Pathophysiology of colorectal cancer.pptx

EDUCATION

1. Pathophysiology of colorectal cancer Presented by jeremmie mumo muoki

2. introduction Colorectal Cancer is one of the cancers of the Gastrointestinal System and usually affects the lower GI system and precisely the colon and the rectum. Colorectal cancer arises from the gland cells that line the wall of the colon and the rectum. The work of these cells is to produce mucus that lubricates fecal matter for proper movement through the colon and the rectum Colorectal Cancer usually accounts for more than 157850 cases and 53400 deaths in the United States annually. It usually begins as a button like growth on the surface of the intestinal or rectal lining called a polyp[ a polyp is a small overgrowth in the tissue lining of the colon and the rectum]. As the cancer grows, it begins to invade the wall of the intestine or rectum. Nearby lymph nodes also may be invaded. Because blood from the wall of the intestine and much of the rectum is carried to the liver, colorectal cancer can spread (metastasize) to the liver after spreading to nearby lymph nodes . colon cancer is largely preventable through intensive, mass screening programs to remove premalignant colonic polyps

3. Anatomy Adult large intestine includes the colon, rectum, and anal canal. It can be divided into the right colon (cecum, ascending colon, and right 2/3 transverse colon) and left colon (left 1/3 transverse colon, descending colon, and sigmoid colon). The blood supply of the colon is mainly from the mesenteric artery; The veins are accompanied by the arteries of the same name, and the lymphatic network drains through the regional lymph nodes

4. It is innervated by the vagus and pelvic nerves. Function of Right colon is mainly to absorb water and some nutrients, Left colon is to store and excrete feces. The colon also secretes gastrointestinal hormones and alkaline mucus The rectum joins the sigmoid colon, and the lower end joins the anal canal at the dentate line

5. The rectal blood supply mainly comes from the superior and inferior rectal arteries. Venous reflux mainly flows from the superior rectal vein to the liver. The regional lymph nodes of the rectum include pararectal lymph nodes, superior and inferior rectal artery lymph nodes, etc. Rectum is innervated by the autonomic nerves whose main physiological function is defecation. It also absorbs a small amount of water, salt, glucose, and some drugs

6. Based on sites of onset, rectal cancer accounts for 49.66%, colon cancer accounts for 49.09%, and both sites combined account for 1.25%. Among colon cancers, the most common sites are Sigmoid colon (55%), Ascending colon (23.3%), T ransverse colon (8.5%), D escending colon (8.1%), C ecum (8.0%), and crossing site (2.1%)

7. ETIOLOGY Still unclear but believed to be a combination of several factors. Genetic factors:  About 20% of cases are related to genetic factors Investigations have shown a 3-fold increased risk of cancer in the first-generation relatives of CRC patients. Familial Adenomatous Polyposis (FAP) has been identified as a genetic syndrome that predisposes to CRC, and the Mismatch Repair Gene (MMR) has also been linked to inherited CRC .

8. Dietary factors:  It is currently believed that high fat, high animal protein, and low cellulose diet are related to the incidence of CRC. Excessive fat intake will promote bile secretion, bile acid decomposition, increased intestinal carcinogens, and the activity of intestinal anaerobic bacteria

9. Non-cancerous diseases Non-cancerous diseases such as Colorectal polyps, C olorectal adenomas, U lcerative colitis and Crohn’s disease among others can contribute to CRC. About 3–5% of ulcerative colitis patients will develop CRC I ncidence of malignant transformation is greater than 10% in patients with ulcerative colitis lasting more than 20 years.

10. About 15–40% of colon cancers originate from colonic polyps, with a precancerous course of 2–5 years. Adenomas less than 1 cm in diameter have a less than 2% chance of becoming cancerous, while those larger than 3 cm have a more than 40% chance of becoming cancerous . Other factors :  Carcinogenic exposure and lifestyle, such as sedentary and overweight T he incidence of sigmoid and rectal cancer is higher in patients undergoing pelvic radiation therapy

11. Colorectal cancer arises from 2 types of precursor polyps via two distinct pathways: Conventional adenomas by the conventional adenoma-to-carcinoma sequence (most colorectal cancers arise from pre-cancerous polyps broadly categorized as either traditional tubular adenomas or serrated polyps). Adenomas develop when normal mechanisms that regulate DNA repair are altered and serrated adenomas according to the serrated adenoma-to-carcinoma theory. Conventional adenomas arise from mutation of the APC gene (a tumor suppressor gene Progression to colon cancer is a multistep process. The fundamental genetic defect in serrated adenomas is unknown.

