Nmu.ua
Ministry of Public Health of Ukraine
National O.O.Bohomolets Medical University
Oncology Department
Study Guide
of the Lecture Course “Oncology”
Part II
For the students of medical faculties
Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD, DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.
Kyiv - 2008
Ministry of Public Health of Ukraine
National O.O.Bohomolets Medical University
Oncology Department
“APPROVED”
Vice-Rector for Educational Affairs
Professor O. Yavorovskiy
______________
“___” __________ 2008
Study Guide
of the Lecture Course “Oncology”
Part II
For the students of medical faculties
Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD, DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.
Kyiv - 2008
The texts of the lectures are approved by the methodical counsel
of Oncology Department.
Protocol № 19 « 17 » march 2008.
CONTENTS
Lecture 8
Gastric cancer
Lecture 9
Colorectal cancer
Lecture 10
Pancreatic Cancer. Liver cancer. Gallbladder cancer.
Lecture 11
Tumors of the bones
Lecture 8
Gastric cancer
Incidence
■ The crude incidence of gastric cancer in the European Union has been decreasing during the last decades and currently is approximately 18.9/100 000 per year, the mortality 14.7/100 000 per year with about 1.5 times higher rates for males than females and with a peak incidence in the seventh decade.
■ The most higher incidence of gastric cancer was observed in Japan (59/100 000 per year ) and Finland (49/100 000 per year )
■ In Ukraine gastric cancer takes third place in males and forth place in females among all oncology diseases.
■ In Ukraine 27/100 000 per year, 35/100 000 per year for males and 20/100 000 per year for females. The mortality 21.7/100 000 per year, 28,4/100 000 per year for males and 15/100 000 per year for females.
Etiology
■ Infection with Helicobacter pylori enhances the risk of gastric cancer. Other risk factors include:
■ Male sex
■ Daly intake food with large concentration of nitrites, nitrates and salt
■ Pernicious anemia
■ Smoking
■ Menetrier’s disease
■ Genetic factors such as hereditary non-polyposis colon cancer
■ Patients after surgical treatment of gastric ulcer disease: resection of stomach and vagotomy.
Anatomy.
The stomach is a muscular organ that functions in storage and digestion. It has three parts and two sphincteric mechanisms (gastroesophageal, pylorus). In accordance with Japanes classification, stomach is divaded into three part –upper (C), medium (M), lower (A).
Fig. 1. Parts of the stomach.
■ 1. Cardia
■ 2. Fundus –C part
■ 3. Body– M-part
■ 4. Antrum – A-part
■ 5. Pilorus
Microscopic anatomy.
The stomach has four layers and three distinct mucosal areas.
The layers of the stomach wall are serosa, muscularis, muscularis mucosae, and mucosa. The layers of muscle fibers are longitudinal, oblique, and circular.
The divisions of the mucosa correspond to the gross divisions of cardia, body, and antrum.
1. The cardiac gland area js a glands secrete mucus.
2. The parietal cell area comprises the proximal three-quarters of the stomach. Four types of cells are found in its glands:
• Mucous cells secrete an alkaline mucous coating for the epithelium. This 1mm-thick coating primarily facilitates food passage. It also provides some mucosal protection.
• Zygomatic or chief cells secrete pepsinogen. They are found deep in the fundic glands. Pepsinogen is the precursor to pepsin, which is active in protein digestion. Chief cells are stimulated by cholinergic impulses, by gastrin, and by secretin.
• Oxyntic or parietal cells produce hydrochloric acid and intrinsic factor. They are found exclusively in the fundus and body of the stomach. They are stimulated to produce hydrochloric acid by gastrin.
• Argentaffin cells are scattered throughout the stomach. Their function is unclear
3. The pyloroantral mucosa is found in the antrum of the stomach.
• Parietal and chief cells are absent here.
• C cells, which secrete gastrin, are found in this area. They are part of the amine precursor uptake and decarboxylase (APUD) system of endocrine cells. Gastrin is a hormone that causes the secretion of hydrochloric acid and pepsinogen in the stomach. It also influences gastric motility.
Innervation. The nervous supply of the stomach is via parasympathetic and sympathetic fibers.
