My Clinical Notes

Polyps

 

• A tumourous mass that protrudes into the lumen of the gut. All polyps are thought to start off as small sessile lesions and some can become stalked and are termed pedunculated
• They may be non-neoplastic or neoplastic

 

Non-neoplastic polyps

• Result from abnormal mucosal maturation, inflammation or architecture
• They have no malignant potential
• Account for 90% of colonic epithelial polyps
• Types;
  • Hyperplastic polyps
    • Small epithelial polyps found in 50% of people over the age of 60
    • Result from delayed surface epithelial cell shedding
  • Hamartomatous polyps
    • Malformations of the glands and stroma
    • Types;
      • Juvenille polyps
        • Usually sporadic involving the small intestine and colon
        • Generally large, pedunculated with cystically dilated glands and abundant LP
        • Most occur in children under 5 and involve the rectum
        • If they are found in adults they are called retention polyps
        • The rare juvenile juvenile polyposis syndrome is autosomal dominant , with numerous polyps and increased risk of adenomas and adenocarcinoma
      • Peutz-Jeghers polyps
        • Large pedunculated polyps, with a network of CT and smooth muscle extending into the polyp and surrounding normal abundant glands
        • May occur singly of multiply in Peutz Jeghers syndrome which is an autosomal dominant condition associated with melanotic pigmentation of the skin and mucosal surfaces and increased risk of carcinoma (pancreas, breast, lung, ovary, uterus)

 

• Other non-neoplastic polyps are;
  • Inflammatory polyps associated with IBD and called pseudopolyps
  • Lymphoid polyps which are essentially a normal variant of the mucosal bumps containing intramucosal lymphoid tissue

 

Adenomas – Neoplastic polyps

• Arise from dysplastic epithelial proliferation and adenocarcinoma generally arises from adenomas
• Dysplasia may range from low grade to high grade (carcinoma in situ)
• Prevalence of colonic adenoma is 50% after 60
• Slow growing, the time it takes them to double in size is 10 years
• They can be separated into three subtypes based on epithelial architecture;
  • Tubular adenomas – tubular glands
  • Villous adenomas – villous projections
  • Tubulovillous adenoma – a mixture of the above
• There is generally much overlap between these categories
• The malignant risk of an adenomatous polyp is correlated with 3 features; polyp size, histological architecture and severity of epithelial dysplasia;
• Carcinoma is rare is polyps smaller than 1cm
• The risk of cancer is high in sessile villous adenomas more than 4cm in diameter (40%)
• Severe dysplasia when present is often found in villous areas

 

Morphology

• By definition all adenomas exhibit dysplastic epithelium – tall hyperchromatic disorderly cells with increased nuclear:cytoplasmic ratio and cigar shaped nuclei
• Tubular adenomas
  • Begin as smooth mucosal bumps involving only a few adjacent crypts which can grow to become a large bulky neoplasm protruding into the lumen
  • Histologically the stalk is composed of fibrous tissue and prominent blood vessels and is normally covered by non-neoplastic mucosa
• Villous adenoma
  • Are larger when discovered and are generally sessile, up to 10cm in diameter and are velvety or cauliflower like lesions that project 1-3cm above the normal surrounding mucosa
  • Histologically there is fround like villiform extension of the mucosa
• Tubulovillous adenomas
  • Intermediate between the tubular and villous lesion in terms of their having a stalk or being sessile, their size and the level of dysplasia
  • The risk of harbouring in situ or invasive carcinoma generally correlates with the proportion of the lesion that is villous

 

Clinical

• Villous adenomas are more frequently symptomatic compared with tubular adenomas and are more likely to present with overt rectal bleeding
• Small intestine adenomas can cause obstruction and intussusception
• Rarely large villous adenomas in the colon hypersecrete copious amounts of protein and potassium rich mucus
• Endoscopic removal of the pedunculated malignant polyp is adequate treatment provided that the invasive component is superficial and doent not approach the margin, there is not evidence of vascular or lymphatic invasion and the invasive component is not poorly differentiated
• Invasive adenocarcinoma arising in a sessile polyp cannot be cannot be adequately ressected by polypectomy

 

Familial Syndromes

 

Familial adenomatous polyposis (FAP) syndrome

• Caused by mutations in the adenomatous polyposis cole (APC) gene on chromosome 5
• Based on clinical presentation, FAP can be divided into;
• Classic FAP
  • Patients typically have 500 to 2000 colonic adenomas
  • 100 polyps are required for an FAP diagnosis
  • Histologically the polyps are tubular in nature
  • May have colorectal cancer at the time of presentation
  • Progression of cancer develops 10 to 15 years from onset
  • There is 100% of adenocarcinoma by midadulthood
  • Prophylactic colectomy is curative
• Attenuated FAP
  • Patients tend to develop fewer polyps
  • The lifetime risk of cancer development is 50%
• Gardner syndrome
  • As well as adenomas these patients have multiple osteomas, epidermal cysts and fibromatosis as well as abnormalities in dentition
  • They have a higher incidence of duodenal and thyroid cancer
• Turcot syndrome
  • Rare syndrome marked by the combination of adenomatous colonic polyposis and tumours of the CNS
  • 2/3 have an APC mutation and develop brain medulloblastomas
  • Remaining 1/3 have mutations associated with HNPCC and develop brain glioblastomas

