Genetics, Epidemiology, and Misc. Colorectal

Question 1

Describe the clinical criteria for identifying patients at risk of Lynch Syndrome

Answer 1

The clinical criteria for identifying patients with a high risk of being affected by LS are referred to as the Amsterdam criteria, with very high specificity (98%) but low sensitivity (22–42%), as more than 50% of families with LS fail to meet these criteria.

(1) Three or more relatives with histologically verified LS-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis), 1 of which is a first-degree relative of the others.
(2) Cancer involving at least 2 generations.
(3) One or more cancer cases diagnosed before the age of 50.
(4) Familial adenomatous polyposis should be excluded.

Question 2

Describe the Bethesda criteria and its genesis

Answer 2

The Amsterdam criteria has low sensitivity so the Bethesda, then revised Bethesda guidelines were created. These guidelines improve selection of cases that should benefit from a tumor analysis, i.e., microsatellite analysis and/or immunohistochemistry of the MMR proteins.

The revised Bethesda Guidelines yielded significantly greater sensitivity compared to the Amsterdam criteria but lower specificity (82–95% and 77–93%, respectively).

(1) CRC or endometrial cancer diagnosed <50.
(2) Presence of synchronous or metachronous CRC or other LS-associated tumors, regardless of age.
(3) CRC with MSI-high pathologic-associated features (Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern) diagnosed in an individual younger than 60.
(4) Patient with CRC or LS-associated tumor diagnosed below 50 in at least 1 first-degree relative.
(5) Patient with CRC or LS-associated tumor diagnosed at any age in 2 first-degree or second-degree relatives.

Question 3

According to the 2021 United Kingdom “Preoperative Assessment and Optimisation for Adult Surgery” guidelines, what are the five domains where patient status can be optimised?

Answer 3

1. Comorbidities
2. Nutritional status
3. Psychological preparedness
4. Functional status
5. Specific comprehensive geriatric assessment for older adults.

Question 4

What are the 5 key-questions within the “Shared Decision Making” model?

Answer 4

1. What will happen if we watch and wait?
2. What are the best treatment options?
3. What are the risks and benefits of each treatment option?
4. How do the risks and benefits weigh up for the patient?
5. Does the patient have enough information to make a choice?

Question 5

Define emotional intelligence

Answer 5

Emotional intelligence is the ability to recognize and perceive one’s own emotions as well as those around you and act accordingly in an appropriate manner.

Question 6

What are the 5 key traits within emotional intelligence?

Answer 6

1. Empathy
2. Self-awareness
3. Motivation
4. Self-control
5. Social skills

Question 7

Define Burn-out

Answer 7

Burnout has been defined as a prolonged response to chronic emotional and interpersonal stressors on the job. The hallmark features exhibited include:

1. De-personalisation
2. Low sense of Personal Accomplishment
3. Emotional exhaustion

Question 8

What are the indications for bridging Enoxaparin?

(according to the American College of Chest Physicians)

Answer 8

• VTE/PE within the last 3 months
• Inherited thrombophilias:
  
  • Protein C deficiency
  • Protein S deficiency
  • Anti-thrombin III deficiency
• AF withv CHA₂DS₂VAS₂ of 6 or more
• CVA or TIA within the last 3 months
• Rheumatic heart disease
• Any Mitral valve replacement
• Any caged-ball or tilting aortic valve replacement

Question 9

What are the mechanisms of action of the NOACs?

Answer 9

Dabigatran is a direct thrombin inhibitor, preventing fibrinogen being converted to fibrin, while Rivaroxaban and Apixaban are both factor Xa inhibitors, blocking the primary regulatory step in the clotting cascade.

Question 10

Can the therapeutic activity of the NOACs be monitored?

If so, how?

Answer 10

Dabigatran

• aPTT is raised in most cases, but is unreliable as 20% with have a normal aPTT
• A normal thrombin time (TCT) essentially rules out the presence of dabigatran.

Apixaban and Rivaroxaban

• Both APTT and prothrombin time (PT) are affected by the Factor Xa inhibitors, but the correlation between serum drug levels and PT is poorer.

TEG-Patelet Mapping (TEG-PM) in an experimental setting shows good correlation with serum drug levels.

Question 11

What are the mechanisms of action of the commonly used anti-platelets?

For each medication, state when they should be ceased pre-operatively.

Answer 11

Aspirin is a non-selective Cox-1 inhibitor, which exerts its antiplatelet action by preventing the production of thromboxane A2.

• Stop at least 5 days prior, can often be continued.

Clopidogrel is a thienopyridine antiplatelet which works by irreversibly inhibiting P2Y12 receptors on platelets, which bind ADP.

Prasugel and Ticagrelor are 2 other thienopyridine-class antiplatelets, which inhibit P2Y12 receptors in a similar fashion to Clopidogrel.

• Cease 5-7 days prior

Dipyridamole is another older antiplatelet which works by inhibiting cyclic AMP and preventing clot formation.

• Cease 2 days prior.

Question 12

How long should DAPT continue following endo-arterial stent placement?

What is the risk of significant bleeding on DAPT?

Answer 12

The consensus from most international bodies remains that while continuation of DAPT is desirable for at least 6 months after coronary stent revascularisation, it may be acceptable to continue with single-agent therapy after 30 days.

Minimal evidence re surgery on DAPT; available data show a 20-fold increse in bleeding risk.

