Patho sheet # 11 -Aseel hattar

Aseel hattar
Pathology sheet # 13
Date of lec.:7 /3/2011


Adenocarcinomas constitute the vast majority of colorectal cancers and represent 70% of all malignancies arising in the gastrointestinal tract. Curiously, the small intestine is an uncommon site for benign or malignant tumors despite its great length and its vast pool of dividing mucosal cells.
A polyp is a mass that protrudes into the lumen of the gut; traction on the mass may create a stalked, or pedunculated, polyp. Alternatively, the polyp may be sessile, without a definable stalk.Polyps may be formed as the result of abnormal mucosal maturation, inflammation, or architecture. These polyps are non-neoplastic and do not have malignant potential.Those polyps that arise as the result of epithelial proliferation and dysplasia are termed adenomatous polyps or adenomas. They are true neoplastic lesions and are precursors of carcinoma.Hyperplastic polyps are the most common polyps of the colon and rectum. When single, they do not have malignant potential. However a lesion known as sessile serrated adenoma, which has some similarities with hyperplastic polyps, may have malignant potential
Some polypoid lesions may be caused by submucosal or mural tumors. However, as with the stomach, the term polyp, unless otherwise specified, refers to lesions arising from the epithelium of the mucosa.
Sessile :-non-pedunculated polyp , without a definable stalk , flate .

Non-Neoplastic Polyps

. Non-neoplastic polyps represent about 90% of all epithelial polyps in the large intestine and are found in more than half of all persons age 60 years or older. Most are hyperplastic polyps. They may occur singly but are more often multiple. Although they may be anywhere in the colon, well over half are found in the rectosigmoid region.
Although the vast majority of hyperplastic polyps have no malignant potential, it is now being recognized that some "hyperplastic polyps," the so-called sessile serrated adenomas, located on the right side of the colon, may be precursors of colorectal carcinomas. They may be solitary or multiple ("hyperplastic polyposis"). As discussed later, these polyps show microsatellite instability and can give rise to colon cancers by the mismatch repair pathway. Juvenile polyps are essentially hamartomatous proliferations, mainly of the lamina propria, enclosing widely spaced, dilated cystic glands. They occur most frequently in children younger than 5 years old but also are found in adults of any age; in the latter group they may be called retention polyps.

Irrespective of terminology, the lesions are usually large in children (1-3 cm in diameter)

, they occur singly and in the rectum, and being hamartomatous they have no malignant potential. Juvenile polyps may be the source of rectal bleeding
Adenomas

Adenomas are neoplastic polyps that range from small, often pedunculated, tumors to large lesions that are usually sessile.
The prevalence of colonic adenomas is 20% to 30% before age 40, rising to 40% to 50% after age 60
. There is a well-defined familial predisposition to sporadic adenomas, accounting for about a fourfold greater risk for adenomas among first-degree relatives, and also a fourfold greater risk of colorectal carcinoma in any person with adenomas..

All adenomatous lesions arise as the result of epithelial proliferation and dysplasia, which may range from mild to so severe as to represent transformation to carcinoma
. Adenomatous polyps are segregated into four subtypes on the basis of the epithelial architecture:
1) Tubular adenomas
2)Villous adenomas
3)Tubulovillous adenomas
4)Sessile serrated adenomas
Tubular adenomas are by far the most common; 5% to 10% of adenomas are tubulovillous, and only 1% are villous. Most tubular adenomas are small and pedunculated; villous adenomas tend to be large and sessile.
The malignant risk with an adenomatous polyp is correlated with three interdependent features-polyp size, histologic architecture, and severity of epithelial dysplasia-as follows:
Cancer is rare in tubular adenomas smaller than 1 cm in diameter.The likelihood of cancer is high (approaching 40%) in sessile villous adenomas larger than 4 cm in diameter.Severe dysplasia, when present, is often found in villous areas.Among these variables, maximum diameter is the chief determinant of the risk of an adenoma's harboring carcinoma; architecture does not provide substantive independent information.
The most important variable is the polyp size.

Clinical Features

The smaller adenomas are usually asymptomatic, until such time that occult bleeding leads to clinically significant anemia. Villous adenomas are much more frequently symptomatic because of overt or occult rectal bleeding. The most distal villous adenomas may secrete sufficient amounts of mucoid material
to produce hypoproteinemia or hypokalemia. On discovery, all adenomas, regardless of their location in the alimentary tract, are to be considered potentially malignant; thus, in practical terms, prompt and adequate excision is mandated.
Adenoma :- there is a displasia in the epithilum and this displasia might be mild , modert or sever.

