions are ideal & pts w T2 or T3 lesions not suitable as recurrence rate after local excision has been unacceptable
    • If a traditional local excision is performed, cautery used to score a 1cm margin around lesion; traction used and a full-thickness incision is performed down to perirectal fat – defect can be sutured closed or left open to heal by secondary intention
    • Local excision is safe when performed for lesions that are located lateral to or posterior to the rectum due to the presence of the mesorectum
      • if located in anterior rectum in women, there is risk of iatrogenic rectovaginal fistula or, in case of men, injury to prostate
      • if go higher above 6 or 7cm, concern that one may be intraperitoneal – these procedures are most safely performed in lower rectum
  • Transanal endoscopic microsurgery (TEMS) and transanal minimally invasive surgery (TAMIS)
    • In past, local excision could only be done transanally under direct vision
    • Equipment & technique of TEMS was developed to allow transanal surgical access to virtually the entire rectum – i.e. made possible the excision of larger lesions & lesions higher than could be safely performed using conventional transanal surgery – required a specialized set of instruments & demanded a v special set of skills working w rigid instruments w a high learning curve
      • Has been modified to adopt transanal use of lap instruments (TAMIS) – i.e. TEMS been largely supplanted w the technique of TAMIS, whereby standard lap instruments & an access port similar to that used for single-port laparoscopy is used in anal canal to allow for safe excision of lesions above the level of the v distal rectum
      • Due to the anchoring of the lap access device itself, this technique not suitable for lesions in the very lower rectum
    • TEMS been shown to successfully treat selected early rectal cancers w favourable pathology (pT1, <3cm in diameter, well differentiated, no LVI)
      • If full-thickness histo shows adverse features, early completion surgery been shown to provide similar cancer-specific survival to conventional upfront rectal excision surgery
    • Advocates of TEMS for ERC (T1N0V0) argue no difference in cancer-specific survival & morbidity of major resectional surgery is avoided
    • TREC trial aiming to assess combo of neoadj therapy & TEMS compared w conventional rectal excisional surgery
53
Q

Describe incidence and types of anal cancer

A
  • rare - 2-4% of large bowel cancers
  • 80% squamous origin (SCC) - from squamous epithelium of anal canal & perianal area
    • SCC of anal canal 5x more common than perianal SCC
  • 10% adenocarcinomas - from glandular mucosa of upper anal canal, anal glands & ducts
  • anal melanoma = v rare & aggressive
  • lymphomas & sarcomas even less common but increased incidence in recent yrs espec in pts w HIV

WHO classification of carcinoma of anal canal

  • intraepithelial neoplasia
    • anal/perianal intraepithelial neoplasia
    • Paget’s disease
  • carcinoma
    • SCC
      • WHO now reccomends generic diagnostic term ‘SCC be used for all squamous malignancies of anal canal & can give additional descriptive comment about specific histo features eg basaloid features previously basaloid differentiation pattern was known as cloacogenic carcinoma but this now obsolete term
      • 2 variants differ in prognosis from typical squamous tumours
        • verrucous carcinoma (aka giant condyloma or Buschke-Lowenstein tumour) - resembles condyloma macroscopically but larger & fails to respond to conservative therapy - intermediate between benign & malignant; locally aggressive & exhibit malignant behaviour but true invasive growth pattern not present - WLE or APR; some may respond to chemorad
        • SCC w mucinous microcysts - unfavourable prognosis cf that of SCC
      • term ‘epidermoid tumours’ includes squamous cell, basaloid/cloacogenic carcinomas & muco-epidermoid cancers
    • BCC
    • adenocarcinoma
    • mucinous adenocarcinoma
    • poorly differentiated neuroendocrine carcinoma
      • large cell neuroendocrine carcinoma
      • small cell neuroendocrine carcinoma
    • undifferentiated carcinoma
    • others
54
Q

What are the risk factors for and pathogenesis of anal SCC?

A
  • history of receptive anal intercourse in men (RR 33x)
  • history of genital warts (RR 27x in men, 22% in women)
  • HIV
  • association w HPV type 16 & less commonly types 18, 31, 33 - DNA found integrated into genoma of the SCC
    • HPV infection of anogenital region v common - >70% sexually active adults have at some time had occult or overt genital HPV infection
    • common warts = HPV 1&2
    • genital warts = HPV 6&11; also may be isolated w LSIL
    • HPV types 16 (84%), 18 (next most common), 31 and 33 = much less commonly assoc w genital warts but more commonly found in HSIL & invasive carcinomas

Anal SCC is considered to be a virally induced malignancy; HPV serotypes 16 and 18 cause chronic infection in the anogenital epithelium and progress from intra-epithelial malignancy to invasive disease due to chronic dysplastic changes as well as protein mediated inhibition of p53 and Rb (tumour suppressor genes) from protein E6 and E7 respectively.

