Large Bowel Polyps & Carcinoma

Colo-rectal Pathology

Objectives:

      1. Common polyps
      2. Neoplasms
      3. Hereditary neoplastic syndromes
      4. Colorectal carcinoma
        1. Presentation, diagnosis staging, Mx,
        2. Pathogenesis /molecular pathology

Polyps

      • A mass protruding into lumen

Image result for polyps

      • Most Neoplasms can present as polyps; but not all polyps are neoplastic
        • Overlapping but not equivalent

Hence, the presentations depends on size and location of polyp (is lumen big there?)

Presentations:

      1. Bleeding (especially left side and large)
      2. May e occult bleeding (screening)
      3. Obstruction – small lumen
      4. Intussusception
      5. Anemia
      6. Altered bowel habit
      7. Sometimes Ars due to altered blood chemistry eg potassium

Diagnostics

      • Patients sent test (>60)
      • Blood detected – visually in stools
      • Faecal occult blood test (sometimes present as false positive)
      • Faecal immunochemical test (more specific test)
      • Gastroenterology perform endoscopy (check for polyps visually)

If polyps present snared and sent to pathology:

      • Number and type of polyp noted and discussed at MDT
      • Decision taken regarding surveillance or further management
      • If carcinoma referred to surgery

Note: Benign = no can of malignancy as it is kept localised in the epithelial layer

      • Malignancy
      • Neoplastic ≠ Malignancy

Neoplasm: new and abnormal growth of tissue

 

Types of Polyps

Benign Polyps

Serrated polyps
(No signs of malignancy)

  1. Hyperplastic Polyps
  2. Hamartoma
  3. Inflammatory
 Because serrated polyps lie on a spectrum, they cannot be classified under (benign/neoplastic)

  1. Hyperplastic (no consequence)
  2. Sessile Serrated -adenoma (malignant potential)
  3. Traditional Serrated (adenomatous)

Hyperplastic                         Sessile Serrated                  Traditional Serrated

 

Neoplastic Polyps

Polyps with new abnormal growth
  1. Epithelial (most common)
    1. Adenomas (benign but can develop malignancy)
    2. Carcinomas (Malignant)
    3. Neuroendocrine tumours
  2. Non-epithelial
    1. Lipomas, vascular tumours e.g. angiosarcomas
    2. Stromal tumours (GIST)
    3. Lymphoma e.g. MALT, Mantle, DLBCL
Stroma Parenchyma
Supportive Framework

(glands/ connective tissue)

 Functional Tissue of an organ

Lipomas are found in the Submucosa layer; HIV is a risk factor for Lipodystrophy; refers to the changes in body fat t. Lipodystrophy can include buildup or loss of body fat.

Benign Polyps

Hyperplastic Polyps

Adenoma (glandular) hyperplastic mucosa;

Location: Anywhere along bowel length (rectosigmoid)

Significance: < 0.5 cm

      • very common
      • Asymptomatic
      • Malignancy potential is rare
      • No clinical significance

Hamartomatous Polyps

Hamartoma: Mature (differentiated) disorganised tissue native to the site

      • Solitary “tree-like shape”

 

Syndromes:

Peutz-Jeghers

Others
Autosomal dominant syndrome, hamartomatous polyps can be found in small/large bowel

  • Multiple hamartomas
  • No increase in malignancy (each)
  • Polyp itself has risk of malignant transformation
  • Melanotic accumulation (blue/grey macules)
    • Hands,mouth,lips,genitals
  • Associated with mutation STK11
  • Risk of CRC, Breast Ca, Gastric Ca, Gynae CA
  • Risk of intussusception (Any mass)

Requires Surveillance
  1. Cowden,
  1. Cronkite Canada Syndrome,
  1. Tuberous sclerosis
  1. Juvenile Polyps

Inflammatory Polyps

Inflammation (granulation tissue): Mass-like due to florid inflammation at site

Causes:

      • Chronic inflammatory bowel disease: Ulcerative Colitis / Crohn’s
      • Rectal prolapse

Serrated Polyps

Serrated lesions exist on a spectrum : Range → can’t clearly define as benign / neoplastic

      1. (Benign): Hyperplastic Polyps (HPP)
      1. (Unknown Malignant potential) treated as adenomas (benign with a small malignant potential) : Sessile Serrated Polyps (SSL)
      1. (Adenomatous) increased potential of malignancy: Traditional Serrated Adenomas (TSA)

Hyperplastic

Sessile Serrated

Traditional Serrated
Straight deep crypts Boot shaped Branching all the way down to glands

 

Definitions

Hamartoma: Recapitulation of normal tissue native to the site (mature-differentiated)

Neoplasm: Autonomous and excessive uncoordinated growth of tissue

Adenoma: Benign(no metastatic potential) neoplastic growth of gland bearing tissue with

dysplasia

Dysplasia: Abnormal cells in tissue without metastatic but with malignant potential may be low

grade or high grade in colon

No such thing as carcinoma in situ in the colon (in situ: localised w/o invasion)

