CL2 - Colorectal Cancer

Principles of surgery in cancer

• remove cancer without damaging surrounding structures

• lymph nodes and blood vessels supplying the cancer also need to be removed

• in bowel cancer the lymph nodes run alongside the arteries so you need to remove them too which removes more bowel than just where the tumour is

Role of surgery

• Control local disease

• Stages disease (TNM) - radiology cannot tell us this so we need the pathology

• Offer cure, extended life (e.g. metastasectomy in CRLM)

• Palliate symptoms – stops bleeding, bypass obstruction

• Psychological benefits for patients (“just want tumour out”)

• Facilitate chemotherapy e.g. reduce malignant cells and thus resistant clones

• Risk reducing e.g. BRCA patients

Ways to discuss a disease - “In a surgeons gown, physicians may make some progress”

• incidence - how often it happens

• age

• sex

• geography

• path - microscopic/macroscopic

• symptoms

• prognosis

Management of colorectal cancer

Management of any condition in Medicine depends upon diagnosis:

• Diagnosis is based upon history, examination and special investigations

• Management of cancer follows the above principles at first, and once the diagnosis is made, it all depends upon the stage

Other factors to consider

• “Patient factors” (e.g. other comorbidities) and “tumour factors”

• “Decisions are more important than incisions”

• The art of surgery (and medicine) is in tailoring the treatment to the individual patient (balancing the benefits with the risks/recovery)

Colorectal cancer

CRC (Colorectal carcinoma) - the occurrence of malignant lesions in the mucosa of the colon and rectum.

Colorectal cancers are all adenocarcinomas.

Anal cancer is a different disease

Bowel Anatomy

Bowel Wall Layers

• mucosa - epithelium, lamino propria

• submucosa - rich in lymphatic and blood vessels (only cancer when it invades this layer through the muscularis mucosa)

• muscularis propria - circular and longitudinal muscle

• Serosa (visceral peritoneum) and subserosal fat (important in cancer surgery)

Epidemiology of Bowel Cancer

• The fourth commonest cancer in the UK (but second commonest cause of cancer death)

• 1 in 14 men, 1 in 19 women will be diagnosed with CRC in their lifetime

• Age – median 60

• Sex 1.5:1 M:F

• Geography: higher in the West – diet related

• Pathology: Macro – Annular, polypoid, ulcerated

• Path: Micro – moderately differentiated typical, dirty necrosis

Symptoms of Bowel Cancer

Depends upon location, general ones include:

• rectal bleeding

• change in bowel habit

• weight loss

• iron deficiency anaemia

• bowel obstruction

Prognosis depends on stage but early detection has around 5 year survival

Pathology of Bowel cancer

• Polyps - main cause

• Diet – not quite so simple. Interplay with genes.

• Family history – 1^st degree relatives key

• IBD

• Genetic Syndromes (HNPCC, FAP) – 75% are sporadic

• Previous cancer/radiation

• Obesity, smoking, alcohol

Rarer causes:

• Ureterosigmoidostomy

• Diabetes

• Cholecystectomy

• Acromegaly

Polyps

a protuberant growth from the mucosa

Can be pendunculated (on a stalk) or sessile (flat)

• Pendunclated is better for surgery

• Sessile has saline injected underneath it to make it rise slightly above the surface to be surgically removed

Benign epithelial tumour of cells derived from glandular epithelium → mainly adenomas

They are all dysplastic and have disregulated proliferation.

They fail to fully differentiate and are all premalignant (though not all progress to cancer).

Grading of Polyps

Based on velocity

• Tubular adenoma

• Villous adenoma

• Tubulo-villous adenoma

Non-neoplastic polyps

• hamartomas

• hyperplastic

Adenoma Crcinoma sequence

Normal mucosa

→ APC inactivation or B-catenin activation ~ Wnt pathway

Causes abberant crypt foci

→ COX-2 upregulation

Causes early adenoma

→ K-Ras activation

causes intermediate adenomas

→ SMAD4 inactivation

causes late adenoma

→ p53 inactivation

causes carcinoma which progresses to metastasis

Evidence for adenoma-carcinoma sequence

• Distribution of polyps matches cancer and background polyps in cancer

• Carcinomas found in adenomas (“polyp-cancer”)

• Coexistence in high risk groups e.g. FAP

• Follow-up of patients declining polypectomy

Pathology of Bowel cancers

• 98% are large bowel/colon cancers are adenocarcinoma.

• Other rare tumours depend upon the cell of origin that has become malignant (NET, lymphoma etc)

Macroscopic classifications

• Annular (circumferential – causes bowel obstruction)

• Polypoidal - can cause anaemia

• Ulcerated (2/3) - can perforate

Grading of Bowel cancer

How much like normal tissue does it look like?