55
Q

What are the premalignant lesions of the anus?

A

LSIL (low-grade squamous (anal) intraepithelial lesions) - includes AIN I

HSIL (high-grade anal intraepithelial lesions) - includes AIN II-III (mod or high grade)

anogenital intraepithelial neoplasia of cervix (CIN), vulva (VIN), vagina (VAIN) & anus (AIN) = graded from I-III, according to number of thirds of epithelial depth that appear dysplastic on histo section - ie in grade III, cells of whole thickness of epithelium = dysplastic, synonymous w carcinoma in situ

56
Q

What are the patterns of spread of anal cancer?

A
  • Local
    • mainly cephalad - may appear to have arisen in rectum
    • outwards - into sphincters & rectovaginal septum, perineal body, scrotum or vagina
  • lymph node mets frequent, espec in tumours of anal canal
    • initially to perirectal nodes, then inguinal, haemorrhoidal & lateral pelvic nodes
    • only 50% enlarged nodes at presentation will subsequently be shown to contain tumour (rest enlarged from secondary infection)
  • haematogenous spread late, usu assoc w advanced local disease
    • liver, lung, para-aortic nodes & bones = principal sites
    • also kidneys, adrenals, brain
57
Q

What is the management of anal SCC?

A
  • current standard of care for anal SCC = chemoradiotherapy w 45-50Gy radiotherapy in 28 daily fractions with mitomycin C and 5FU - in all cases except those where local excision = complete or there are contraindications to radiotherapy
    • mitomycin given on day 1 with 5FU infusions given on days 1-4 and 29-32
    • includes prophylactic low-dose rad to clinically uninvolved inguinal nodes for all T2-4 tumours of anal canal & margin due to high risk of recurrence
    • pts w T2 lesions & residual disease after 45Gy, T3 or T4 tumours or node-positive disease are nusu treated w an additional 9-14Gy for a total dose of 54-59Gy
  • achieves equivalent survival rates to surgery but w advantage of stoma avoidance in majority
  • inguinal LN involvement now treated by chemorad but if this is contraindicated then block dissection can be done at APR
  • role of surgery:
    • initial dx - EUA
    • lesions at anal margin - T1 lesions (<2cm) may be treated by local excision alone, avoiding need for chemorad; need clear margin of skin & deeper tissue (≥5mm) which may require excision of part of distal sphincter complex
    • lesions of anal canal - don’t locally resect bc of risk of incontinence; APR only if contraindication to primary chemorad/declines
    • defunctioning stoma prior to oncological treatment if: incontinence, obstruction, perianal sepsis, fistulisation
    • role for surgery after failure of primary non-surgical therapy, either early or late; 4 situations - residual tumour, complications of treatment (eg radionecrosis of anal lining w severe pain), incontinence or fistula after tumour resolution, subsequent tumour recurrence
      • myocutaneous flap for recon of perineal area recommended in salvage APR
    • if extensive pelvic disease extending around vagina/bladder, pelvic exenteration in fit pts may need to be considered
  • APR for anal ca similar to that for rectal ca but particular care taken to clear space below pelvic floor (20% cases incurable surgically at presentation)
58
Q

What is the management of LSIL & ASIL of anus?

A
  • natural hx of anal HPV infection & intraepithelial neoplasia = in large part dependent on infecting viral type & on host immune state
    • LSIL = high risk of subsequent dx of HSIL but LSIL considered to represent marker for risk of HSIL rather than direct precursor
      • risk factors for HSIL in these pts incl HIV/CD4 count, presence of HPV & presence of multiple types
    • HSIL = true cancer precursor w potential to progress to invasive anal SCC
      • less likely to regress than LSIL, regardless of HIV status (HPV16 lesions least likely to regress)
  • Tx of LSIL optional since not considered precancerous
  • Few high-quality studies addressing efficacy of various treatments for anal SIL & optimal approach not defined
  • HSIL should be treated (though whether this reduces risk of progression to anal ca unknown); and v little data on rate of progression of anal HSIL to invasive ca since usu treated once identified
    • modalities include topical therapies, either clinical or pt applied (eg trichloroacetic acid, 5FU, imiquimod); office-based ablative therapies eg electrocautery, infrared coagulation; surgical excision in small subset of ptsaggressive surgical excision of whole perianal skin & anal canal & resurfacing w SSG and defunctioning colostomy has been used to treat wide areas of AINIII but signif morbidity for condition of uncertain malignant potential
  • HPV vaccine - can still provide protection against infection w HPV types not already acquired though has no therapeutic effect on pre-existing HPV infection & no role in preventing progression of HSIL to invasive anal ca​
  • impossible to eradicate HPV infection by surgical excision - surgical excision of condylomas is for sx relief & cosmesis

Follow-up

  • AIN I/II = low risk of progression to AIN III; can be discharged w appropriate advice & reassurance
  • AIN III = 6monthly f/u w clinical exam, which may include analcolposcopy/high res anoscopy & phtodocumentation of the area w biopsy of any suspicious or bleeding area
  • those w immune-compromise in particular need reg f/u as risk of progression to invasive disease = greater
59
Q

What regimen is used to treat Anal SCC?