12. Adenomatous polyposis coli (APC) gene mutation is the key molecular step in adenoma formation. Most APC mutations cause a condition called Familial Adenomatous Polyposis[F.A.P] which increases the risk of getting colorectal cancer. Mismatch repair gene mutation is a less common alternative pathway. Progression from adenomas to colon cancer is a multistep process, involving mutations of the DCC, which is deleted in CRC DCC is a tumor suppressor gene that induces cell death on epithelial cells when no netrin-1 is bound. DCC gives instruction for synthesis of netrin I receptor which when bound to ligand is involved in development of nervous system. However, in absence of ligand, it acts as a tumor suppressor

13. k- ras which is an oncogene, and p53 genes, a tumor suppressor gene whose mutation is associated with breast, colorectal , liver, lung and ovarian cancers; loss of heterozygosity in which cells loose one allele of some genes from chromosomal loss; and DNA methylation which can silence DNA expression

14. Environmental factors They can increase the risk for colon cancer. Advanced colon cancer often presents with symptoms, but early colon cancer and premalignant adenomatous polyps commonly are asymptomatic, rendering them difficult to detect This provides the rationale for mass screening of adults over age 50

15. Correlation between migration, religious factors, and the CRC suggests that the incidence of CRC is strongly related to environmental factors, lifestyle, and diet, but has no obvious relationship with ethnicity. Incidence of CRC differs by regions, with the highest incidence reported in North America, Western Europe, and Oceania Lowest incidence reported in Africa, Asia, and South America. In the mainland of China, the CRC incidence also follows an east-to-west gradient The incidence of CRC is higher in the economically developed eastern coastal areas, while the incidence is relatively lower in the economically backward western areas . The incidence and mortality of second-generation immigrants from low-incidence areas of CRC to high-incidence areas are similar to those of residents

16. Age The risk increases with age. Incidence and mortality low the age of 45 Increase significantly after that, peaking in the age group over 80 A significant number of cases still occur in adolescents. Patients under 30 account for 10–20% in China A ge of onset is 12–18 years earlier than in western countries. The morbidity and mortality of CRC have shifted over time.

17. The rising rate of the original high-incidence regions slows down or decreases, while the low-incidence regions show an increasing trend, such as China. In the past 30 years, the incidence and mortality of CRC have been increasing year by year in China, especially in cities. This may be related to an aging population, changing lifestyles, and changing environment

18. Causes and progression The exact cause of CRC still unclear. It occurs when healthy cells undergo mutations leading to abnormal division which then result to tumors The majority of colon cancer cases are sporadic, which means a genetic mutation may happen in that individual However, approximately 5 percent of individuals with colon cancer have a hereditary form, which means that they have inherited a mutation from one of their parents that causes the disease. In those families, the chance of developing colon cancer is significantly higher than in the average person. 

19. Rare inhFAP Gardner syndrome, a subtype of FAP Juvenile polyposis syndrome (JPS) Muir-Torre syndrome, a subtype of Lynch Syndrome MYH-associated polyposis (MAP) Peutz-Jeghers syndrome (PJS) Turcot syndrome, erited conditions.Members of families with certain uncommon inherited conditions have a higher risk of colorectal cancer, as well as other types of cancer. These include: Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC) Familial adenomatous polyposis (FAP) Attenuated familial adenomatous polyposis (AFAP), a subtype of a subtype of FAP and Lynch Syndrome 6. Inflammatory bowel disease eg ulcerative colitis or Crohn`s disease have a higher risk 7. Adenomatous polyps[adenomas]- they may grow to become malignant tumors 8. lifestyle factors like smoking, poor diet, obesity, physical inactivity