■ The parasympathetic supply is through the vagus nerves. The anterior or left vagus supplies the anterior portion of the stomach. The posterior or right vagus supplies the posterior stomach. The vagi contribute to gastric acid secretion both by direct action on parietal cell secretion and by stimulating the antrum to release gastrin. They also contribute to gastric motility.
■ The sympathetic innervation is via the greater splanchnic nerves. These terminate in the celiac ganglion, and postganglionic fibers travel with the gastric arteries to the stomach. The sympathetic afferent fibers are the pathway for perception of visceral pain.
Vasculature
Arterial supply to the stomach is via the right and left gastric arteries, the right and left gastroepiploic arteries, and the vasa brevia.
1. The right gastric artery is a branch of the common hepatic artery and supplies the lesser curvature.
2. The left gastric artery is a branch of the celiac axis and supplies the lesser curvature.
3. The right gastroepiploic artery is a branch of the gastroduodenal artery and supplies the greater curvature.
4. The left gastroepiploic artery is a branch of the splenic artery and supplies the greater curvature.
5. The vasa brevia arise from either the splenic artery or the left gastroepiploic artery . and supply the fundus.
Venous drainage of the stomach is both portal and systemic.
1. The right and left gastric and gastroepiploic veins accompany their corresponding arteries. They drain into the portal system.
2. The left gastric vein also has multiple anastomoses with the lower esophageal venous plexus. These drain systemically into the azygous vein.
Fig. 2. Regional lymph nodes of the stomach (part 1)
[pic]
Lymphatic drainage of the stomach is extensive. Lymph nodes that drain the
stomach are found at the cardia (1,2) along the lesser and greater curvatures (3,4a,b), supra and infra pyloric (5,6). This is perigastric stations.
Fig. 3. Additional Regional lymph nodes of the stomach (part 2)
[pic]
Additional regional lymph nodes stations are also: along left gastric artery (7), common hepatic artery (8), Lineal (splenic) artery (10,11), celiac
Trunk (9) and hepatica-duodenal lymph nodes (12).
Histology
Approximately 90%-95% of gastric tumors are malignant and of the
malignancies, 95% are carcinomas.
Gastric adenocarcinoma is divided on two types: intestinal and diffuse
1. intestinal (epidemic) type is retained glandular structure and cellular polarity, it usually has a sharp margin. It arises from the gastric mucosa and is associated with chronic gastritis, atrophy and intestinal metaplasia. It correspond with papillary and tubular groups
2. Diffuse type has little glandular formation. Mucin production is common. It correspond with mucinous and signet ring cell groups.
Gastric carcinoma is classified according to its gross characteristics.
1. Fungating. These are the least common lesions and have a better prognosis.
2. Ulcerating. These are the commonest.
3. Diffusely infiltrating (linitis plastica). The tumor causes extensive submucosal infiltration.
Other malignances of the stomach
Gastric lymphoma can be primary or can occur as part of disseminated disease. The stomach is the commonest site of primary intestinal lymphoma. The tumors may be bulky with central ulceration.
Diagnosis preoperatively is crucial since the surgical approach differs markedly from that used with gastric cancer.
Surgical treatment involves local resection (partial gastrectomy). Most lesions also require treatment with radiation therapy, chemotherapy, or both.
Prognosis is good with 5-year survival up to 90%.
Leiomyosarcomas are bulky, well-localized tumors. They are slow to metastasize and can be treated with partial gastrectomy.
Benign tumors
1. Leiomyomas are the commonest benign gastric tumors. They are usually asymptomatic but may undergo hemorrhage or cause a mass effect. They are submucosal and well encapsulated.
2. Gastric polips are of two tipes. They often can be excised via endoscope.
■ Hyperplastic polips are the commonest and are not premalignant
■ Adenomatous polips are associated with a high risk of malignancy, especially those greater then 1.5 cm.
3. Other benign tumors are fibromas, neurofibromas, aberrant pancreas, and angiomas.
TNM – classification.