Question 13

What do you do if someone needs major surgey and is on DAPT?

How does Desmopressin work?

Answer 13

Platelet transfusion continues to be used in the emergent situation for patients receiving DAPT, but the results are disappointing and the current evidence still does not support it.

Desmopressin has low-level evidence extrapolated from other surgical scenarios. Desmopressin is an agent that increases plasma clotting factor and platelet calcium concentrations.

Call a haematologist and consider using TEG-PM.

Question 14

How does Heparin work?

Answer 14

Heparin binds to antithrombin III, and then inactivates thrombin, factor Xa and other components of the clotting cascade.

Question 15

Describe the risks of blood transfusion.

What is the leading cause of transfusion-associated death?

Answer 15

• 1/10 volume overload in critically unwell patients
• 1/100 mild reaction including fevers / urticaria
• 1/20,000 rate of TRALI
• 1/60,000 acute haemolytic reactions
• 1/100,000 anaphylaxis
• 1/1,000,000 risk of infection

TRALI is the leading cause of transfusion-related death.

Question 16

What constitues a “massive transfusion”?

Answer 16

A massive transfusion is usually defined as the requirement to replace a patient’s blood volume (10 units) in 24 hours, or 50% in 3 hours.

Question 17

What is the role and rationale for extended VTEP?

Answer 17

Extended DVT prophylaxis (for four weeks postoperatively) is indicated for patients with high- risk features:

• Pelvic malignancy
• An operation longer than two hours
• Poor mobility
• Previous history of thromboembolism.

Randomised trial evidence suggests that extended DVT prophylaxis significantly reduces the incidence of ultrasound detected (but asymptomatic) DVT in patients undergoing laparoscopic bowel resection for colorectal cancer without increasing the risk of postoperative bleeding. This is in keeping with the conclusions of a previous Cochrane review.

Question 18

What is the difference between unfractionated and LMW Heparin?

Why does this matter?

Answer 18

Unfractionated heparin has a highly variable molecular weight (ranging from 5,000 to 30,000 Daltons) and unpredictable pharmacodynamics, meaning that close monitoring with APTT is required.

LMWH consists of heparins with a molecular weight of less than 8,000 Daltons, and is administered subcutaneously. It has predictable pharmacokinetics meaning monitoring is not necessary.

Question 19

Describe the pathogenesis of endometriosis

Answer 19

Two schools of thought:

1. Endometrial rests originating outside the uterus
   
   • Coelomic metaplasia
   • Abnormal stem cell differentiation
   • Embryonic Mullerian rests
2. Retrograde implantation from inside the uterus to out
   
   • Retrograde menstruation - most widely accepted
   • Lymphovascular spread theories

Question 20

What are the pathologic variants of endometriosis?

Answer 20

1. Peritoneal endometriosis
   
   • The majority of cases
   • Small burn-dots with less than 5mm invasion
2. Endometrial ovarian cysts
   
   • Chocolate cysts
3. Deeply invasive endometriosis
   
   • 20% of cases
   • Often require multi-disciplinary management

Question 21

Discuss imaging and imaging characteristics of endometriosis

Answer 21

MRI has demonstrated excellent accuracy (up to 94%) for the presence of deeply invasive disease, involvement of the rectum, and the need for colorectal surgical involvement.

Deeply invasive implants appear as hyperintense on T1-weighted imaging and hypointense in T2 phase (cf rectal cancer, which is intermediate signal on T2).

Where DIE is suspected clinically, MRI performed prior to diagnostic laparoscopy allows multidisciplinary assessment at laparoscopy and facilitates later definitive surgical planning.

Question 22

What processes under-pin the pathophysioloigy of endometriosis?

Answer 22

• Neuro-angiogenesis
• Neuro-inflammation

The endometriotic cells elicit a localised inflammatory response with proinflammatory cytokines, chemokines and prostaglandins. This inflammatory response, combined with the hormonal changes, promotes cell growth and vascularisation.

These factors alone do not explain the chronic pain from endometriosis, and studies have also found changes in brain chemistry and function, which changes pain perception

Question 23

How is endometriosis staged?

Answer 23

Stage 1

• Minimal isolated disease

Stage 2

• Mild superficial peritoneal disease, less than 5 cm total and no significant adhesions

Stage 3

• Multiple superficial and deep implants. Peri-ovarian and peri-tubal adhesions

Stage 4

• Multiple implants +/- large ovarian endomertiomas, with filmy and dense adhesions

Question 24

What are the rates of surgical re-intervention following surgery for endometriosis?

Answer 24

50% undergo surgery again by 5 years

Question 25

What are the goals of surgery in endometriosis?

What are the relative merits of “shave” versus full thickness resection?

Answer 25

Goal = Removal of all visible endometriotic implants and restoration of normal anatomy should be the goal of all surgical approaches.

Shave vs. disc vs. segmental resection:

• Consider segemental resection with nodules >3cm, >50% bowel circumference involved, >50% stenosis, or multiple areas affected
• Higher recurrence rates are seen with shave-technique but it is less invasive.

Question 26

What are the classes of laxative medication? (8 classes)

Provide examples of each and important clinical issues where relevant.