• Grade I – well differentiated (15%)

• Grade II – moderately differentiated (70%)

• Grade III – poorly differentiated (15%)

Modes of spreading

• Direct –invades other structures through the bowel wall e.g. bladder, abdominal wall

• Lymphatic – critical. Basis of original Dukes staging

  • run with the blood vessels and are a critical aspect of surgery

• Haematogenous – metastases get to liver via portal vein

  • 25% of CRC patients present with mets

• Transcoelomic – spread throughout the peritoneal cavity.

  • T4 cancer spreads and sheds of cancer cells in abdominal cavity

  • Classically to ovaries – Krukenberg tumours (MASSIVE tomours in the abdominal cavity) – very chemoresistant

• Implantation – suture line, wound, laparoscopic ports sites

Dukes Pathological staging of bowel cancer

Stopped being used in 2018 and was replaced with TNM

• Dukes A: Confined to bowel wall

• Dukes B: Through bowel wall

• Dukes C: Lymph nodes involved

• Dukes D: Distant Metastases

Genetic syndromes

Two key inherited bowel cancer syndromes are HNPCC and FAP

Associated with other cancers

Screening of patient and family

HNPCC

Hereditary non-polyposis colon cancer - Also known as Lynch syndrome – slight distinction between them in terms of MMR status

• Inherited colon cancer

• 5% of new cases per year

• Germline mutation in Mismatch repair gene (MMR) which is a tumour suppressor gene which corrects wrong base pairing

• Have microsatellite instability – DNA repeats

• Average age of diagnosis 45

• Usually develop on the right

• Synchronous and metachronous

• Biologically aggressive, rapid transformation from benign to malignant

• Associated with other cancers – must screen for them (though these are not as aggressive as de novo of the same):

  • Endometrial cancer

  • Ovarian cancer

  • Gastric

Amsterdam Criteria

identifies high risk families for genetic testing (3,2,1)

FAP

Familial adenomatous polyposis

• 1% of all CRC

• APC mutation on 5q – β-catenin and Wnt pathways

• 100% risk of CRC by 20-30s

• Autosomal dominant inheritance

• Multiple extra-intestinal manifestations

• Originally defined by the presence of >100 colorectal adenomas

Difference between family history bowel cancer

General rule of thumb is:

relative right, life left

General Symptoms

• Anorexia

• Weight loss

• Anaemia

• Fatigue - severe

Right sided - Local Symptoms

• Abdominal mass

• Iron deficiency anaemia (IDA)

• Small bowel obstruction

• Perforation

• Symptomless

Left sided - Local Symptoms

• Rectal bleeding

• Change in bowel habit

• Bowel obstruction/abdominal colic

• Mucus discharge (more often associated with a large polyp)

• Fistula – to e.g. bladder

• Perforation

25-30% of patients with left sided colon tumours present as an emergency – usually LBO/perforation

Rectal Tumours

• Rectal bleeding (60% of patients)

• CIBH including mucus PR

• Tenesmus (sensation of incomplete evacuation even if you went - brain can’t distinguish the difference between stool and the lump)

• Rarely fistula

Signs of bowel cancer

Get this from the rectal exam

• Conjunctival pallor from anaemia

• Cachexia - pt looks very skinny and washed out

• Abdominal Mass

• Palpable rectal mass

• Palpable liver/jaundice in sclera (eye)

• Lymphadenopathy

Rectal examination is critical - can assess lesion size/nature (i.e. hard cancer or soft polyp), location in relation to sphincters, local fixity/mobility, sphincter quality

Synchronous vs Metachronous

Synchronous - more than 1 cancer at the same time

Metachronous - more than 1 cancer in 10 years

Distant Disease

Also affects:

• Liver – jaundice, RUQ pain, ascites

• Lung – incidental on scan often, SOB

• Other – lymphadenopathy, bony pain

Investigating Bowel Cancer

• Barium enema – outdated now – traditionally used

  • due to lower sensitivity of detection of CRC

    (82-85%)

• Endoscopy: flexible sigmoidoscopy and colonoscopy – latter is Gold standard

• CT Colonoscopy – Good sensitivity/specificity. Cannot biopsy. Good for completion “scope” if obstructing tumour/cannot complete endoscopically

Sigmoidoscopy is the same camera as colonoscopy but stops earlier

Loco-regional staging

• CT C/A/P – looks for mets.