Fig. 4. T – tumor, T1- tumor involve mucosa and submucosa, T-2 tumor invade the muscularis propria
[pic]
Fig. 5. TNM – classification. T – tumor, T2
■ Tumor invasion of mucosa and muscularis layers
■ T2a –up to muscularic
■ T2b –up to serosa
Fig. 6. TNM – classification. T – tumor, T3
• Tumor invasion of mucosa, muscularic and serosa layers
[pic]
Fig. 7. TNM – classification. T – tumor, T3
[pic]
Tumor invasion of mucosa, muscularic and serosa layers
Fig. 8. TNM – classification. T – tumor, T3,4
[pic]
■ T3 - Tumor invasion of mucosa, muscularic and serosa layers
■ T4 – tumor invasion up to adjusting organs
Fig. 9. TNM – classification. N – nodules, N-1
[pic]
• N1- 1-6 lymph nodes with tumor
Fig. 10. TNM – classification. N – nodules, N-2
■ N2- 7-15 lymph nodes with tumor
[pic]
Fig. 11. TNM – classification. N – nodules, N-3
[pic]
• N3- more then 15 lymph nodes with tumor
Fig. 12. TNM – classification. M – metastases, M-1
[pic]
• M0- no metastases
• M1 – obtained distant metastases
Table 1. TNM 2002 (5-th edition) and AJCC stage grouping
|Stage |T |N |M |
|I A |T1 |N0 |M0 |
|I B |T1 |N1 |M0 |
| |T2a,T2b |N0 |M0 |
|II |T1 |N2 |M0 |
| |T2a,T2b |N1 |M0 |
| |T3 |N0 |M0 |
|IIIA |T2a,T2b |N2 |M0 |
| |T3 |N1 |M0 |
| |T4 |N0 |M0 |
|IIIB |T3 |N2 |M0 |
|IV |T4 |N1,N2,N3 |M0 |
| |T1,T2,T3 |N3 |M0 |
| |Any T |Any N |M1 |
Clinical manifestations
Due to the fact that both the stomach and abdominal cavity
are large to distention the symptoms of gastric cancer are obtained at
an advanced stage.
Early symptoms such us vague gastrointestinal distress, nausea,
vomiting and anorexia are common for different diseases.
The most common symptoms at diagnosis are
■ Abdominal pain (65%)
■ Weight loss (40%)
■ Anemia (17%)
■ Dysphagia in patients with proximal cancer localization
■ Early satiety
■ Gastrointestinal bleeding
Diagnosis
• Physical examination
• laboratory stadies, endoscopic ultrasonography
• Endoscopies with biopsy
• chest X-ray and barium swallow (Fig. 13,14)
• CT-scan of the abdomen
• laparoscopy
• CEA, CA-125
Fig. 13. Radiologic examination of the stomach. Double contrast study. The arrows outline the area of irregular mucosa which was caused by an invasive gastric carcinoma.
The stomach is temporarily paralyzed by administration of glucagon, filled with dense barium, and distended with gas using effervescent granules. Hence both barium and air are used for contrast. Images are obtained as the patient rolls in various positions to coat the gastric mucosa with contrast. Double-contrast technique provides improved visualization of the gastric mucosa.
Fig. 14. Radiologic examination of the stomach. Single contrast study from the same patient showing the apple core appearance of the stomach due to the invasive gastric adenocarcinoma
The stomach is filled and distended with dilute barium or a water-soluble contrast agent. Water-soluble contrast should be used when perforation or post-operative anastomotic failure is suspected. The stomach is compressed either manually or by positioning to allow for adequate x-ray penetration in the evaluation of each anatomical segment. Single-contrast technique assesses thickness of the gastric folds and evaluation of gastric emptying. Large luminal defects can be detected.
■ Diagnosis should be made from a gastroscopic or surgical biopsy and the histology given according to the World Health Organisation criteria.
Fig. 15. Gastroscopic examination of the stomach.
Staging and risk assessment
• Staging consists of clinical examination, blood counts, liver and renal function tests, chest X-ray and CT-scan of the abdomen, as well as of endoscopy. Endoscopic ultrasound and laparoscopy may help to optimally determine resectability. The stage is to be given according to the TNM 2002 system and the AJCC stage grouping, as shown in Table 1.
Surgery
■ Multi-disciplinary treatment planning is mandatory. Surgical resection is the only potentially curative option and is recommended for stages Tis-T3N0-N2M0 or T4N0M0.
■ The choice for gastric resection include segmental resection, distal subtotal, total and proximal subtotal gastrectomy and is dependent upon the location of the tumor, its histologic type and stage of desease.