Answer 26

1. Fibre
   
   • Soluble and insoluble fibres; bulk stool and retain water
   • Low harm, some patients experience bloating/discomfort
2. Osmotic laxatives
   
   • Draw fluid into the lumen
   • PEG as well as Na/Mg phosphates
   • Includes non-digestible disacharides e.g. Lactulose
   • Caution with Magnesium in renal failure
3. Stimulant laxatives
   
   • Act locally at the smooth muscle of intestine
   • Bisacodyl and Sodium Picosulphate (metabolised by colonic bacteria into bisacodyl)
   • Cause cramping and electrolyte wasting
   • Senna is a milder plant based form
   • Possible tachyphylaxis
4. Stool softeners
   
   • Docusate acts as a detergent and allows more water to enter stool
   • Paraffin does the same but can cause fat malabsorption
5. Peripherally active mu-opioid receptor antagonists
   
   • Naloxagol and Almivopan
   • Growing evidence but not widely used
6. Serotonin agonists
   
   • Prucalopride activates the cholinergic system
   • Much more selective than Cisapride (withdrawn)
7. Guanylate cyclase-C receptor agonists
   
   • Derived from E. coli - not widley available
8. Chloride channel activators
   
   • Orally administered secretagogue
   • Not available in Australia

Question 27

What class of drug is Loperamide?

How does it work?

Answer 27

Loperamide is a low potency mu opioid receptor agonist which is poorly absorbed from the gut and does not cross the blood-brain barrier well, so risk of abuse is low.

Loperamide reduces sensitivity of the recto-anal inhibitory reflex and increases internal anal sphincter tone. Additionally, it has an effect on rectal compliance in incontinent patients with diarrhea.

Question 28

What class of drug is Lomotil?

How does it work?

Answer 28

Diphenoxylate/atropine is available in Australia as Lomotil.

It is a compounded drug where the diphenoxylate is a mu-opioid agonist which (unlike Loperamide) does cross the BBB. The atropine enhances the constipatory effect via the anticholinergic pathway.

It has a worse side effect profile and more potential for abuse compared with Loperamide.

Question 29

How does Bismuth relieve diarrhoea?

Answer 29

The mechanism of action of bismuth is unclear but is thought to be due to anti-secretory, antibacterial and anti-inflammatory actions.

It promotes fluid and electrolyte absorption to reduce fluid accumulation in the intestinal lumen and may also have absorptive properties.

Question 30

Classify and list the commonly encountered species of bacteria during colorectal surgery.

Answer 30

• Skin
  
  • Gram positive aerobes
    
    • S aureus
    • S epidermidis
  • Gram positive anaerobes
    
    • Proprionibacterium acne
• Gut
  
  • Gram positive facultative anaerobes
    
    • Enterococcus
  • Gram positive anaerobes
    
    • Peptostreptococcus
    • Clostridia sp.
  • Gram negative facultative anaerobes
    
    • E coli
    • Klebsiella sp.
    • Enterobactericeae
  • Gram negative anaerobes
    
    • Bacteroides fragilis

(NB - no aerobes in the commonly encountered organisms)​

Question 31

What are the 3 most clinically important protozoal infections of the intestine?

Answer 31

1. Entamoeba histolytica
2. Giardia intestinalis
3. Cryptosporidium hominis

Question 32

How are protozoal infections best diagnosed?

Is there a role for microscopy?

Answer 32

Using ELISA (enzyme-linked immuno-sorbent assays) in stool specimens is the most sensitive method.

There is a triage panel that can distinguish between E. histolytica and E. dispar, as well as Cryptosporidium, and Giardia.

Stool microscopy, and thread tests (recoverable swallowed threads) have been outdated by ELISA.

Amoebic liver abscesses may have positive serology, but this does not distinguish from previous infection, so has limited utility in endemic areas.

Question 33

How is amoebic dysentery treated?

Answer 33

1. Metronidazole 600mg PO TDS for 7 days
2. Followed by Paromycin 500mg TDS for 7 days

The Paromycin is to kill the trophozoites in the intestine after eradicating the active amoeba.

*Increase the Metronidazole to 800mg in severe infections.

Question 34

What is the classical presentation of Giardia infection?

How is it treated?

Answer 34

Mild infections are asymptomatic, more severe infections cause non-bloody diarrhoea.

Treat with Metronidazole 400mg PO TDS 5 days.

Question 35

What is the clinical presentation of Cryptosporidium?

Who does it affect in developed nations?

How is it treated?

Answer 35

Ranges from moderate non-bloody diarrhoea to more severe profuse diarrhoea that is self-limiting in 15–40 days in immunocompetent individuals, but can become chronic in immunocompromised patients, including those with advanced HIV infection.

On those with immunocompromise, optimising immune status is the key to treatment.

For persistent, severe cryptosporidial diarrhoea, Nitazoxanide 500mg orally, 12 hourly for 3 days, can be considered, although trials have demonstrated its efficacy predominately for HIV-negative patients. Paromomycin reduces oocyst output but does not clear infection.

Question 36

Compare the clinical manifestations of protozoal versus helminthic parasitic infections of the gut.

Answer 36

• The protozoal colitides more frequently cause diarrheal illnesses and malnutrition.
• The helminthic colitides, on the other hand, generally result in obstructive symptoms rather than diarrhoea; the obstructive symptoms can be caused by stricture secondary to local inflammation or by a high worm burden resulting in appendicitis or even a bowel obstruction.
• Medical management of all protozoal infections remains first line treatment, while surgical therapy is reserved only for complications or failed medical management.