20. Genes responsible for colorectal cancer HNPCC (hereditary nonpolyposis colon cancer) also called Lynch Syndrome HNPCC gene mutation leads an e stimated 80% percent lifetime risk of developing colon or rectal cancer. However , these accounts for only 3-5% all CRC cases So far, five HNPCC genes have been discovered: MSH2 on chromosome 2 MLH1 on chromosome 3 PMS2 on chromosome 7 MSH6 on chromosome 2 PMS1 on chromosome 2

21. . Mutations in MSH2 and MLH1 are the most common mutations that cause HNPCC. A mutation in PMS1 was originally reported in a single family with HNPCC, however, this mutation was not found in all members of the family who had developed the disease. For this reason, the role of PMS1 in HNPCC is currently being questioned. The genes that cause HNPCC and FAP were relatively easy to discover because they exert strong effects. Other genes that cause susceptibility to colon cancer are harder to discover because the cancers are caused by a number of genes, each of which individually exerts a weak effect

22. PATHOGENESIS CRC is a multi-factorial disease. The epithelial cells of colorectal mucosa can undergo hyperplasia, atypical hyperplasia (mild, moderate, severe) and adenomas, that can eventually develop into carcinoma . Process usually initiated by carcinogenic factors, causing structural changes in DNA, leading to the malignant transformation of cells into cancer. Morphology includes epithelial hyperplasia, atypical hyperplasia, a adenoma formation, carcinoma in situ, and invasive carcinoma

23. PATHOLOGICAL TYPE AND METASTASIS In early stages, CRC confined to the intestinal mucosa and submucosa. Lymphatic metastasis usually does not occur in early CRC . When the tumor breaks through the submucosa, lymphatic metastasis occurs in about 10% of patients. The gross types of CRC mainly include uplift, ulceration, and infiltration . The pathological histological types mainly include papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, undifferentiated carcinoma, adenosquamous carcinoma, squamous cell carcinoma, and carcinoid carcinoma . Adenocarcinoma has the highest incidence, accounting for more than 90% (colon cancer)

24. CRC metastasizes and spreads through the following ways: Local invasion: The tumor infiltrates into the local area of the primary lesion and adjacent structures. Lymphatic metastasis: The neoplastic cells use the intramucosal lymphatic system to reach regional lymph nodes, eventually causing distant lymph node metastasis; about 60% of CRC metastasis occurs through this route Hematogenous metastasis: The cancer cells spread via the blood vessels. The most common target organs being the liver and lung; about 30% of CRC are transferred through this route . Implantation and metastasis: After the cancer cells fell off, they are implanted in the abdomen and pelvic peritoneum to form metastatic foci

25. History and physical evaluation Early stages usually asymptomatic. Due to the different anatomical and physiological functions of colon and rectum, the clinical manifestations of tumors in different anatomical sites are also different. Abdominal mass and systemic symptoms are more common in right colon cancer Blood stool and obstruction are more common in left colon cancer, and Changes in defecation habits are more common in rectal cancer However , with the progress of the disease, a patient may present with the following ; Hematochezia : In small amount of hematochezia, general stool has no visible changes, but fecal occultation test can be positive; blood stool, mucus blood stool, or jam-like stool may appear when there is a lot of blood in the stool  

26. Intestinal obstruction:  It is often a characteristic of advanced CRC; abdominal pain, abdominal distention, nausea, vomiting, exhaustion, and defecation will occur when intestinal obstruction caused by the enlargement of the mass

27. DIAGNOSIS Based on clinical findings, laboratory investigations, radiological findings and even through histological analysis Lab investigations CBC , Biomarker testing of the tumor, Radiological investigations- colonoscopy, chest x-ray, endorectal ultrasound,CT scan and also MRI Histological analysis- includes a biopsy of the tumour to check whether the cells are benign or malignant Currently , common screening and diagnosis methods for CRC include FOBT, fecal immunohistochemistry (FIT), tumor markers, and colonoscopy. 