AdenoCarcinoma: Invasive neoplastic growth arising within dysplastic glandular epithelium

with metastatic potential

Intussusception

Proximal colon telescopes onto adjacent portion of colon

Causes:

      • Idiopathic in children
      • Adults: associated with tumour masses that increases gastrointestinal motility

Results:

      • Obstruction (retention of intestinal content)
      • Infarction (pinching of mesenteric blood supply

Volvulus

Uncommon twisting of the gastrointestinal tract around its mesenteric attachment

  • Obstruction & Infarction
  • Common: Sigmoid colon
  • Treatment: sigmoidoscopy – straighten things out

Neoplastic Polyps

  1. Adenomatous (benign) Polyps

Dysplastic Epithelium: the different configuration (dysplastic grades) increases potential to develop into malignant = neoplastic; some may already have invasive cancer

Risk: Middle age Adults

Macroscopic: Polypoid/Pedunculated/Sessile Location: Left > Right colon

Tubular Adenoma

Tubulovillous

Villous Adenoma
Malignancy %: Low

Small and pedunculated

 Malignancy %: Moderate

Similar to tubular

  • Surface is villous
 Malignancy %: High

– Appears flattened and sessile with velvety surface

– Random architecture

Villus Adenoma  

 

Molecular Basis of Cancer in Colon

Benign Tumours can develop into Carcinomas

  • Vogelstein model of cancer:
  • Stepwise progression
  • Increase size and dysplasia increase risk
  • Accumulation of key driver mutations over time
  • Screening programme is based on this
  • Linked to Familial Adenomatous Polyposis

(real process is more complicated…)

General Risk of progression to malignancy

  1. Size
    1. Cancer rare in adenoma < 10 mm
    2. 40% adenomas > 40 mm have a cancer
  1. Degree of dysplasia
    1. High
    2. Low
  1. % of villous growth
    1. Tubular
    2. Tubulovillous (>20%)
    3. Villous (>8%)

Malignancy is dependent on depth (layers) the tumour goes into → spread

 

Carcinoma (malignant) Neoplastic polyps

  1. Familial Adenomatous Polyposis (FAP)

Autosomal dominant (AD);

  • Inactivating mutation in APC gene (adenomatous polyposis coli) on chromosome 5 tumour suppressor gene
  • 2-hit hypothesis (Knudson)
  • Loss of APC is the beginning of the path to colorectal cancer

Multiple (hundreds) of polyps arising within the colon

  • 1% risk of cancer in each polyp; definition of FAP>100 polyps; ~ 100% develop CRC

Treatment: Usually prophylactic surgery (20s)

Bowel Screening

FIT test (Faecal Immunochemical test)

Indications:

  1. Family History of FAP
  2. Age 60-69

– Every 2 Years

Colonoscopy

Indications:

  1. Positive results in FIT test

Management

  • May go back to FIT testing e.g. 2 HPPS
  • May need surveillance e.g. numerous ~ 8 adenomas
  • More frequent if higher risk (> dysplastic) e.g. two high grade dysplastic adenomas
  • May need limited resection e.g. very large tubulovillous adenomas
  • May need oncological resection e.g. suspicious for carcinoma

Epidemiology/Risk factors for colorectal Carcinoma

  • Peak 60-70s
  • US, Canada ++
  • Diet:
    • High calorie, fat and refined carbohydrate intake,
    • Low vegetable fibre intake
    • Low vitamin A, E, C
  • Smoking
  • Aspirin protective (Nurses Health Study)
  • Sporadic adenomas/Hx of removal of polyps
  • Family history
    • 1st degree relatives have 2-3 fold increased risk of developing CRC
  • Ulcerative Colitis

 

But Vogelstein model (tumour suppressor gene) not the only route to cancer
: Microsatellite Instability Model (DNA mismatch repair)

Sessile Serrated Route

DNA Mismatch Repair
4 major collection of proteins involved in DNA repair

  • Complexes; Form heterodimer pairs
    • MLH1-PMS2; MSH6-MSH2

Scenario:

  1. Defect in gene coding for MMR proteins (2 hit hypothesis)
  2. Reduced Capacity to repair specific types of CNA damage in certain cells
  3. Increased rate of Mutation; accumulation in microsatellite DNA
  4. Colorectal Carcinoma

 

Germline could be due to HNPCC (lynch syndrome)
    1. Lynch Syndrome / HNPCC (hereditary Nonpolyposis Colorectal Cancer)
    2. Autosomal Dominant; Mutations in DNA MMR genes
    3. 80% lifetime risk of CRC
      • Onset: 45 years
    4. Rapid growth
    5. Right side (multiple, mucinous)
    6. Carcinoma of SB & endometrium