Question 37

What are the most clinically important helminthic species?

How are they transmitted?

Answer 37

The most important intestinal worms clinically are the nematodes known as the soil-transmitted helminths. Two groups:

1. Those where infection occurs via swallowed eggs
   
   • Ascaris lumbricoides (large roundworm)
   • Trichuris trichuria (roundworm)
   • Entoerobius vermicularis (pinworm)
2. Those where infection occurs via skin penetration (then lungs, then swallowed, then gut!)
   
   • Necator (hookworm)
   • Ancylostoma
   • Strongyloides

Question 38

What are the clinical manifestations of helminthic infection?

Answer 38

• Systemic:
  
  • Eosinophilia and associated hypersensitivity
  • Malnutrition in children
  • Iron deficiency anaemia
  • Overwhelming sepsis in immunocompromised
• Gastrointestinal:
  
  • Chronic mild intestinal discomfort
  • Chronic diarrhoea
  • Obstruction with high worm burden (dead or alive)
  • PR bleeding (rarely)
  • Pruritis ani (pinworm)
• Lung (affected as part of cycle)
  
  • Pneumonitis

Question 39

How are helminthic parasitic infections diagnosed?

Answer 39

All of the soil-transmitted species can be diagnosed by finding eggs or larvae in a fresh stool.

Acute infections with Ascaris, hookworms and Strongyloides are often accompanied by a marked blood eosinophilia. Although this is not diagnostic, it is a strong indicator of helminth infection.

Strongolydes has an ELISA.

“Scotch tape test” for pinworm (must be taken on awakening on three consecutive nights!).

Question 40

How do you treat helminthic infections of the gut?

What about immunocompromised patients?

Answer 40

Albendazole 400mg PO for 1-3 days (varies with worm) for everyone in the house!!

Ivermectin with immuno-compromise

Question 41

Is colorectal cancer incidence rising in young people?

What is the incidence of yCRC?

Answer 41

Yes - probably (def in North America, mixed data for ANZ)

Australian and NZ registry data shows an annual percentage increase of 1-4% per year in those <50-years-old.

(Baseline incidence of CRC in ANZ is ~50/100,000)

Incidence of CRC in <50-years in NZ is 8.2/100,000

Question 42

What are some of the postulated reasons why CRC incidence is on the rise in young people?

Answer 42

​Thought to be a combination of:

• Dietary factors
  
  • Processed meats
  • Low intake of fruit and vegetable
• Epi-genetic changes:
  
  • Obesity
  • Sedentary lifestyle

Question 43

What are some of the clinicopathologic features associated with yCRC?

Answer 43

Colorectal cancer in the young (<50) have higher rates of:

• MSI-H (though most are still MMR proficient)
• Signet ring histology
• Synchronous metastases
• Distal colonic / rectal cancer

They tend to have lower rates of:

• BRAF mutations
• APC mutations
• MAPK mutations

Question 44

What are the WHO’s core principles of screening?

(S.C.R.E.E.N.I.N.G)

Which cancers fufil the criteria?

Answer 44

• S - Suitable test
• C - Cost effective test
• R - Readily accepted by population
• E - Early / latent stage to the disease
• E - Equipment for diagnosis and management in place
• N - Natural history understood
• I - Important health problem
• N - Know who to treat and how to treat
• G - Goes on and on (not a once off)

Breast, Cervical, Colorectal

Question 45

Define screening

Answer 45

Screening is the practice of performing a non-diagnostic test on asymptomatic individuals to identify those who probably have a disease so they can be referred for a test to determine if they have the disease.

Mammograms, Pap Smears, and iFOBT are not diagnostic.

Question 46

Why does the New Zealand Bowel Screening Program result in reduced health gains for Maori compared with non-Maori?

Why did the BSP not include Maori from 50-74?

Answer 46

1. Māori have lower rates of new cases of bowel cancer registrations per year
2. Screening programmes are less successful in engaging with Māori
3. Māori have lower life expectancy than non-Māori.

With critical consideration to the balance of benefits with harms of moving to screen the 50–59 year old age group for Māori, this balance was not clearly favourable, given the lower rate of cancer in this age group and the risk of harm from colonoscopy.

ref - NBSP paper on considering potential impacts for Maori

Question 47

What is the age-standardised rate of Colorectal Cancer in Maori and non-Maori in New Zealand?

Answer 47

Maori 33/100,000

Non-Maori 43/100,000

Question 48

What is the NNS to detect a cancer by iFOBT?

What about to detect an advanced adenoma?

What is the NNS to prevent one death from CRC?

Answer 48

Cancer NNS = 208

Adv. adenomaNNS = 55

Death NNS = ~400

Question 49

What are the possible ways of improving the bowel screening program?

Answer 49

• Improve uptake
  
  • Small increases in uptake can offset large differences in efficacy; 10% uptake saves 17,000 deaths (Aus data).
• Increase the screening age
  
  • Find more cancer, cause more harm, screen A LOT more people
• Integrate one-off colonoscopy
  
  • Colonoscopy has the highest sensitivity and specificity of all bowel screening tests
  • Could be used in all who accept, with iFOBT used in those who decline…
  • Overwhelming co$t.
• Tailoring screening to the individual
  
  • Variable iFOBT positivity thresholds could be selected for those who have genetic or lifestyle risk factors for CRC.