■ Endoscopic mucosal resection is recommended for very early cancers without nodal involvement
■ The extent of regional lymphadenectomy required for optimal results is still debated. Randomized trials have failed to prove the superiority of D2 over D1 resection but a minimum of 14, optimally at least 25 lymph nodes should be recovered.
Fig. 16. Total and subtotal gastrectomy
[pic]
Fig. 17. Gastrojejunostomy after subtotal gastrectomy
[pic]
Fig. 18. Reconstruction after total gastrectomy with Roux limb
[pic]
Fig. 19. Reconstruction after total gastrectomy splenectomy and distal pancreatectomy with Roux limb.
[pic]
Chemoradiotherapy
■ A North American Intergroup randomized trial demonstrated that 5 cycles of postoperative adjuvant 5-fluorouracil/ leucovorin chemotherapy before, during, and after radiotherapy with 45 Gy given in five 1.8-Gy fractions/week over 5 weeks led to an approximately 15% survival advantage after 4–5 years. While this treatment is regarded as standard therapy in North America, it has not yet been generally accepted in Europe because of concerns about toxicity with abdominal chemo-radiation and the type of surgery used.
■ As judged by meta-analyses, adjuvant chemotherapy alone confers a small survival benefit. However, the toxicity of chemotherapy is considerable and careful selection of patients is mandatory.
■ The most effective chemotherapy (20-40% response rate) are
FAM, FAMTX, 5-fu+cisplatin, ECF
Treatment of locally advanced disease (stage III: T3-4, N1)
■ Some patients with locally advanced disease may benefit from preoperative chemotherapy with down-staging and higher rates of resectability but the results of phase II trials are conflicting and no optimal regimen has yet been defined.
■ Other patients may be treated as those with localized disease (see above).
■ Therapy for patients with incomplete resection remains palliative.
Treatment of metastatic disease (stage IV)
■ Patients with stage IV disease should be considered for palliative chemotherapy. Combination regimens incorporating cisplatin, 5-fluorouracil with or without anthracyclines are generally used.
■ Epirubicin 50 mg/m2, cisplatin 60 mg/m2 and protracted venous infusion 5-fluorouracil 200 mg/m2/day (ECF) is one among the most active and well tolerated combination chemotherapy regimens.
■ Alternate regimens including oxaliplatin, irinotecan, docetaxel, and oral fluoropyrimidines can be considered.
Follow-up
■ There is no evidence that regular intensive follow up after initial therapy improves the outcome. Symptom-driven visits are recommended for most cases.
■ History, physical examination, blood tests should be performed, if symptoms of relapse occur. Radiological investigations should be considered for patients who are candidates for palliative chemotherapy. Note Levels of Evidence and Grades of Recommendation as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
Prognosis
Prognosis depends largely on the depth of invasion of the gastric wall, involvement of regional nodes and the presents of distant metastases but still remains poor. Tumor not penetrating the serosa and not involving the regional nodes are associated with approximately 70% 5-year survival. This number drops dramatically if the tumor is through the serosa or into regional nodes. Only 40% of patients have potentially curable disease at the time of diagnosis.
5-year survival
■ Stage I – 75%
■ Stage II – 46%
■ Stage III – 28%
■ Stage IV – 12%
Lecture 9
Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. It is the third most common form of cancer and the second leading cause of cancer-related death in the Western world. Colorectal cancer causes 655,000 deaths worldwide per year. Many colorectal cancers are thought to arise from adenomatous polyps in the colon. These mushroom-like growths are usually benign, but some may develop into cancer over time. The majority of the time, the diagnosis of localized colon cancer is through colonoscopy. Therapy is usually through surgery, which in many cases is followed by chemotherapy.
Symptoms
Colon cancer often causes no symptoms until it has reached a relatively advanced stage. Thus, many organizations recommend periodic screening for the disease with fecal occult blood testing and colonoscopy. When symptoms do occur, they depend on the site of the lesion. Generally speaking, the nearer the lesion is to the anus, the more bowel symptoms there will be, such as:
• Change in bowel habits
o change in frequency (constipation and/or diarrhea),
o change in the quality of stools
o change in consistency of stools
• Bloody stools or rectal bleeding
• Stools with mucus
• Tarry stools (melena) (more likely related to upper gastrointestinal eg stomach or duodenal disease)
• Feeling of incomplete defecation (tenesmus) (usually associated with rectal cancer)
• Reduction in diameter of feces
• Bowel obstruction (rare)
Constitutional symptoms
Especially in the cases of cancer in the ascending colon, sometimes only the less specific constitutional symptoms will be found:
• Anemia, with symptoms such as dizziness, malaise and palpitations. Clinically there will be pallor and a complete blood picture will confirm the low hemoglobin level.