 

Hereditary Nonpolyposis Colorectal cancer (HNPCC) syndrome

• Autosomal dominant syndrome
• Characterised by increased risk of colorectal cancer and extraintestinal cancer particularly that of the endometrium and ovary
• Carcinoma is mainly of the proximal colon
• Cancer doesn’t arise from adenomatous polyps
• Due to mutations in mismatch repair genes resulting in microsatellite instability
• There are at least four genes involved in HNPCC but MSH2 and MLH1 are particularly common
• An affected individual inherits one defective gene copy  and acquires the ‘second hit’ to the colonic epithelial cells

 

Colorectal carcinogenesis

 

• Adenoma-carcinoma sequence model proposed by Fearon and Volgelstein
• Based on the following observation;
• Populations with a high risk of adeomas have a high risk of adenocarcinoma and vice versa
• The distribution of adenomas within the intestine is comparable to that of colorectal cancer
• The peak incidence of adenomatous polyps preceeds to peak for colorectal cancer
• The risk of cancer is directly related to the number of polyps
• Invention programs that screen for adenomas reduce the incidence of colorectal cancers

 

• The occurrence of some colorectal cancers without evidence of adenomatous precursors suggests that some dysplasic lesions can degenerate into malignancy without passing through a polyploidy phase

 

• It is believed that there are two distinct pathways for the development of colon cancer
• The first pathway id the APC/β-catenin pathway. The genetic correlates of this pathway are;
• Loss of the APC gene
  • APC regulates levels of β-catenin which is an important mediator in the Wnt/β-catenin signalling pathway
  • β-catenin also plays a role in cell to cell adhesion and can act as a TF
  • Therefore normal APC function promotes cell adhesion and regulates cell proliferation, absence of APC function leads to decreased cell adhesion and increased cellular proliferation
• Mutations in K-ras
  • Frequently activated oncogene in adenomas and colon cancers
• Loss of SMADs
  • SMADs are involved in TGF-β signalling
• Loss of p53
  • Mutations occur frequently in adenocarcinoma but not adenomas suggesting it is a late mutation in carcinogenesis
• Activation of telomerase
  • It is the accumulation of mutations that are important and not the precise order by which they occur

 

• The second pathway is the microsatellite instability pathway seen in the mismatch repair gene mutations which occur in HNPCC and in 10-15% of sporadic tumours

 

Colorectal Carcinoma

 

• 98% of the tumours of the large intestine are adenocarcinomas
• Account for 10% of all cancer deaths in the US
• Peak incidence is between 60 and 80
• M:F I:I apart from rectal cancer which has a slight male bias

 

Pathogenesis

• APC, HNPCC and IBD increase the risk of developing carcinoma however most arise spontaneously from polyploidy adenomas
• Dietary factors may play a role and explain and explain the contrasting incidence in geographical areas
• Dietary factors that may play a role;
  • Energy intake greater than requirement
  • Low vegetable fibre intake
  • High content of refined carbohydrates
  • High intake of red meat
  • Decreased intake of protective micronutrients e.g. Vit A, C, E
• There is evidence that the use of asprin and other NSAIDs may have a protective role

 

Morphology

• Grossly lesions may be a polyploid exophytic mass – especially those involving the proximal LI or an annular mass with a ring forming obstruction, more common in the distal colon
• Both may penetrate the bowel over the course of many years
• Histologically the tumours are typically composed of tall columnar cells resembling adenomatous neoplastic epithelium but with invasion into the submucosa, muscularis propria and beyong
• A minority produce copious amounts of mucin
• Carcinomas may be poorly differentiated, solid tumours without gland formation
• Tumours characteristically induce desmoplastic stromal responses with mesenchymal inflammation and fibrosis
• Less commonly foci of neuroendocrine differentiation, signet ring features of squamous differentiation occur

 

Clinical

• Generally insidious onset
• Proximal colonic cancers present with fatigue, weakness and iron deficiency anaemia
• Left sided lesions present with occult bleeding, changes in bowel habit and left lower quadrant pain
• In order of preference the favoured sites of metastatic spread are;
  • Regional lymph nodes
  • Liver
  • Lungs
  • Bones
• The most important prognostic indicator of colorectal carcinoma is the stage of the tumour
• 5 year survival rates are 100% for lesions limited to the mucosa and 25% for extensively invasive tumours

 

Dukes classification

 

Stage	Characteristics
Dukes Stage A	Carcinoma in situ limited to the mucosa or submucosa (T1, N0, M0)
Dukes Stage B	Carcinoma that extends into the muscularis (B1) or into or through the serosa (B2) (T2 disease)
Dukes Stage C	Carcinoma that extends to the regional lymph nodes (T3)
Dukes Stage D	Cancer that has metastasized to distant sites (T4)

 

This entry was posted on Monday, February 25th, 2008 at 5:10 pm and is filed under Gastrointestinal. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.