Sabiston 2 Flashcards
(128 cards)
The molecular events in CRC
include early APC (adenomatous polyposis coli) gene mutations, subsequent activating mutations in the oncogene KRAS, as well as mutations resulting in inactivation of the tumor suppressor gene TP53
CpG Island Methylator Phenotype
- involves a mutation of the BRAF gene resulting in inhibition of normal colon cell apoptosis.
- development of hyperplastic or sessile serrated adenomas or polyps > prone to epigenetic silencing of genes within “CpG islands”
- The hMLH1 gene (one of the DNA repair genes involved in Lynch syndrome) is one of the best characterized genes that undergoes this type of epigenetic silencing by CpG hypermethylation.
- result in a microsatellite instable-high (MSI-H) cancer if there is further gene mutation or methylation.
- most cancers arising from sessile serrated adenomas will have a MSI-H phenotype and are often located in the right colon.
Microsatellite Instability Mutator Pathway
- These genes include mutL homologue 1 (MLH1), MLH3, mutS homologue 2 (MSH2), MSH3, MSH6, or PMS1 homologue 2 (PMS2)
- These associated cancers will be MSI-H
- often characterized by location in the proximal colon, large local tumor, typical absence of metastatic disease, and poor tumor differentiation.
- When this occurs in patients with sporadic cancer, they are often elderly; when this occurs in the hereditary form (i.e., Lynch syndrome), patients are often younger (<50 years old)
- Testing for the presence of a BRAF mutation will aid in differentiating sporadic (BRAF mutation present) from inherited forms
Epithelial-Mesenchymal Transition
- Epithelial-mesenchymal transition is the process whereby cells lose their epithelial functional and morphologic functional features and gain a “mesenchymal” phenotype.
- Through this process, locally growing cancer cells gain the ability to invade through the bowel wall and spread to regional lymph nodes.
- Once cancer cells reach a metastatic site, they must reverse this process and undergo mesenchymal-to-epithelial transition.
Polyp
endoscopic appearance into pedunculated (with a stalk) sessile (flat)
histologic appearance
(adenomas, hamartomas, inflammatory, serrated, etc.).
Nonneoplastic Polyps
- Hyperplastic polyps :
> small sessile lesions, usually less than 5 mm, consisting of elongated colonic crypts with a papillary configuration of epithelial cells without atypia.
> They are common colonic polyps, frequently grossly indistinguishable from small adenomas. - Inflammatory polyps (pseudopolyps) are found in regions of healing inflammation.
> may be large, mimicking a neoplasm.
> found in diseased colons otherwise at risk for cancer (e.g., in IBD) - Hamartomas
> uncommon polyps found in the GI tract
> sporadic or related to a genetic syndrome such as Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and PTEN hamartoma syndrome. - No malignant potential.
- Removal is indicated for obstructive symptoms or bleeding.
Serrated Polyps
three types:
> hyperplastic polyps (which are not considered precancerous)
> sessile serrated polyps
> traditional serrated adenomas.
- Sessile serrated polyps and traditional serrated adenomas are combinations of adenomatous and hyperplastic polyps, sharing features of both types including colonic crypts with a saw-tooth serrated configuration and nuclear atypia :
increased risk of CRC
follows the serrated neoplasia pathway in contrast to the classic adenoma–carcinoma pathway seen in adenomatous polyps. These polyps should be removed, and patients should be followed with serial endoscopy.
Neoplastic Polyps
- All adenomas have a malignant potential.
> Tubular adenomas
Villous adenomas
Tubulovillous adenomas
The most common type are tubular adenomas,
frequently pedunculated.
- Villous adenomas are commonly sessile.
The risk of malignancy increases dependent on the size (large), gross shape (sessile), histologic type (villous), and grade of dysplasia.
Patients with an advanced adenoma defined as
- size at least 1 cm
- high-grade dysplasia
- tubulovillous or villous histology are at a significantly increased risk of developing CRC.
Polyp Excision
forceps and snares.