• Anorexia
• Asthenia, weakness
• Unexplained weight loss.
Metastatic symptoms
There may also be symptoms attributed to distant metastasis:
• Shortness of breath as in lung metastasis
• Epigastric or right upper quadrant pain, as in liver metastasis.
Risk factors
The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person's risk of developing the disease. These include:
• Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.
• Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.
• History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.
• Heredity:
o Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives
o Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated
o Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
• Long-standing ulcerative colitis or Crohn's disease of the colon, approximately 30% after 25 years if the entire colon is involved
• Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that "Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked."
• Diet. Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently ate fish showed a decreased risk. However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding. The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.
• Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.
• Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.
• Alcohol. See the subsection below.
• Primary sclerosing cholangitis offers a risk independent to ulcerative colitis
• Low selenium.
• Inflammatory Bowel Disease. About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.
• Environmental Factors. Industrialized countries are at a relatively increased risk compared to less developed countries or countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk.
• Exogenous Hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens. There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast,there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.
Alcohol
One study found that "People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer." Another found that "The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer."
One study found that "While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.".
Other research suggests that "to minimize your risk of developing colorectal cancer, it's best to drink in moderation"
Drinking may be a cause of earlier onset of colorectal cancer.
Diagnosis, screening and monitoring
[pic]
Endoscopic image of colon cancer identified in sigmoid colon on screening colonoscopy in the setting of Crohn's disease.
Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the chances of a cure. Therefore, screening for the disease is recommended in individuals who are at increased risk. There are several different tests available for this purpose.
• Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.
• Fecal occult blood test (FOBT): a test for blood in the stool.
• Endoscopy:
o Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and lower colon to check for polyps and other abnormalities.
o Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be immediately removed. Tissue can also be taken for biopsy.
Other screening methods
• Double contrast barium enema (DCBE): First, an overnight preparation is taken to cleanse the colon. An enema containing barium sulfate is administered, then air is insufflated into the colon, distending it. The result is a thin layer of barium over the inner lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can be detected this way. This technique can miss the (less common) flat polyp.
• Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above) with a special computed tomography scan and requires special workstation software in order for the radiologist to interpret. This technique is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.
• Standard computed axial tomography is an x-ray method that can be used to determine the degree of spread of cancer, but is not sensitive enough to use for screening. Some cancers are found in CAT scans performed for other reasons.
• Blood tests: Measurement of the patient's blood for elevated levels of certain proteins can give an indication of tumor load. In particular, high levels of carcinoembryonic antigen (CEA) in the blood can indicate metastasis of adenocarcinoma. These tests are frequently false positive or false negative, and are not recommended for screening, it can be useful to assess disease recurrence.
• Genetic counseling and genetic testing for families who may have a hereditary form of colon cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP).
• Positron emission tomography (PET) is a 3-dimensional scanning technology where a radioactive sugar is injected into the patient, the sugar collects in tissues with high metabolic activity, and an image is formed by measuring the emission of radiation from the sugar. Because cancer cells often have very high metabolic rate, this can be used to differentiate benign and malignant tumors. PET is not used for screening and does not (yet) have a place in routine workup of colorectal cancer cases.
• Whole-Body PET imaging is the most accurate diagnostic test for detection of recurrent colorectal cancer, and is a cost-effective way to differentiate resectable from non-resectable disease. A PET scan is indicated whenever a major management decision depends upon accurate evaluation of tumour presence and extent.
• Stool DNA testing is an emerging technology in screening for colorectal cancer. Pre-malignant adenomas and cancers shed DNA markers from their cells which are not degraded during the digestive process and remain stable in the stool. Capture, followed by Polymerase Chain Reaction amplifies the DNA to detectable levels for assay. Clinical studies have shown a cancer detection sensitivity of 71%-91%.
Pathology
[pic]
Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.
The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.
Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.
Histopathology: Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.
