B55 tumors of the intestines

Question 1

What are the types of polyps of the GI?

Answer 1

By morphology the are sessile or pedunculated

Non-neoplastic - result from abnormal mucosa growth, hyperplasia, or inflammation.

• hyperplastic polyps are the most common type.
• found in 50% of elderly patients

Hamartomatous polyps

• disorganized growths of mature, non-neoplastic cells of normal tissue for that organ.
• Occurs most often as Juvenile polyps, which can be sporadic or part of juvenile polyposis syndrome.
• Occur most frequently in the rectum
• They are vascular and usually present with rectal bleeding, and sometimes polyp prolapse outside of the anus.
• These hamartomas all carry a low risk for adenocarcinoma transformation, and the syndrome has an increased cancer risk

Peutz-Jeghers polyps

• rare polyps that occur as part of peutz jeghers syndrome
• multiple hamartomas
• form anywhere in the intestine, unlike most polyps which usually form in the colon
• Can become large and cause risk of obstruction and intussusception.
• Increased risk for many kinds of cancers including GI.

Adenomatous or neoplastic

• Adenomatous polyps are distinguished from non-neoplastic, hyperplastic polyps by extensive, crowded and disorganized glands , with dysplastic epethelial cells lining them. The epithelial cells have less goblet cells, and hyperchromatic, enlarged nuclei.
• Can be in one of several types based on their morphology, but all are defined by the dysplastic epethelium.
  
  • Tubular - froms tubular glands, and often looks like a smooth polyp, which can become ulcerated. risk of malignancy is correlated to the size. <1cm very low risk. above 4cm, ~50% risk.
  • Villous - forms structures like intestinal villi, with long fingerlike projections of dysplastic epithelium like a mat of cauliflower. Usually quite large. about 40% transform to invasive adenocarcinoma.
  • Tubulovillous- a mixture
  • Sessile serrated polyp/adenoma - This one lacks epethelial dysplasia, and is defined by being sessile, with deep serations, and most importantly, large, dilated, abnormal Crypts. lack the normal architechture of immature cells at the base and mature cells towards the lumen. have mature cells throughout.

Question 2

What are the types of malignant cancers that develop in the intestine?

Answer 2

1. Colorectal carcinoma = adenocarcinoma of the colon 98% of large intestine cancer.
2. Adenocarcinoma of the small intestine (very rare)
3. Gastrointestinal stromal tumors GIST
4. Gastrointestinal lymphoma, MALT lymphoma
5. Carcinoids
6. Squamous cell carcinoma of the anus
7. Leiomyosarcomas

Question 3

What is the main precursor lesion to colorectal carcinoma, and where does it usually occur?

Answer 3

80% arise from adenomatous polyps, which are the main precursor lesion, others are sessile serrated poylps, villous adenoma

They usually arise in the sigmoid colon and rectum, sometimes in the descending colon. Rare in the ascending colong. So, they arise in the left colon.

Question 4

Colorectal carcinoma epidemiology

Answer 4

• Peaks at 60-70 yrs,
• slight male preference
• 15% of all cancer related deaths.
• Second most common cancer related death after lung cancer, in both sexes.
• High incidence in western countries, low incidence in developing countries, probably associated with low dietary fiber and high intake of refined carbs.
• If it occurs inyoung people, suspect a backround of Ulcerative colitis, Crohns, FAP, or HNPCC.

Question 5

What are the two pathways of mutation that colon cancer develops from?

Answer 5

APC pathway and the DNA mismatch repair pathway.

APC, beta-catenin pathway. APC mutations seen in ~80% of sporadic cases. APC mutation –> K-Ras mutation –> 18q21 deltion, DCC, SMAD2 and SMAD4 –> p53 mutation/deletion –> Colorectal adenocarcinoma. more associated with adenomatous polyps.

1. APC promotes beta-catenin degradation. Homozygous mutation causes excess beta-catenin. (two hit hypothesis)
   
   • ​b-catenin is a transcription factor, stimulates trascription of MYC and Cyclin D1 genes and other pro-mitotic genes.
2. K-Ras mutation occurs
   
   • activating mutation blocking the Ras GTPase activity
3. 18q21 deletion
   
   1. loss of SMAD2 and SMAD4, loss of TGF-beta mediated cell cycle inhibition.
4. Loss of p53. found in 70-80% of all colon cancers

The order of these mutations is not critical aside from the APC mutation usually occuring first.