A

The Nigro protocol is the pre-operative use of 60 Gy of radiation over a five week period, as well as continuous administration of fluorouracil for the first four days and on days 29-32, with mitomycin administered on the first day of each chemotherapy treatment .

It is named after Norman Nigro (1912–2009), who developed it in the mid-1970s.

60
Q

Describe the grading of ano-genital intraepithelial neoplasia

A

Anogenital intraepithelial neoplasia of the cervix (CIN, vulva (VIN), Vagina (VAIN), and Anus (AIN) is graded from I-III, according to the number of thirds of epithelial depth that appear dysplastic on histological section. Grade III is synonymous with carcinoma in situ.

61
Q

What are the 3 anatomic regions in which anal or perianal SCC may be manifested?

A
  • anal canal - can’t be visualised or are incompletely visualised by gentle traction of buttocks
  • perianal lesions - completely visible, arise within 5cm of anal opening when buttocks gently spread
  • skin lesions - outside the 5cm radius
62
Q

What investigations do you consider for someone suspected of having anal SCC?

A
  • consider HIV testing
  • female pts - gynae exam & make sure cervical screening up to date
  • detailed EUA & anoscopy
    • optimum assessment of tumour in terms of size, involvement of adjacent structures & nodal involvement
    • biopsies
    • papillomavirus-associated lesions may be seen w naked eye or w high-res anoscopy w application of acetic acid to epithelium -> ‘aceto-white’ lesion - allows targeted biopsy
    • HSIL may be hyperkeratotic or assoc w changes in pigmentation of epithelium - white, red/brown, lesions may be flat or raised but ulceration suspicious of malignancy
  • biopsy or FNA groin nodes if radical block dissection contemplated
    • may not be required if had PET/CT that shows avid uptake
  • tumour markers not useful
  • staging: MRI pelvis (locoregional) CT chest/abdo/pelvis (metastatic disease)
  • FDG PET/CT not routine
  • endoanal USS - may be useful in small tumours; usu more info available from MRI, espec on spread beyond anal canal
63
Q

What is the management of inguinal mets in anal SCC?

A
  • prophylactic low-dose rad to clinically uninvolved inguinal nodes currently advised for all T2-4 tumours of anal canal & margin due to high risk of recurrence
  • CT & MRI not sensitive to discriminate between involved & uninvolved nodes (PET may help…)
    • enlarged nodes in up to 1/3 of pts w anal cas but in up to 50% lymphadenopathy may be due to inflammation alone
  • inguinal LN involvement treated with chemorad; if this contraindicated then block dissection may be done at APR but need histo confirmation first
  • enlargement of groin nodes sometime after primary therapy = most likely due to recurrent tumour; radical groin dissection indicated in this situation w up to 50% 5yr survival
64
Q

What are the outcomes for anal SCC?

A

Despite high success rates w definitive chemorad, 15-30% wil have recurrence or fail to respond completely - pts w persistent disease up to 6mo post treatment or w local recurrence generally require APR

Up to 50% of pts treated w salvage APR can expect 5yr cure

In pts presenting w anal SCC in setting of HIV, disease severity (CD4 count & use of antiretroviral therapy) has significant impact on success of standard chemorad - equal 2yr survival rates

65
Q

Adenocarcinoma of anal canal

A

Usually a v low rectal cancer that has spread downward to involve canal but true adenocarcinoma of anal canal does occur, prob arising from columnar epithelium of anal glands, which arise around dentate line & pass radially outward into sphincter muscles.

V rare, quite radiosensitive & increasingly treated by chemorad

66
Q

Paget’s disease of the anus

A
  • Definition:
    • A rare intraepithelial adenocarcinoma
  • Epidemiology
    • More commonly manifested in older pts (usually in 7th decade of life)
  • Aetiology/Pathogenesis
    • Often seen in areas of high density of apocrine sweat glands
    • Over time can develop into invasive ca of underlying apocrine glands
  • Clinical
    • Most common presenting sx = intractable itch; sometimes pts w long-standing sx misdiagnosed w pruritis ani
    • Typical appearance: eczematous, well-demarcated plaque w occasional ulceration & scaling
  • Investigations
    • Histo demonstrates presence of periodic acid-Schiff-positive (bc of significant mucin) Paget cells (large, vacuolated cytoplasm w eccentric nuclei), confirming dx
    • Extramammary Paget = associated w underlying invasive carcinoma in 30-45%, but visceral malignant neoplasms may be seen in up to 50% pts
  • Management
    • Depends on local extent of disease & presence or absence of invasion
    • Limited, noninvasive disease best managed by WLE & closure of defect primarily or w V-Y advancement flaps
    • Recurrences can generally be treated w re-excision as long as disease remains noninvasive
    • In pts medically unfit for surgery & w non-invasive disease – other techniques include topical 5-FU, imiquimod, cryotherapy or argon beam laser therapy
      • Close observation in these cases advised & biopsies for sx recommended
    • If invasive component, consider radical resection w APR
  • Prognosis