Staging
Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is performed for diagnostic and research purposes, and to determine the best method of treatment. The systems for staging colorectal cancers largely depend on the extent of local invasion, the degree of lymph node involvement and whether there is distant metastasis.
Definitive staging can only be done after surgery has been performed and pathology reports reviewed.
Dukes' system
Dukes' classification, first proposed by Dr Cuthbert E. Dukes in 1932, identifies the stages as:
• A - Tumour confined to the intestinal wall
• B - Tumour invading through the intestinal wall
• C - With lymph node(s) involvement
• D - With distant metastasis
TNM system
Main article: TNM
The most common current staging system is the TNM (for tumors/nodes/metastases) system, though many doctors still use the older Dukes system. The TNM system assigns a number:
• T - The degree of invasion of the intestinal wall
o T0 - no evidence of tumor
o Tis- cancer in situ (tumor present, but no invasion)
o T1 - invasion through submucosa into lamina propria (basement membrane invaded)
o T2 - invasion into the muscularis propria (i.e. proper muscle of the bowel wall)
o T3 - invasion through the subserosa
o T4 - invasion of surrounding structures (e.g. bladder) or with tumour cells on the free external surface of the bowel
• N - the degree of lymphatic node involvement
o N0 - no lymph nodes involved
o N1 - one to three nodes involved
o N2 - four or more nodes involved
• M - the degree of metastasis
o M0 - no metastasis
o M1 - metastasis present
AJCC stage groupings
The stage of a cancer is usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and likely a worse outcome.
• Stage 0
o Tis, N0, M0
• Stage I
o T1, N0, M0
o T2, N0, M0
• Stage IIA
o T3, N0, M0
• Stage IIB
o T4, N0, M0
• Stage IIIA
o T1, N1, M0
o T2, N1, M0
• Stage IIIB
o T3, N1, M0
o T4, N1, M0
• Stage IIIC
o Any T, N2, M0
• Stage IV
o Any T, Any N, M1
Pathogenesis
Colorectal cancer is a disease originating from the epithelial cells lining the gastrointestinal tract. Hereditary or somatic mutations in specific DNA sequences, among which are included DNA replication or DNA repair genes, and also the APC, K-Ras, NOD2 and p53 genes, lead to unrestricted cell division. The exact reason why (and whether) a diet high in fiber might prevent colorectal cancer remains uncertain. Chronic inflammation, as in inflammatory bowel disease, may predispose patients to malignancy.
Treatment
The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However when it is detected at later stages (when distant metastases are present) it is less likely to be curable.
Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient's staging and other medical factors.
Surgery
Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.
Curative Surgical treatment can be offered if the tumor is localized.
• Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.
• In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.
• Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.
In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.
If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.
The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures would do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to "open and close" procedures are now diagnosed in advance and surgery avoided.
Laparoscopic-assisted colectomy is a minimally-invasive technique that can reduce the size of the incision, minimize the risk of infection, and reduce post-operative pain.
As with any surgical procedure, colorectal surgery may result in complications including
• wound infection, Dehiscence (bursting of wound) or hernia
• anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis
• bleeding with or without hematoma formation
• adhesions resulting in bowel obstruction (especially small bowel)
• blind loop syndrome as in bypass surgery.
• adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder
• Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc
Chemotherapy
Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy if surgery is not indicated (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration.
• Adjuvant (after surgery) chemotherapy. One regimen involves the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)
o 5-fluorouracil (5-FU) or Capecitabine
o Leucovorin (LV, Folinic Acid)
o Oxaliplatin (Eloxatin)
• Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab
o 5-fluorouracil (5-FU) or Capecitabine
o Leucovorin (LV, Folinic Acid)
o Irinotecan (Camptosar)
o Oxaliplatin (Eloxatin)
o Bevacizumab (Avastin)
o Cetuximab (Erbitux)
o Panitumumab (Vectibix)
• In clinical trials for treated/untreated metastatic disease.
o Bortezomib (Velcade)
o Oblimersen (Genasense, G3139)
o Gefitinib and Erlotinib (Tarceva)
o Topotecan (Hycamtin)
Radiation therapy
Radiotherapy is not used routinely in colon cancer and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:
• Colon cancer
o pain relief and palliation - targeted at metastatic tumor deposits if they compress vital structures and/or cause pain
• Rectal cancer
o neoadjuvant - given before surgery in patients with tumors that extend outside the rectum or have spread to regional lymph nodes, in order to decrease the risk of recurrence following surgery or to allow for less invasive surgical approaches (such as a low anterior resection instead of an abdomino-perineal resection)
o adjuvant - where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke's B or C tumors)
o palliative - to decrease the tumor burden in order to relieve or prevent symptoms
Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.