DNA mismatch repair pathway. ~15% of sporadic cases. Microsatellite instability occurs with accumulation of mutations in areas of repeated sequences. Accumulation of mutations in the promoter or regulatory regions of TGF-beta Receptor gene and the BAX gene, BRAF (ser/thr kinase) as well as many other genes regulating proliferation or apoptosis. More associated with sessile serrated adenoma

Question 6

What is familial polyposis syndrome? How is it diagnosed clinically and treated?

Answer 6

• An autosomal dominant disorder due to mutation of the APC gene. Born with one mutated copy, extremely high rates of adenomatous polyp development in the colon.
• Requires complete colectomy or definitely will develop carcinoma by mid life, and colectomy is standard treatment.
• Diagnosed by over 100 polyps in the colon, or from known gene mutations.
• Adenomas also form in the small intestine and duodenum, but not nearly as numerous.

Has important extraintestinal symptoms:

• Increased risk for other neoplasias
• Gardner syndrome:
  
  • Osteomas in the mandible, skull, and long bones.
  • Desmoid tumors
  • Thyroid tumors
  • Abnormalities of the teeth, extra teeth.
• Turcot syndrome:
  
  • ​less common than Gardner
  • Tumors of the CNS, especially meduloblastomas and glioblastomas

Question 7

What is hereditary nopolyposis colorectal cancer?

Answer 7

A heritable syndrome which causes multiple types of cancers. Also called Lynch syndrome.

Caused by heritable mutations to one allele of one of the mismatch repair genes MLH1, MLH2, and MSH2.

Tumors have microsatellite instability, with expansion and mutation of these areas of repeated DNA sequences during DNA replication.

Forms right sided colonic tumors, of the ascending and transverse colon, in young patients.

The tumors are far less numerous than in APC but are very aggressive.

Question 8

Clinical presentation of colorectal cancer

Answer 8

Typically develop insidiously and present with advanced symptoms

• weight loss
• occult blood in the stool
• resulting in Iron Def. Anemia –> in old men with iron deficient anemia assume there is colorectal cancer until you have definitively excluded it.
• fatigue

Left sided cancers may be detected earlier by noticeable blood in the stool or altered defecation habits.

Note that the most frequent sites of adenocarcinoma are the sigmoid and rectum, thus screening with digital rectal exam and colonscopy is essential.

Question 9

How does colorectal cancer spread?

What are its major sites of metastasis

Answer 9

1. By local direct local invasion of surrounding structures.
2. By lymphatic spread
3. By hematogenous spread

Metastasis sites, in order.

1. Regional lymph nodes
2. Liver (due to portal drainage and hematogenous spread)
3. Lungs
4. Bones

Question 10

What are the factors determining the prognosis of colorectal cancer?

Answer 10

Two most important factors are depth of invasion and the presense or absence of lymph node metastases.

Uses the TNM Tumor-Node-Metastasis staging system.

Limitation to the mucosa and submocosa, with no invasion through the tunica muscularis is the best prognosis. Once it invades the muscular layer the prognosis is markedly worse.

Involvment of lymph nodes make is significantly worse than that.

Stage 1, T1 or T2, with N0 and M0: Tumor invading into the submucosa or into, but not past the tunica musclaris, with no lymph node involvment, and no metastasis: 5yrS of 75%

Stage 3, Any tumor size, with N2 and M0. More than 4 regional lymph nodes involved, but no metastasis: 5yrS 30%

Stage 4, With metastasis, 5yrS 5%

Question 11

What are the types of tumors of the small intestine

Answer 11

Benign tumors (rare)

• Mesenchymal tumors - Lipomas and schwannomas
• Peutz-Jeghers hamartomatous polyposis

Malignant tumors (rare)

• Neuroendocrine tumors (carcinoids) - about half of all small intestinal tumors. May express gastrin, insulin, histamine/serotonin –> carcinoid syndrome
• Adenocarcinoma - arise in the duodenum, and are usually aggressive and locally invasive, almost always have lymph node infiltration and often metastasis at time of diagnosis. But have a better prognosis than colonic adenocarcinoma, with ~70% 5yrS rate on excision and chemo, even with lymph or other metastases.
• GISTS - can have multiple morphologies, but all express the c-KIT tyrosine kinase receptor mutation. are susceptible to imatinib. Originate from interstitial Cajal cells of the ENS or from a common stem cell.
  
  • smooth muscle differentiation (previously classsed as leiomyosarcomas)
  • neural differentiation
  • mixed differentiation
  • undifferentiated
• MALToma
• Intestinal T-cell lymphoma, associated with Celiac disease.

Question 12

What are the most frequent sites for MALT lymphomas to form?

Answer 12

(1) Stomach – 55‐60%
(2) Small intestine – 25‐30%
(3) Proximal colon – 10‐15%
(4) Distal colon ‐ <10%