 

Other Polyposis Syndromes

Adenomas:

      • Juvenile Polyposis
      • Peutz-Jeghers
      • Gardner
      • Turcot
      • Attenuated FAP
      • MYH-associated polyposis (MAP)

 

Colorectal Carcinoma

Non-inherited genetic change: Gene silencing; Epigenetic changes

      • Loss of mismatch repair proteins may not be hereditary → May be epigenetic
      • I.E. loss of gene expression due to external factors (e.g. hypermethylation)
      • Prevents expression of MMR proteins
        • Increases risk of cancer (not removing faulty DNA strands)
Other risk factors for ColoRectal Cancer
Carcinoma and Ulcerative Colitis
The risk of CRC is increased in patients with inflammatory bowel disease, but it is not

completely clear how chronic inflammation mediates carcinogenesis.

  • Risk in long-standing UC with pancolitis (all over the colon – inflammation)
    • Overall incidence is low
    • Symptoms masked by underlying disease
  • Multiple carcinomas without obvious mass

Treatment: Colectomy

  • Helps Ulcerative Colitis (location only in Colon)
  • Does not help Crohn’s disease (anywhere along GIT)

Invasive Carcinoma

Grading (differentiation – maturity)

TNM staging (tumour, Nodes, Metastasis):

  • Depth of invasion (T)
  • Lymph node involvement (N)
  • Metastasis to other organs (M)
 Spread of tumour cells:

  • Blood / Lymph / Direct

Modalities (instruments)

  • Radiology: CT abdomen ± thorax; bone scans
  • Pathology: examination of resection

 

Prognosis (outcome) is related to stage:

(5 year survival):

  • 95% if tumour limited to submucosa
  • 75% if node-positive disease
  • 4% if metastasis present

Treatment of CRC

Surgery with clear margins

Chemotherapy

(5FU + others)

Targeted therapy
+ radiotherapy for tumours below the peritoneal reflection to ensure clearance at circumferential margin Stage II, N0 disease with adverse features

Stage III, NP disease

Stage IV, Metastatic disease

 MSI will do worse with 5FU

Do not give anti-EGFR TKIs in the setting of KRAS or BRAF mutated CRC

Targeted Therapy

Targeted therapy is a type of cancer treatment that uses drugs or other substances to more precisely identify and attack cancer cells (only).

Examples:

– Monoclonal antibodies are bioengineered proteins that may help leverage the body’s natural immune response to recognize, attack and destroy colorectal cancer cells

Drugs: panitumumab / cetuximab

However, it is unknown if targeted therapy is the best choice; as targeted therapy helps more people, but they die more quickly. As drugs help in the process of “natural selection” and tumour cells that are more “survivable” remain and recolonise quickly (since destruction re-activates their growth process)

 

Immunotherapy

The pathway includes two proteins called:

      1. Programmed Death-1 (PD-1) -receptor, on the surface of immune cells
      2. Programmed Death Ligand-1 (PD-L1), on the surface of cancer cells.

Process:

      • Cancer cell present PD-L1 to Immune cell (T-cell)
      • T-cell recognises death signal
      • T-cell undergoes apoptosis
      • Cancer cell evades destruction of immune system (causes immunocompromisation)

Immunotherapy
  • Anti-PDL1, amongst others
  • Programmed Death Ligand 1
  • Shuts down the immune response to some colorectal tumours

T-cell remains alive → Can attack cancer cells

Cases

    1. 5 mm polyp in the rectum
      Benign or malignant?
    2. Smooth, colour similar to surrounding, small → Benign

 

Case 2)

 

 

 

 

 

A 19-year-old girl presents to A&E

      • Short history of abdominal pain and constipation.
      • Ultrasound and CT demonstrate intussusception
      • On closer examination, her palms and oral mucosa are spotted with multiple 1-2 mm blue-gray macules
      • Surgery for the obstruction
      • Follow up endoscopy show several polyps in the colon

Would you be worried about the polyps?

Peutz-Jeghers Polyps (benign; Hamartoma)

    • Not too worried, but keep under surveillance
      • As she has multiple polyps (each 1% ~ has risk of malignancy)

 

Case 3)

  • 64 year old (risk factor)

Screening case:

  • 10 polyps (many)
    • 9 are 5-8mm (small / medium)
    • 1 is 15mm (Huge)

 

Worried for Carcinoma

  • Lesion, although looks well defined, is not on closer inspection (microscope endoscopy)
  • “Bumpy” surface
  • Different colouring from surrounding tissue

Likely to be a Neoplastic → biopsy

(might not be malignant, but requires either resection or surveillance)

 

Summary:

What I need to know:

  • Types of polyps and adenomas
  • Polyposis syndromes (FAP and HNPCC)
  • Molecular basis of colon cancer
  • Presentation, dx and Mx of colon cancer