Question 50

Describe some alternatives to iFOBT for colorectal cancer screening.

Answer 50

• Molecular imaging (radiolabelled nucleotides for CRC)
• Capsule endoscopy
• Faecal tumour DNA - endorsed in the USA!
• Micro-RNAs
• Volatile Organic Compounds
  
  • Dogs or electronic noses assesing gas per orum/rectum
  • 97% sensitive and 99% specific
  • Watch this space
• Microbioma
  
  • Ratio of fusibacterium nucleatum to bifidobacterium can predict CRC (85% sensitive and 92% specific)

Question 51

List the most commonly encountered colorectal congenital disorders that an adult colorectal surgeon may encounter.

Note their frequency and gender distribution.

Answer 51

1. Hirschsrpung’s disease
   
   • 1/5,000
   • M:F 4:1
2. Anorectal malformations
   
   • 1/5,000
   • M:F 3:2
3. Colorectal duplications
   
   • 1/5,000
4. Rotational abnormalities
   
   • 1/6,000
5. Colorectal atresias
   
   • 1/50,000

Question 52

Briefly describe the rotation of the gut in embryology.

What are the key mediators of embryological gut development?

Answer 52

• Physiological herniation of the midgut outside the coelomic cavity at 4 weeks
• Mid gut counter-clockwise rotation of 90 degrees
• Proximal limb (to SMA) elongates +++
• Distal limb forms caecal bud
• Further counter-clockwise rotation of 180 degrees
• Returns to the coelomic cavity by the 12^th week
• Regional differentiation is regulated by expression of different transcription factors via molecular signalling through retinoic acid.
• Epithelial-mesenchymal interactions through sonic hedgehog expression determine the type of structure that forms in each respective component of the gut tube.

Question 53

Describe the types of rotational abnormalities of the midgut.

Answer 53

• Non-rotation
  
  • Most common form of rotational abnormality
  • No rotation during embryological development
  • DJ and SB on the right side of the abdomen with large bowel on the left.
  • Narrow mesentery ++ prone to volvulus
• Malrotation
  
  • Incomplete rotation during embryology
  • Caecum located abnormally, associated Ladd’s bands
• Reverse rotation
  
  • Distal midgut limb rotates clockwise underneath SMA such that the tranverse colon passes behind the SMA (and may be compressed by it).

Question 54

What is Hirschsprung’s disease?

Describe the histopathologic findings in Hirschsprung’s disease

Answer 54

Hirschsprung’s disease (HD) is the most common cause of intestinal obstruction in the neonate with a reported incidence of 1 in 5000 live births.

HD is characterized by the absence of ganglion cells in the myenteric plexus of the large bowel. The extent of the aganglionosis is variable in length but always extends proximally from the anorectal junction, such that the internal anal sphincter is always involved.

The absence of ganglion cells and hypertrophied nerve trunks is diagnostic of HD. Staining for acetylcholine esterase and immunohistochemistry can also aid diagnosis.

Question 55

How is Hirschsprung’s disease managed?

Answer 55

Management of HD is dependent on the extent of the disease:

• Short segment disease can be managed conservatively in the neonatal period with regular rectal irrigation. This can allow surgery to be delayed for usually 3 months.
• Long segment disease and total colonic aganglionosis will generally require emergent surgery, often with a diverting stoma in the first instance.

Question 56

Describe the different types of pull-through procedures for Hirschsprung’s disease.

Answer 56

• Swenson first described the full-thickness pull-through in 1948.
• Duhamel modified it in 1956 by avoiding the anterolateral dissection and leaving an anterior cuff of lower rectum, onto which the ganglionated colon is side-to-side stapled to restore continuity.
• Soave described his approach around the same time (1955) whereby he spared the autonomic nerves by performing a submucoal dissection to 4cm above the peritoneal reflection, followed by a colon anal anastomosis after pulling the conduit through the aganglionic internal sphincter complex.

Question 57

Classify and describe anorectal malformations.

How can they be treated?

Answer 57

Low and high;

• Low anomalies are those in which the bowel traverse the pelvic floor and then either becomes stenosed or ectopic lower down
  
  • Anal stenosis, anal membrane, anal agenesis
  • Addressed with single-stage repair; either anoplasty, or anal re-siting through the sphincter complex
• High abnormalities include those where the rectum terminates above the pelvic floor
  
  • Anorectal agenesis, rectal atresia, persistent cloaca
  • Addressed usually with a two stage procedure; stoma then pull-through after myoelectrical identification of the sphincter complex.

Question 58

List the adenomatous polyposis syndromes.

Outline any points of clinical relevance.

Answer 58

• Familial adenomatous polyposis syndrome (and attenuated FAP)
• MUTYH Associated Polyposis Syndrome
  
  • AR with lifetime risk of 80% for CRC
• Polymerase-Proofreading Associated Polyposis
  
  • AD with oligopolyposis and early onset CRC
• NTHL1 Associated Polyposis
  
  • AR with multiple different polyps (HPs and SSPs)
• Constitutional MMR Deficiency Syndrome
  
  • Mimicks FAP but no APC mutation or MAP mutation
  • Can develop lymphoma and Cafe-au-Lait spots

Question 59

How can polyposis syndromes be classified?

Answer 59

1. Adenomatous
2. Hamartomatous
3. Serrated or mixed

polyposis syndromes

Question 60

List the harmatomatous polyposis syndromes and any clincal points of interest.