5yr disease-specific survival ranges from 50-70% in all pts w extramammary Paget disease

67
Q

Management of BCC of anus

A

rare

pearly borders w central depression

mostly can do WLE; reserve APR for extensive lesions or those involving sphincter mechanism

68
Q

What is the management of condyloma acuminiatum and what causes them

A

Most commonly HPV 6 and 11

  • Dx generally made by direct inspection of perineum & genitals; anoscopy & proctosigmoidoscopy must be performed as often spreads intra-anally & some pts have disease limited to anal canal
    • check rest of perineum/genitals
    • dx usu clinical dx, confirmed w histo
  • Partners should be evaluated & treated
  • Screen pts for immunologic compromise incl HIV - risk for developming malignancy
  • High-res anoscopy with or without 5% acetic acid may improve detection of disease

Management

  • Treatment approaches involve physical or chemical destruction, immunologic therapies & surgery
  • Despite various multimodal therapies, recurrence rates of 30-70%
  • Topical agents
    • Podophyllin
      • Cytotoxic & can be irritating to normal skin – use limited to pts w minimal extra-anal disease, take care to avoid systemic toxicity
      • Although simple & cheap, high recurrence rates
    • Trichloroacetic acid
      • Can be used both perianally & intra-anally; less irritating than podophyllin
      • Recurrence rates w this and podophyllin much higher than w surgical excision
    • 5-FU (Efudix)
    • Imiquimod 5% cream (Aldara - upregulates cytokines): 3x per wk for 4mths
      • Can be used as primary treatment or as adjunct after initial resection or destruction of disease
      • Although not currently approved for intra-anal use, some centres applied it like this w similar results
  • Electrocautery (needle tip cautery)
    • Effective & used extensively, often combined w excision of larger lesions
  • CO2 laser
    • Also effective but cost higher w/o evidence of increased efficacy
  • Excision
    • At base w small scissors – precise, minimizes destruction of skin and can be used on larger lesions
    • GA or regional often required
69
Q

Verrucous Carcinoma / Buschke-Lowenstein tumours / Giant condyloma acuminatum

A
  • Definition
    • giant condylomata that resemble condyloma macroscopically but are larger & fail to respond to conservative therapy
    • locally aggressive, exhibit malignant behavior but benign histo
    • should be considered as intermediate lesion btwn warts & invasive SCC
  • Pathology
    • Endophytic growth present in verrucous carcinoma but true invasive growth pattern not present
    • Unlike SCC (most of which assoc w HPV16), most verrucous carcinomas assoc w HPV6&11
  • Clinical
    • Slow growing & may be complicated by fistulisation, infection or malignant transformation
  • Treatment
    • Wide local excision recommended; in rare cases when all disease can’t be removed, APR is necessary
  • Prognosis
    • Regarded as biologic intermediates between condylomas & SCCs, w better prognosis than SCC
    • Those that progress to SCC = associated w poor prognosis
    • But some may respond favourably to combined chemoradiotherapy
70
Q

Which common colorectal conditions require colonoscopic surveillance and what are your protocols?

A
  • Colorectal cancer
    • Index colonoscopy within 3 months of diagnosis (if not done at time of Dx)
    • 1-year post op
    • 3-5 yearly according to risk profile
  • Inflammatory bowel disease
    • Commence surveillance at 8 years post diagnosis
    • Annual surveillance with:
      • Active disease
      • Family history CRC
      • Previous dysplasia
    • 3-5 yearly surveillance otherwise
    • Colectomy with HGD!
    • Consider chromo-endoscopy
71
Q

What features determine prognosis in the setting of liver metastases?

A

Apply the Clinical Risk Score (Fong et al):

    • CEA >200
  • Liver metastses >5cm
  • More than one liver metastases
  • Nodal disease + on primary resection.

Each positive criterion is assigned one point. 5-year-survival with 0 points is 60% and with 5 points is 14%.

This data is out-dated so likely better than this with current chemo.

72
Q

Describe how peritoneal cancer spread is classified

A

The Peritoneal Cancer Index

13 regions each scored with 3 points for maximum of 39. Correlates to disease burden and can be used to guage response to therapy.

Alex (36 decks)

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