  • Occasionally used in elderly, frail unfit patients used to rule out large obvious lesion cause they wont tolerate a colonoscopy

• MRI for rectal cancer good for CRM and “N” stage

• TRUS for early rectal cancer – assess suitability for local excision – good for “T” stage only really

Endoscopy

• Flexible sigmoidoscopy and colonoscopy – same scope but end points different

• Flexible fibre optic tubes

  • better for patients who can’t tolerate the colonoscopy such as IBD patients

• Bowel prep +/- conscious sedation

• 90% caecal intubation (we are audited on this)

• 1:1000 perforations

• Can biopsy, tattoo and treat

CTC/CT pneumocolon

• Less invasive

• Pretty much 100% caecal imaging

• High sensitivity for polyps and cancer

• Can assess other intra-abdominal structures

CEA blood test

Carcinoembryonic antigen

good at baseline - if tumour is a CEA secreting lesion it can be a good test for surveillance and recurrence

Management of this Cancer

• principles of cancer resection

  • what are you trying to achieve - reduce local recurrence, cure, palliation, prolonging life

• if non-metastatic remove the mets to stop a local problem and staging

• lymphadectomy key - for staging and treatment

Management: If the cancer is Metastatic disease

Secondary or primary dealt with first?

• deal with mets first if fatal unless primary is causing anaemia and more damaging etc

Types of Bowel Cancer Surgery

Methods for colon removal surgery

Can do open, laparoscopic (“keyhole”), robotic or transanal if rectal cancer

Risks of this include:

• Anaesthesia

• Bleeding

• Infection (chest, wound, urine)

• Anastomotic leak

• Injury to other structures (e.g. ureter)

• Stoma

• MI

• DVT/PE

• Death

What are the steps post surgical removal of cancer?

Once the specimen is out and pt has recovered

• Await histopathological assessment – this is key to prognosticate and decide further treatment

• Defines the stage of tumour: TNM and excision margins

• If no blood vessel or nodal involvement the patient is considered surgically cured

• Continue surveillance to ensure doesn’t develop new primary or metastatic disease

Decisions after the surgery

• If nodal or vascular invasion is present– consider giving “adjuvant” chemotherapy to reduce the risk of developing metastases

• If margin is involved this is bad news…. May need to consider further treatment such as radiation to the tumour bed, not that effective…

What can surgery help with?

• Local recurrence

• Overall survival/Disease free survival (governed by metastases)

• In-hospital mortality

• Quality of life (nerves of sexual/urinary and bowel function)

Surgery will cure cases whereby the cancer can be resected with an R0 resection

Principles of CRC surgery

• Resection of not only primary tumour but draining lymphatics and blood vessels within mesenteric envelope

• Complete tumour removal (R0)

• Dissection in precise embryological, “holy” planes to produce an undisrupted mesocolic/mesorectal specimen

  • holy plane means resecting the primary cencer and the package of tissue it is housed in

Ontogenetics

• The mapping of body compartments established during early embryologic development

• Traditional cancer surgery is based on wide excision with a safe margin

• The ontogenetic theory of local tumour spread claims that local dissemination is facilitated in the ontogenetic compartment of origin, but suppressed at its borders in the early stages of cancer development.

• Optimal local control of cancer is achieved by whole compartment resection with intact margins following ontogenetic “planes”.

MRI role in cancer

MRI tells us which cases of rectal cancer stay in this ontological envelope

• Designed to reduce risk of developing metastases

• Best given to “Dukes C” patients

• Usually 5FU based: 3-6 months

• Work on DNA

• Problems related to toxicity

Examples of chemotherapy drugs

• 5-Fluorouracil – interferes with RNA synthesis and DNA replication

• Leucovorin – potentiates 5FU

• Oxaliplatin – cross links DNA – thus inhibits synthesis

• Irinotecan – Topoisomerase inhibitor

• Bevacizumab – VEGF inhibitor

• Cetuximab – EGFR inhibitor – only for Ras WT

Screening/Prevention of bowel cancer

• Bowel cancer screening programme – biannual – 60-74

• Faecal occult blood testing:

  • If negative – repeat in 2 years

  • If positive – offered colonoscopy:

  • At scope - 50% normal, 40% adenoma, 10% cancer

• Bowel scope is new – flexi sig for all >50yrs

Surveillance/Prevention of Bowel Cancer

• Family History

• Genetic syndromes: Lynch, FAP – prophylactic surgery

• Previous cancer

• Previous polyp

Standard Follow-up post CRC surgery

• CT C/A/P years 1 and 2

• Colonoscopy years 1 and 5 (some do year 3 also)

• CEA 6 monthly for first three years, then annually for 2 more

• Generally stop after 5 years – considered cured