Answer 60

1. Peutz-Jeghers Syndrome
   
   • AD with germline mutation in STK11
   • Harmatomatous polyps and mucocutaneous pigementation
   • Polyps may affect entire GIT; intussusception with SB
   • Large polyps cause symptoms, may become malignant
   • 90% of cancers of various types; CRC is 40%
2. Juvenile Polyposis Syndrome
   
   • AD with germline mutation in SMAD4
   • 40% lifetime risk of CRC
3. PTEN Harmatomatous Tumour Syndrome
   
   • Heterogenous group
   • COWDEN and Bannayan-Riley-Ruvalcaba syndrome
   • Germline mutation in the PTEN tumour suppressor gene
   • Low risk (10%) of CRC but many other cancers.

Question 61

What are the genetic mutations behind Hereditary Mixed Polyposis Syndrome and Serrated Polyposis Syndrome?

Answer 61

• HMPS = GREM-1 (Gremlin-1 gene)
• SPSS = RNF43 (RiNg Finger-43 gene)

Question 62

How does a mutation in the APC gene cause colorectal cancer?

Answer 62

APC supresses Wnt (Wingless integrated) signalling, which is an ancient, evolutionarily conserved pathway that regulates crucial aspects of cell differentiation, signalling, migration, and organogenesis.

Mutations in APC prevents its action as a tumour supressor gene and allows beta-catenin build up in cells, leading to activation of the “growth-promoting” pathway.

Question 63

How is the phenotype of FAP affected by location of mutation on the APC gene?

Answer 63

The APC gene, located on 5q21, has 15 exons. Mutations at different points of the gene mainfest differently, within the remit of APC’s multifarous role in cell differentiation, signalling, and migration;

Mutations at the 3’ or 5’ end cause attenuated FAP.

Codon-site mutation location has been shown to correspond to phenotype, with codon-segments related to CHRPE, Desmoids, and osteomas detected.

Question 64

List the extra-intestinal manifestations of FAP

Describe the (now historic) Gardner and Turcot syndromes.

Answer 64

• CHRPE
• Fibromas
• Osteomas
• Desmoid tumours
• Nasal angiofibromas
• Papillary thyroid cancer
• Hepatoblastomas
• Brain tumours
• Pancreaticobiliary tumours

Gardner syndrome

• FAP
• • osteotomas, dental abnormalities, cutaneous lesions, desmoid tumours, CHRPE, adrenal adenomas, and nasal angiofibromas.

Turcot syndrome

• FAP or Lynch
• Primary tumours of the CNS (glioblastoma, medulloblastoma)

Question 65

Which of the extra-intestinal manifestations of FAP require surveillance?

Answer 65

Benign:

• Dental abnormalities - OPG every 1-2 years
• CHRPE - slit lamp examination
• Desmoids - CT in those with symptoms, APC mutation beyond codon-1444, patients with a mass, patients with bowel obstruction

Malignant:

• Papillary thyroid cancer
  
  • 10% lifetime risk, annual thyroid USS
• Brain lesions
  
  • Periodic MRI brain - interval undecided
• Hepatoblastoma
  
  • Data unclear, regular USS and FAP
• Gallbladder and Bile Ducts
  
  • Data unlcear, annual LFTs ?MRCP

Question 66

There are three stages of embryological midgut development.

Describe the first stage and the resultant clinical entities with errors in this stage.

Answer 66

The first stage of gut development occurs between the 4th and 10th week of gestation

Characterised by rapid growth of the primary intestinal loop with physiological herniation of the mid-gut and a 90° anti-clockwise rotation.

Failure to return to abdomen results in exomphalos or omphalocoele

Question 67

There are three stages of embryological midgut development.

Describe the second stage and the resultant clinical entities with errors in this stage.

Answer 67

Stage two occurs between the 10th-12th weeks of gestation.

Characterised by the midgut returning to the abdomen with a further 90° of anti-clockwise twist. The proximal jejunum returns first lying on the left and then right, with the caeco-colic loop returning last, lying in the RUQ.

Errors here result in non-rotation or mal-rotation and rarely reverse rotation or hyper-rotation.

Question 68

There are three stages of embryological midgut development.

Describe the third stage and the resultant clinical entities with errors in this stage.

Answer 68

The third stage of embryological gut development occurs in the 12th week and is characterised by the final 90° of counter-clockwise rotation so that the caecum descends to the RLQ and the DJ loop lies behind and to the left of the superior mesenteric vessels.

The third stage is also characterised by the peritoneal junctions fusing with the paracolic gutters and omentum.

Errors here result in defective fixation, which can predispose to volvulus.

Question 69

Describe the embryological abnormalities that result in:

• anorectal malformations
• rectourethral and rectovaginal fistula
• perineal fistula and anal atresia
• imperforate anus

Answer 69

• Anorectal malformations are result from abnormalities in development of the cloaca and urogenital sinus.
• Rectourethral and rectovaginal fistulas result from failure of the urorectal septum to extend far enough caudally, shifting the hindgut opening anteriorly and leading to development of the fistula.
• Perineal fistulas and atresia result from defects in gene expression during epithelial-mesenchymal signalling.
• Failure of the anal membrane to break down results in an imperforate anus.

Question 70

What is the urorectal septum?

When does it develop?

What is the adult structure it becomes?