28. MANAGEMENT The treatment principle of CRC is an individualized comprehensive treatment based on surgery, supplemented by chemotherapy, radiotherapy, molecular targeted therapy, immunotherapy, and other program The 5-year survival rate of patients with early CRC, who receive surgery-based treatment, is over 90%. Therefore , surgery remains the cornerstone of CRC treatment. For initially inoperable CRC patients, and some CRC patients with metastasis, the feasibility of surgery should be evaluated after neoadjuvant therapy to strive for the opportunity of surgical treatment. The surgical methods mainly include radical surgery and palliative surgery

29. CRC chemotherapy mainly includes neoadjuvant chemotherapy, adjuvant chemotherapy after radical surgery, and palliative chemotherapy Neoadjuvant chemotherapy is often used in combination with radiotherapy This can reduce the clinical stage of the tumor, strive for the opportunity of surgery, improve the quality of life of patients, and reduce postoperative recurrence. Adjuvant chemotherapy can eliminate the remaining tumor cells after radical surgery and further consolidate the effect of radical surgery.

30. Aim of palliative chemotherapy is to improve the quality of life and prolong the survival time of patients with advanced CRC. Commonly used chemotherapy drugs include fluorouracil , irinotecan , oxaliplatin , and raltitrexed . These chemotherapy drugs are often used in combination Most commonly used combination include FOLFOX, FOLFIRI, CAPEOX, FOLFOXIRI

31. Radiotherapy is mainly used for rectal cancer patients It can improve local control rate, quality of life, and prolong survival . The radiotherapy schemes for rectal cancer mainly include preoperative radiotherapy, preoperative concurrent chemoradiotherapy , and postoperative concurrent chemoradiotherapy combined with adjuvant chemotherapy

32. STAGING OF COLORECTAL CANCER TNM staging system T-Tumor N- nodes M- metastasis Stage 0: This is called cancer in situ. The cancer cells are only in the mucosa, or the inner lining, of the colon or rectum. Stage I: The cancer has grown through the mucosa and has invaded the muscular layer of the colon or rectum. It has not spread into nearby tissue or lymph nodes (T1 or T2, N0, M0). Stage IIA: The cancer has grown through the wall of the colon or rectum but has not spread to nearby tissue or to the nearby lymph nodes (T3, N0, M0 ).

33. Stage IIB: The cancer has grown through the layers of the muscle to the lining of the abdomen, called the visceral peritoneum. It has not spread to the nearby lymph nodes or elsewhere (T4a, N0, M0) Stage IIC: The tumor has spread through the wall of the colon or rectum and has grown into nearby structures. It has not spread to the nearby lymph nodes or elsewhere (T4b, N0, M0) Stage IIIA: The cancer has grown through the inner lining or into the muscle layers of the intestine. It has spread to 1 to 3 lymph nodes or to a nodule of tumor cells in tissues around the colon or rectum that do not appear to be lymph nodes but has not spread to other parts of the body (T1 or T2, N1 or N1c, M0; or T1, N2a, M0)

34. Stage IIIB: The cancer has grown through the bowel wall or to surrounding organs and into 1 to 3 lymph nodes or to a nodule of tumor in tissues around the colon or rectum that do not appear to be lymph nodes. It has not spread to other parts of the body (T3 or T4a, N1 or N1c, M0; T2 or T3, N2a, M0; or T1 or T2, N2b, M0). Stage IIIC: The cancer of the colon, regardless of how deep it has grown, has spread to 4 or more lymph nodes but not to other distant parts of the body (T4a, N2a, M0; T3 or T4a, N2b, M0; or T4b, N1 or N2, M0) Stage IVA: The cancer has spread to a single distant part of the body, such as the liver or lungs (any T, any N, M1a). Stage IVB: The cancer has spread to more than 1 part of the body (any T, any N, M1b) Stage IVC: The cancer has spread to the peritoneum. It may also have spread to other sites or organs (any T, any N, M1c)

35. Tumor (T) Using the TNM system, the "T" plus a letter or number (0 to 4) is used to describe how deeply the primary tumor has grown into the bowel lining. Stage may also be divided into smaller groups that help describe the tumor in even more detail. Specific tumor information is listed below. TX: The primary tumor cannot be evaluated. T0 (T zero): There is no evidence of cancer in the colon or rectum. Tis: Refers to carcinoma in situ (also called cancer in situ). Cancer cells are found only in the epithelium or lamina propria , which are the top layers lining the inside of the colon or rectum.