Treatment of colorectal cancer metastasis to the liver
According to the American Cancer Society statistics in 2006 greater than 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.
Resectability of a liver met is determined using preoperative imaging studies (Ct or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic "segments", while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic "wedge" resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimines. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.
Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.
Poor pronostic factors of patients with liver metastasis include
• Synchronous (diagnosed simultaneously) liver and primary colorectal tumors
• A short time between detecting the primary cancer and subsequent development of liver mets
• Multiple metastatic lesions
• High blood levels of the tumor marker, carcino-embryonic antigen (CEA), in the patient prior to resection
• Larger size metastatic lesions
Follow-up
The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that develop later but did not originate from the original cancer (metachronous lesions).
A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.
Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. These guidelines are based on recent meta-analyses showing that intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.
Surveillance
Most colorectal cancer arise from adenomatous polyps. These lesions can be detected and removed during colonoscopy. Studies show this procedure would decrease by > 80% the risk of cancer death, provided it is started by the age of 50, and repeated every 5 or 10 years.
Lecture 10
Pancreatic Cancer. Liver cancer. Gallbladder cancer.
I. Pancreatic Cancer
Epidemiology
Incidence
• The crude incidence and mortality of pancreatic cancer in the European Union is about 11/100 000 per year.
• In around 5% of patients some genetic basis for the disease can be found.
• In the United States, the incidence of pancreatic cancer is 9 cases per 100,000 population.
• In theUkraine, the incidence of pancreatic cancer is 9,7 cases per 100,000 population.
• Pancreatic cancer is primarily a disease associated with advanced age, with 80% of cases occurring between the ages of 60 and 80.
• Men are almost twice as likely to develop this disease than women.
• Countries with the highest frequencies of pancreatic cancer include the US, New Zealand, Western European nations, and Scandinavia.
• The lowest occurrences of the disease are reported in India, Kuwait and Singapore.
Etiology and risk factors.
1. Cigarette smoking. The risk increases with increasing duration and amount of cigarette smoking. The excess risk levels off 10 to 15 years after cessation of smoking. The risk is ascribed to tobacco-specific nitrosamines.
2. Diet. A high intake of fat, meat, or both is associated with increased risk, whereas the intake of fresh fruits and vegetables appears to have a protective effect.
3. Partial gastrectomy appears to correlate with a two to five times higher than expected incidence of pancreatic cancer 15 to 20 years later. The increased formation of N-nitroso compounds by bacteria that produce nitrate reductase and proliferate in the hypoacidic stomach has been proposed to account for the increased occurrence of gastric and pancreatic cancer after partial gastrectomy.
4. Cholecystokinin is the primary hormone that causes growth of exocrine pancreatic cells; others include epidermal growth factor and insulin-like growth factors. Pancreatic cancer has been induced experimentally by long-term duodenogastric reflux, which is associated with increased cholecystokinin levels. Some clinical evidence suggests that cholecystectomy, which also increases the circulating cholecystokinin, may increase the risk for pancreatic cancer.
5. Diabetes mellitus may be an early manifestation of pancreatic cancer or a predisposing factor. It is found in 13% of patients with pancreatic cancer and in only 2% of controls.
6. Chronic and hereditary pancreatitis are associated with pancreatic cancer. Chronic pancreatitis is associated with a 15-fold increase in the risk for pancreatic cancer.
7. Toxic substances. Occupational exposure to 2-naphthylamine, benzidine, and gasoline derivatives is associated with a five-fold increased risk for pancreatic cancer. Prolonged exposure to DDT and two DDT derivatives (ethylan and DDD) is associated with a four-fold to seven-fold increased risk for pancreatic cancer.
8. Socioeconomic status. Pancreatic cancer occurs in a slightly higher frequency in populations of lower socioeconomic status.