Pedunculated polyps >
removed using cold or hot snare polypectomy.
Sessile polyps > elevated from the underlying muscularis by injection of saline and then excised using an assortment of techniques.
Sessile polyps with a central depression that do not elevate adequately with saline injection (nonlifting sign) are at increased risk for perforation with endoscopic removal and at higher risk of harboring neoplasia and are commonly referred for surgical removal by segmental colectomy.
Large polyps that cannot be removed endoscopically are also referred for surgery.
Larger polyps can also be removed endoscopically using techniques such as endoscopic mucosal resection and endoscopic submucosal resection.
Malignant Polyps
Malignant polyps are those in which histologic examination following removal of a polyp reveals a focus of carcinoma that has invaded through the muscularis mucosa.
The question that arises is whether complete endoscopic removal of these polyps is sufficient.
Carcinomas that do not pass the muscularis mucosa are considered “carcinoma in situ” and do not carry metastatic risk. However, those that invade the muscularis mucosa harbor a significant risk of local recurrence and lymph node metastasis.
High Risk Polyp
- Malignant polyps are commonly referred for completion colectomy in cases of
- pedunculated Haggitt level 4
- sessile Kikuchi level Sm2 and Sm3
- histologic poor differentiation
- lymphovascular invasion
- incomplete removal or close resection margins
Recommendations for repeat colonoscopy following endoscopic removal of polyps
see
Familial Adenomatous Polyposis
- germline mutation in the APC tumor suppressor gene which is responsible for regulation of β-catenin and located on chromosome 5q21
fewer than 100 adenomas
are considered to have attenuated FAP (AFAP)
A variety of benign and malignant extracolonic manifestations have been described in FAP.
- gastroduodenal adenomas and carcinoma
- desmoids
- osteomas
- epidermoid cysts
- papillary thyroid carcinoma
- small bowel polyps and carcinoma
- congenital hyperplasia of the retinal pigment epithelium (CHRPE)
- dental anomalies
Inherited colorectal cancer syndromes
see
the second most common cause of death in FAP patients
Duodenal adenomas occur in 30% to 70% of patients with FAP, and there is a predilection for the ampullary and periampullary regions.
The lifetime risk for duodenal cancer is 4% to 10%, constituting the second most common cause of death in FAP patients
desmoid tumors
- About half of FAP-associated desmoid tumors arise intraabdominally in the bowel mesentery and 40% develop in the abdominal wall.
- Surgery of intraabdominal desmoid tumors, in general, is not recommended
- NSAIDs and antiestrogens showed similar outcomes to surgery. Combination chemotherapy, including doxorubicin, seems to be the best option for progressively growing intraabdominal desmoids.
CHRPE
CHRPE is a benign lesion
characterized as well-delineated grayish-black or brown oval spots seen in 60% to 85% of FAP patients on fundoscopic scan.
Normally, this does not require intervention but can be used to help make a diagnosis
Gardner syndrome and Turcot syndrome
Gardner syndrome
(FAP with epidermal inclusion cysts, osteomas, desmoid tumors)
Turcot syndrome
(FAP associated with malignant tumors of the central nervous system)
Indications for genetic counseling
family history of FAP
personal history of more than 10 adenomas
personal history of adenomas
and an extracolonic manifestation of FAP.
For individuals suspected of AFAP, gene testing is recommended if 20 or more cumulative colorectal adenomas are found
Screening
Colorectal screening
> begins at age 12 , initiated with flexible proctosigmoidoscopy. If polyps are seen >colonoscopy is warranted.
If no polyps are identified on the initial flexible proctosigmoidoscopy > repeated every 1 to 2 years until the age of 35 and every 3 to 5 years thereafter
Patients at risk for AFAP should receive endoscopic screening with colonoscopy at
ages 12, 15, 18, and 21 years, and then every 2 years
About one-third of patients with AFAP can be managed long-term endoscopically by polypectomy
For the upper GI tract, screening
screening begins at 20 to 25 years of age.
Screening intervals are based on the Spigelman staging system.