36. T0 (T zero): There is no evidence of cancer in the colon or rectum. Tis: Refers to carcinoma in situ (also called cancer in situ). Cancer cells are found only in the epithelium or lamina propria , which are the top layers lining the inside of the colon or rectum. T1: The tumor has grown into the submucosa, which is the layer of tissue underneath the mucosa or lining of the colon. T2: The tumor has grown into the muscularis propria , a deeper, thick layer of muscle that contracts to force along the contents of the intestines. T3: The tumor has grown through the muscularis propria and into the subserosa , which is a thin layer of connective tissue beneath the outer layer of some parts of the large intestine, or it has grown into tissues surrounding the colon or rectum. T4a: The tumor has grown into the surface of the visceral peritoneum, which means it has grown through all layers of the colon. T4b: The tumor has grown into or has attached to other organs or structures.

37. Node (N) The "N" in the TNM system stands for lymph nodes. The lymph nodes are small, bean-shaped organs located throughout the body. Lymph nodes help the body fight infections as part of the immune system. Lymph nodes near the colon and rectum are called regional lymph nodes. All others are distant lymph nodes that are found in other parts of the body. NX: The regional lymph nodes cannot be evaluated. N0 (N zero): There is no spread to regional lymph nodes. N1a : There are tumor cells found in 1 regional lymph node. N1b: There are tumor cells found in 2 or 3 regional lymph nodes. N1c: There are nodules made up of tumor cells found in the structures near the colon that do not appear to be lymph nodes. N2a: There are tumor cells found in 4 to 6 regional lymph nodes. N2b: There are tumor cells found in 7 or more regional lymph nodes.

38. Metastasis (M) The "M" in the TNM system describes cancer that has spread to other parts of the body, such as the liver or lungs. This is called metastasis. M0 (M zero): The disease has not spread to a distant part of the body. M1a: The cancer has spread to 1 other part of the body beyond the colon or rectum. M1b: The cancer has spread to more than 1 part of the body other than the colon or rectum. M1c: The cancer has spread to the peritoneal surface

39. Grade (G )  The grade describes how much cancer cells look like healthy cells when viewed under a microscope . GX:  The tumor grade cannot be identified. G1:  The cells are more like healthy cells, called well differentiated. G2:  The cells are somewhat like healthy cells, called moderately differentiated. G3:  The cells look less like healthy cells, called poorly differentiated. G4:  The cells barely look like healthy cells, called undifferentiated . Grade (G)  The grade describes how much cancer cells look like healthy cells when viewed under a microscope . GX: The tumor grade cannot be identified. G1: The cells are more like healthy cells, called well differentiated. G2: The cells are somewhat like healthy cells, called moderately differentiated. G3: The cells look less like healthy cells, called poorly differentiated. G4: The cells barely look like healthy cells, called undifferentiated.

40. Abdominal mass: It usually occurs in the right colon cancer; this symptom is a mass enlargement to a certain extent, palpable abdominal mass. Systemic symptoms: CRC generally has no obvious symptoms at the early stage, so the course of the disease is relatively long, leading to tumor proliferation, cachexia, anemia, emaciation, and other symptoms.

41. PROGNOSIS The disease stage at initial diagnosis is the most important prognostic indicator of CRC. The 5-year survival rate of patients with localized CRC, who can be surgically resected, is about 90%, The 5-year survival rate of advanced CRC patients who lose the opportunity of surgical treatment is reduced to about 10% . The natural course of progression from normal colorectal epithelial cells to benign lesions such as adenomas and eventually to cancer is generally 5–10 years . This process often involves abnormal changes of multiple genes, such as APC, DCC, P53, K-RAS, C-MYC, BRAF, MCC, and MMR-related genes . Early screening to detect limited-stage lesions in this time window and clinical intervention is crucial to improve the prognosis of CRC patients