9. Coffee. Analysis of 30 epidemiologic studies showed that only one case-control study and none of the prospective studies confirmed a statistically significant association between coffee consumption and pancreatic cancer.
10. Idiopathic deep-vein thrombosis is statistically correlated with the subsequent development of mucinous carcinomas (including pancreatic cancer), especially among patients in whom venous thrombosis recurs during follow-up.
11. Dermatomyositis and polymyositis are paraneoplastic syndromes associated with pancreatic cancer and other cancers.
12. Familial pancreatic cancer. It is estimated that 3% of pancreatic cancers are linked to inherited predisposition to the disease.
Pathology
Nonepithelial tumors (sarcomas and lymphomas) are rare.
Ductal adenocarcinoma makes up 75% to 90% of malignant pancreatic neoplasms: 57% occur in the head of the pancreas, 9% in the body, 8% in the tail, 6% in overlapping sites, and 20% in unknown anatomic subsites. Uncommon but reasonably distinctive variants of pancreatic cancer include adenosquamous, oncocytic, clear cell, giant cell, signet ring, mucinous, and anaplastic carcinoma. Anaplastic carcinomas often involve the body and tail rather than the head of pancreas. Reported cases of pure epidermoid carcinoma (a variant of adenosquamous carcinoma) probably are associated with hypercalcemia.
Cystadenocarcinomas have an indolent course and may remain localized for many years. Ampullary cancer (which carries a significantly better prognosis), duodenal cancer, and distal bile duct cancer may be difficult to distinguish from pancreatic adenocarcinoma.
Metastatic tumors. Autopsy studies show that for every primary tumor of the pancreas, four metastatic tumors are found. The most common tumors of origin are the breast, lung, cutaneous melanoma, and non-Hodgkin’s lymphoma.
Genetic abnormalities. Mutant c-K-ras genes have been found in most specimens of human pancreatic carcinoma and their metastases.
Diagnosis
Symptoms.
Most patients with pancreatic cancer have symptoms at the time of diagnosis.
Predominant initial symptoms include
■ abdominal pain (80%);
■ anorexia (65%);
■ weight loss (60%);
■ early satiety (60%);
■ jaundice (50%);
■ easy fatigability (45%);
■ xerostomia and sleep problems (55%);
■ weakness, nausea, or constipation (40%);
■ depression (40%); dyspepsia (35%);
■ vomiting (30%); hoarseness (25%);
■ taste change, bloating, or belching (25%);
■ dyspnea, dizziness, or edema (20%);
■ cough, diarrhea because of fat malabsorption, hiccup, or itching (15%);
■ dysphagia (5%).
Clinical findings.
■ At presentation, patients with pancreatic cancer have cachexia (44%),
■ palpable abdominal mass (35%),
■ ascites (25%),
■ supraclavicular adenopathy (5%).
■ serum albumin concentration of less than 3.5 g/dL (35%),
Metastases are present to at least one major organ in 65% of patients: to the liver in 45%, to the lungs in 30%, and to the bones in 3%.
Carcinomas of the distal pancreas do not produce jaundice until they metastasize and may remain painless until the disease is advanced.
Occasionally, acute pancreatitis is the first manifestation of pancreatic cancer.
Paraneoplastic syndromes.
Panniculitis-arthritis-eosinophilia syndrome that occurs with pancreatic cancer appears to be caused by the release of lipase from the tumor. Dermatomyositis, polymyositis, recurrent Trousseau’s syndrome or idiopathic deep-vein thrombosis, and Cushing’s syndrome have been reported to be associated with cancer of the pancreas.
Methodes of diagnostic:
1. Ultrasonography
2. CT
3. MRI
4. Endoscopic retrograde cholangiography
5.Percutaneous fine-needle aspiration cytology
6. Angiography
7.Laparoscopy
8.Tumor markers:
a. CA 19-9
b. CEA
Staging
|Stage |Primary |Lymph |Distant |5-year |
| |tumor |nodes |mets |survival |
|Stage 0 | Tis |N0 |M0 |– |
|Stage I |T1-2 |N0 |M0 |5–35% |
|Stage II |T3 |N0 |M0 |2–15% |
|Stage III |T1-3 |N1 |M0 |2–15% |
|Stage IVA |T4 |Any N |M0 |1–5% |
|Stage IVB |Any T |Any N |M1 | ................
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