Answer 70

The urorectum septum is a layer of mesoderm that separates the intestinal and urogenital tracts above the level of the cloaca.

Between the 5th-7th week of gestation, the urorectal septum descends caudally and ruptures the cloacal membrane, creating an anal opening and an urogenital sinus.

The urorectal septum becomes the perineal body.

Question 71

Describe the embryology of the anal canal and the relevance of the dentate line.

Answer 71

An anal pit is formed from ectoderm in the region of the proctodeum which proliferates and invaginates, with subsequent degeneration of the cloacal membrane establishing continuity in the anal canal.

Thus, the upper two-thirds of the anal canal is derived from endoderm (hindgut), whereas the lower one-third derives from ectoderm.

The dentate line represents the plane of fusion between endodermal and ectodermal tubes.

Question 72

What are the most common genetic mutations/anomalies associated with Hirschsprung’s disease?

Answer 72

Mutations in RET account for up to 50% of familial cases and one third of sporadic cases.

In cases of familial HD, knowledge of the specific genetic defect is important as it may have implications for genetic counselling and potential adverse associations, such as familial medullary thyroid carcinoma in MEN2B.

Trisomy 21 is present in about 15% of HD cases.

Question 73

When should Hirschsprung’s disease be considered?

What is the characteristic clinical sign?

Answer 73

A diagnosis of HD should be suspected in any term baby who does not pass meconium within the first 48 hours.

Clinical examination will reveal a tight anal sphincter, empty collapsed rectum and the “squirt sign”: a forceful expulsion of gas and stool as the finger is withdrawn after digital rectal examination.

Question 74

What life-threatening condition may occur in neonates with Hirschsprung’s?

Answer 74

Hirschsprung associated enterocolitis (HAEC) is a condition characterized by fever, distension, diarrhoea and sepsis.

It is associated with significant morbidity and responsible for up to 50% of mortalities associated with HD. HAEC may be the first presentation of HD, and a diagnosis of HAEC may be difficult to establish without a prior diagnosis of HD.

Question 75

What histopathological finding is pathognomonic for HD?

Answer 75

Histochemical staining demonstrating hyperactivity of acetylcholinesterase.

Question 76

How is Hirschsprung’s Disease diagnosed in adult patients?

How is it treated?

Answer 76

Acetylcholinesterase staining on punch biopsy can confirm the diagnosis in patients with suspected adult Hirschsprung’s, however is an unreliable investigation in isolation. In patients with diagnostic uncertainty, a full thickness 60mm rectal strip biopsy will confirm aganglionosis.

One third will present acutely and get defunctioned. For the remainder, the optimal approach is not known, the most commonly used procedure is the Duhamel’s due to the decreased risk of sexual dysfunction.

Question 77

In patients with FAP, what is the rate of:

• Colorectal cancer?
• Duodenal polyps?
• Duodenal cancer?
• Desmoid?
• Hepatoblastoma?
• Papillary thyroid cancer?
• Gastric fundic polyps?

What are the most common causes of death in patients with FAP?

Answer 77

• 100% lifetime risk of colorectal cancer
• 100% lifetime risk of duodenal polyps
• ~5% risk of duodenal cancer by age 57
• 30% risk of desmoid (depends on location of mutation on 5q21)
• <1% risk of hepatoblastoma
• Unknown but increased
• >50% of gastric fundic polyps

CRC is the greatest threat to life. Duodenal cancer and desmoids are joint second.

Question 78

What are the eviQ guidelines for testing of APC gene mutation?

Answer 78

Genetic testing should be considered in any individual with:

• >10 adenomatous polyps before 30
• >20 adenomatous polyps before 60
• Desmoid tumour in the abdomen or abdominal wall older than 10
• Hepatoblastoma
• CHRPE with atypical features
• A relative with APC mutation.

Question 79

How can the severity of duodenal polyposis be staged?

Answer 79

Spigelman Staging

Question 81

Please distinguish Lynch Syndrome from HNPCC.

What are the extra-colonic manifestations and variants of Lynch Syndrome?

Answer 81

Lynch syndrome refers to patients and families with a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene.

Hereditary nonpolyposis colorectal cancer (HNPCC) refers to patients and/or families who fulfill the Amsterdam criteria i.e. those in whom you would suspect an underlying MSI pattern.

Individuals with Lynch syndrome are also at increased risk of endometrial cancer but also cancer of the ovary, stomach, small bowel, hepatobiliary system, renal pelvis and ureter, brain, and sebaceous neoplasms.

LS is often categorized into type I and type II.

• Type 1 LS is characterized by colorectal cancer only
• Type 2 LS is colorectal cancer, associated with additional extra-colonic cancers
• Turcot syndrome is a subcategory of LS whereby people develop brain tumours specifically along with CRC.
• Muir-Torre syndrome is a variant whereby patients develop skin lesions such as sebaceous adenomas, epitheliomas, keratoacanthomas and sebaceous carcinomas as well as CRC.

Question 82

What is meant by an MSI-H tumour?

Answer 82

An MSI-H tumour is one which demonstrates a high number of mutations within micro-satellites.

Abnormal mismatch repair of these 1-6 nucleotide repeats in the genome suggest an underlying mutation in MMR proteins, most commonly MLH₁, MSH₂, MSH₆, and PMS₁.