Familial Polyposis Syndromes



Familial polyposis syndromes are uncommon autosomal dominant disorders. Their importance lies in the propensity for malignant transformation
Individuals with familial adenomatous polyposis (FAP) typically develop 500 to 2500 colonic adenomas that carpet the mucosal surfaace ; a minimum number of 100 is required for the diagnosis.
Most polyps are tubular adenomas; occasional polyps have villous features.
The risk of colonic cancer is virtually 100% by midlife, unless a prophylactic colectomy is performed
Gardner syndrome and the much rarer Turcot syndrome seem to share the same genetic defect as FAP. These syndromes differ from FAP with respect to the occurrence of extra-intestinal tumors in the latter two: osteomas, gliomas, and soft tissue tumors.
Peutz-Jeghers polyps are uncommon hamartomatous polyps that occur as part of the rare autosomal dominant Peutz-Jeghers syndrome, characterized in addition by melanotic mucosal and cutaneous pigmentation. This syndrome is caused by germ-line mutations in the LKB1 gene, which encodes a serine threonine kinase. Cowden syndrome is also characterized by hamartomatous polyps in the gastrointestinal tract and by an increased risk of neoplasms of the thyroid, breast, uterus, and skin. This syndrome is caused by germ-line mutations in the PTEN. This gene encodes a phosphatase that has the ability to regulate many intracellular signaling pathways. It acts as a growth inhibitor by interrupting signals from several tyrosine kinase receptorse.
and by favoring apoptosis through the BAD/BCL2 pathways. Peutz-Jeghers and Cowden syndromes, like the other familial polyposis syndromes, are associated with an increased risk of both intestinal and extraintestinal malignancies.

Colorectal Carcinoma

A great majority (98%) of all cancers in the large intestine are adenocarcinomas, this disease accounts for nearly 15% of all cancer-related deaths in the United States.

Epidemiology

The peak incidence for colorectal cancer is 60 to 70 years of age; fewer than 20% of cases occur before the age of 50 years. Adenomas are the presumed precursor lesion for most of the tumors
. Males are affected about 20% more often than females.
Both genetic and environmental influences contribute to the development of colorectal cancers. When colorectal cancer is found in a young person, preexisting ulcerative colitis or one of the polyposis syndromes must be suspected. In addition, individuals with hereditary nonpolyposis colorectal cancer syndrome (HNPCC, also known as Lynch syndrome), caused by germ-line mutations of DNA mismatch repair genes, are at a high risk of developing colorectal cancers
. Environmental influences, particularly dietary practices, are implicated in the striking geographic variation in incidence. The dietary factors receiving the most attention are
(1) a low content of unabsorbable vegetable fiber.
(2) a corresponding high content of refined carbohydrates.
(3) a high fat content (as from meat).
(4) decreased intake of protective micronutrients such as vitamins A, C, and E.
It is theorized that reduced fiber content leads to decreased stool bulk, increased fecal retention in the bowel, and an altered bacterial flora of the intestine. Potentially toxic oxidative byproducts of carbohydrate degradation by bacteria are therefore present in higher concentrations in the stool and are held in contact with the colonic mucosa for longer periods of time.
Several recent epidemiologic studies suggest that use of aspirin and other NSAIDs exerts a protective effect against colon cancer.
(COX-2) is overexpressed in 90% of colorectal carcinoma and 40% to 90% of adenomas.
its effects may be mediated by production of prostaglandin E2 (PGE2), which seems to favor epithelial cell proliferation, inhibit apoptosis, and enhance angiogenesis. PGE2 may promote angiogenesis by enhancing production of vascular endothelial growth factor.
The development of carcinoma from adenomatous lesions is documented by these general observations:
-Populations that have a high prevalence of adenomas have a high prevalence of colorectal cancer, and vice versa.
-The distribution of adenomas within the colorectum is more or less comparable to that of colorectal cancer
-.The peak incidence of adenomatous polyps antedates by some years the peak for colorectal cancer
-.When invasive carcinoma is identified at an early stage, surrounding adenomatous tissue is often present
-.The risk of cancer is directly related to the number of adenomas, and hence the virtual certainty of cancer in persons with familial polyposis syndromes.
-.Programs that assiduously follow persons for the development of adenomas, and remove all that are identified, reduce the incidence of colorectal cancer.
*all these insures that colorectal cancer arise from adenocarcinoma .
the adenoma-carcinoma sequence, accounts for about 80% of sporadic colon tumors. The genetic correlates of this pathway are as follows:

Loss of the APC tumor suppressor gene.
. Both copies of the APC gene must be lost for adenomas to develop.
. Normal APC promotes the degradation of β-catenin; with loss of APC function, the accumulated β-catenin translocates to the nucleus and activates the transcription of several genes, such as MYC and cyclin D1, which promote cell proliferation. APC mutations are present in 60% to 80% of sporadic colon cancers.Mutation of K-RAS. The K-RAS gene encodes a signal transduction molecule that oscillates between an activated guanosine triphosphate-bound state and an inactive guanosine diphosphate-bound state.
mutated RAS is trapped in an activated state that delivers mitotic signals and prevents apoptosis. K-RAS is mutated in fewer than 10% of adenomas less than 1 cm, in 50% of adenomas larger than 1 cm, and in 50% of carcinomas.18q21 deletion. Loss of a putative cancer suppressor gene on 18q21 has been found in 60% to 70% of colon cancers. Three genes have been mapped to this chromosome location: DCC (deleted in colon carcinoma), SMAD2, and SMAD4. The SMAD genes are considered to be the most relevant ones for colon carcinogenesis. They encode components of the transforming growth factor β (TGF-β) signaling pathway. Because TGF-β signaling normally inhibits the cell cycle, the loss of these genes may allow unrestrained cell growth.Loss of p53. Loss of this tumor suppressor gene is noted in 70% to 80% of colon cancers, yet similar losses are infrequent in adenomas, suggesting that mutations in p53 occur late in colorectal carcinogenesis.
In addition to these changes, alterations in the methylation level of tumor suppressor genes occur in the development of colorectal tumors in the adenoma-carcinoma pathway.
The second pathway of colorectal carcinogenesis is characterized by genetic lesions in DNA mismatch repair genes). It is involved in 10% to 15% of sporadic cases.
. There may be no detectable antecedent lesions, or the tumors may develop from sessile serrated adenomas. Defective DNA repair caused by inactivation of DNA mismatch repair genes is the fundamental and the most likely initiating event in colorectal cancers that follow this path
. Loss of DNA mismatch repair genes leads to a hypermutable state in which simple repetitive DNA sequences, called microsatellites, are unstable during DNA replication, giving rise to widespread alterations in these repeats. The resulting microsatellite instability (MSI) is the molecular signature of defective DNA mismatch repair,
Microsatellites:- are small repetitive non-coding sequences.
. Most microsatellite sequences are in noncoding regions of the genes. However, some microsatellite sequences are located in the coding or promoter region of genes involved in regulation of cell growth. Such genes include type II TGF-β receptor and BAX. TGF-β signaling inhibits the growth of colonic epithelial cells, and the BAX gene product causes apoptosis. Loss of mismatch repair leads to the accumulation of mutations in these and other growth-regulating genes, culminating in the emergence of colorectal carcinomas
sessile serrated adenomas located on the right side of the colon display MSI and may be precancerous. Fully developed tumors that arise via the mismatch repair pathway do show some distinctive morphologic features, including proximal colonic location, mucinous histology, and infiltration by lymphocytes. In general, these tumors have a better prognosis than do stage-matched tumors that arise by the APC/β-catenin pathway.

. Clinical Features

Colorectal cancers remain asymptomatic for years; symptoms develop insidiously and frequently have been present for months, sometimes years, before diagnosis. Cecal and right colonic cancers most often are called to clinical attention by the appearance of fatigue, weakness, and iron deficiency anemia. Left-sided lesions may produce occult bleeding, changes in bowel habit, or crampy left lower quadrant discomfort.
*The presentation is different between the left &right colon becz the diameter of the right colon is larger than left colon so their wont be obstruction in the right colon , just a bleeding .
All colorectal tumors spread by direct extension into adjacent structures and by metastasis through the lymphatics and blood vessels. In order of preference, the favored sites for metastasis are the regional lymph nodes, liver, lungs, and bones
. In general, the disease spreads beyond the range of curative surgery in 25% to 30% of patients. Carcinomas of the anal region are locally invasive and metastasize to regional lymph nodes and distant sites. Almost 80% of malignant tumors of the anal canal are squamous cell carcinomas.