Microsatellite unstable tumors can be divided into two distinct MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L). MSI sporadic colorectal cancers with a high level of MSI (MSI-H) form a well defined group with distinct clinicopathologic features characterized by an overall better long-term prognosis.

Question 83

How are MSI-H tumours diagnosed?

Answer 83

• Indirectly:
  
  • Through IHC staining of the MMR proteins; MLH1, MSH2, MSH6, PMS2.
  • Highly concordant.
  • MMR deficient means one or more proteins are missing
  • MMR proficient means they all stain positively.
  • Most commonly loss of MLH1 / PMS2.
• Directly
  
  • Through PCR testing of the 5 key microsatellite sites
  • Instability of one site = MSI-L
  • Instability of two or more sites = MSI-H
  • None unstable = MSS
  • Gold standard
• Directly
  
  • Next generation sequencing
  • Tests thousands of microsatellite loci, not just 5.
  • Expensive. In use at MSKCC.

Question 84

What is the utility of BRAF testing in the setting of dMMR disease?

Answer 84

In patients with MLH1 loss on immunohistochemistry, testing for BRAF helps to determine whether the MSI-H tumour is germline or non-germline;

• If there is loss of MLH1 and a concurrent BRAF mutation the tumour is non-germline
• If there is loss of MLH1 and the patient is BRAF-wt, then the patient should undergo MLH1 methylation testing.
  
  • If MLH1 is methylated, then the mutation is non-germline
  • If there is no MLH1 methylations, refer to genetics for gene testing.

Question 85

What are the morphological features of MSI-H tumours?

What is their response to adjuvant therapy?

Answer 85

• More often right sided
• Poorly differentiated
• Mucinous
• Signet cells
• Lymphocytic invasion

MSI tumours tend to respond poorly to chemotherapy, but more favourable to immunotherapy, including when there is metastasis to distant organs.

Question 86

Describe the recommended screening protocol for patients with Lynch syndrome.

Answer 86

• Colonoscopy every 1-2 years, starting age 20-25, or 5 years younger than the earliest age of diagnosis in the family
• Gastroscopy at diagnosis and H Pylori test
• *eviq update
  
  • There is no evidence supporting use of yearly female pelvic exams
  • Risk-reducing BSO and TAH is the only proven treatment.
  • There is no evidence supporting the use of gastroscopy surveillance or urological surveillance either!
• Some guidelines recommend the consideration of aspirin, which has been linked to reducing the risk of LS in a person’s family (CAPP2 trial).

Question 87

What is the implication of a BRAF mutation with regard to prognosis in colorectal cancer?

Answer 87

BRAF mutation confers worse prognosis, independant of MSI status and stage of disease.

In mCRC, there is increased survival in BRAF mutated tumours, with the use of Encorafenib.

Question 88

What are the proposed mechanisms for the increase in yCRC?

Answer 88

Globally, the increase in CRC incidence among young patients is attributed to a cohort effect; obesity, diabetes, sedentary lifestyle, heavy alcohol consumption, and a typical “Western” diet of rich in fast food, processed and red meat, and poor intake of vegetables and fruits are associated with increased risk of CRC.

A comparative analysis between patients ages 20-39 with CRC and the same age group in the general population without CRC shows that young patients with CRC have higher prevalence rates of medical comorbidities, such as diabetes, smoking and obesity.

IBD is a known risk factor for CRC, and the incidence of IBD is increasing.

Question 89

Which “natural remedies” increase bleeding risk?

Answer 89

• Fish oil
• Turmeric
• Garlic
• Ginko
• Ginseng may all increase bleeding risk.

Question 90

Is Warfarin cessation neccessary for colonoscopy?

Answer 90

A systematic review by Dunn et al. concluded that patients undergoing upper gastrointestinal endoscopy or colonoscopy (with or without biopsy) did not require warfarin cessation. Other studies have shown a slightly higher rate of bleeding complications.

Question 91

Why not bridge all patients on anti-coagulation prior to surgery or colonoscopy?

Answer 91

What little data there has suggested that while the VTE risk is unchanged in bridged versus non-bridged, the bleeding complication risk is higher in bridged patients!

The consensus from societies such as the American College of Chest Physicians is that the bridging of oral anticoagulation should be reserved for patients with a very high risk of thrombo-embolic events.

Question 92

What are the RACS guidelines regarding antibiotics prophylaxis in colorectal procedures?

What if the patient has a penicillin allergy?

Answer 92

The Royal Australasian Collage of Surgeons endorses the therapeutic guideline recommendations of a combination of cefazolin and metronidazole, or a second-generation cephalosporin alone (cefoxitin).

For patients with severe penicillin allergy, an alternative option is metronidazole and gentamicin

Question 93

Describe the methods of CRC screening and the evidence/rationale for these?

Answer 93

• gFOBT
  
  • Sensitivity and specificity lower than iFOBT so replaced
• iFOBT
  
  • 61% sensitive for AN
  • 95% specific for AN
• Flexible sigmoidoscopy
  
  • Has been used internationally
  • Shown to reduce deaths and incidence compared with no screening
  • Lower uptake than iFOTB
  • Higher uptake than colonoscopy
• Colonoscopy
  
  • Similar CRC detection with iFOBT but colonoscopy better at detecting adenomas (much better for non-advanced adenomas)
• CT Colonography
  
  • Sensitive for AA over 10mm
  • Generates more investigations (10%)
  • Low interval cancer rates