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 facultiesWorked 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 facultiesWorked 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 counselof Oncology Department.Protocol № 19 « 17 » march 2008.
CONTENTSLecture 8Gastric cancerLecture 9Colorectal cancerLecture 10Pancreatic Cancer. Liver cancer. Gallbladder cancer.Lecture 11Tumors of the bones
Lecture 8Gastric cancerIncidence 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 threeparts and two sphincteric mechanisms (gastroesophageal, pylorus). In accordancewith 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. PilorusMicroscopic anatomy.The stomach has four layers and three distinct mucosal areas.The layers of the stomach wall are serosa, muscularis, muscularis mucosae, andmucosa. The layers of muscle fibers are longitudinal, oblique, and circular.The divisions of the mucosa correspond to the gross divisions of cardia, body, andantrum. 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 andsympathetic 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.VasculatureArterial supply to the stomach is via the right and left gastric arteries, the right andleft 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)Lymphatic drainage of the stomach is extensive. Lymph nodes that drain thestomach 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)
Additional regional lymph nodes stations are also: along left gastric artery (7),common hepatic artery (8), Lineal (splenic) artery (10,11), celiacTrunk (9) and hepatica-duodenal lymph nodes (12).HistologyApproximately 90%-95% of gastric tumors are malignant and of themalignancies, 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. Thestomach is the commonest site of primary intestinal lymphoma. The tumors may bebulky with central ulceration. Diagnosis preoperatively is crucial since the surgical approach differsmarkedly from that used with gastric cancer. Surgical treatment involves local resection (partial gastrectomy). Mostlesions 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 tometastasize 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 themuscularis propria
Fig. 5. TNM – classification. T – tumor, T2 Tumor invasion of mucosa and muscularis layers T2a –up to muscularic T2b –up to serosaFig. 6. TNM – classification. T – tumor, T3 • Tumor invasion of mucosa, muscularic and serosa layers
Fig. 7. TNM – classification. T – tumor, T3Tumor invasion of mucosa, muscularic and serosa layersFig. 8. TNM – classification. T – tumor, T3,4
T3 - Tumor invasion of mucosa, muscularic and serosa layers T4 – tumor invasion up to adjusting organsFig. 9. TNM – classification. N – nodules, N-1 • N1- 1-6 lymph nodes with tumorFig. 10. TNM – classification. N – nodules, N-2 N2- 7-15 lymph nodes with tumor
Fig. 11. TNM – classification. N – nodules, N-3 • N3- more then 15 lymph nodes with tumorFig. 12. TNM – classification. M – metastases, M-1
• M0- no metastases • M1 – obtained distant metastasesTable 1. TNM 2002 (5-th edition) and AJCC stage groupingStage T N MIA T1 N0 M0IB T1 N1 M0 T2a,T2b N0 M0II T1 N2 M0 T2a,T2b N1 M0 T3 N0 M0IIIA T2a,T2b N2 M0 T3 N1 M0 T4 N0 M0IIIB T3 N2 M0IV T4 N1,N2,N3 M0 T1,T2,T3 N3 M0 Any T Any N M1Clinical manifestationsDue to the fact that both the stomach and abdominal cavityare large to distention the symptoms of gastric cancer are obtained atan 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 bleedingDiagnosis • 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 gastrectomyFig. 17. Gastrojejunostomy after subtotal gastrectomy
Fig. 18. Reconstruction after total gastrectomy with Roux limbFig. 19. Reconstruction after total gastrectomy splenectomy and distalpancreatectomy with Roux limb.
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, ECFTreatment 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, involvementof regional nodes and the presents of distant metastases but still remains poor. Tumornot penetrating the serosa and not involving the regional nodes are associated withapproximately 70% 5-year survival. This number drops dramatically if the tumor isthrough the serosa or into regional nodes. Only 40% of patients have potentiallycurable 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, includescancerous growths in the colon, rectum and appendix. It is the third most commonform of cancer and the second leading cause of cancer-related death in the Westernworld. Colorectal cancer causes 655,000 deaths worldwide per year. Many colorectalcancers 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. Themajority of the time, the diagnosis of localized colon cancer is through colonoscopy.Therapy is usually through surgery, which in many cases is followed bychemotherapy. Symptoms Colon cancer often causes no symptoms until it has reached a relativelyadvanced stage. Thus, many organizations recommend periodic screening for thedisease 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 tothe 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 theless 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 persons 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 untreatedo Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome• Long-standing ulcerative colitis or Crohns 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 Crohns 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 aslightly higher risk for colorectal cancer." Another found that "The consumption ofone or more alcoholic beverages a day at baseline was associated with approximatelya 70% greater risk of colon cancer." One study found that "While there was a more than twofold increased risk ofsignificant colorectal neoplasia in people who drink spirits and beer, people whodrank wine had a lower risk. In our sample, people who drank more than eightservings of beer or spirits per week had at least a one in five chance of havingsignificant colorectal neoplasia detected by screening colonoscopy.".
Other research suggests that "to minimize your risk of developing colorectalcancer, its best to drink in moderation" Drinking may be a cause of earlier onset of colorectal cancer. Diagnosis, screening and monitoring Endoscopic image of colon cancer identified in sigmoid colon on screeningcolonoscopy in the setting of Crohns disease. Colorectal cancer can take many years to develop and early detection ofcolorectal cancer greatly improves the chances of a cure. Therefore, screening for thedisease is recommended in individuals who are at increased risk. There are severaldifferent 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 patients 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 Histopathologic image of colonic carcinoid stained by hematoxylin and eosin. The pathology of the tumor is usually reported from the analysis of tissue takenfrom a biopsy or surgery. A pathology report will usually contain a description of celltype and grade. The most common colon cancer cell type is adenocarcinoma whichaccounts for 95% of cases. Other, rarer types include lymphoma and squamous cellcarcinoma. 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 veryrarely 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 anapkin ring. Histopathology: Adenocarcinoma is a malignant epithelial tumor, originatingfrom glandular epithelium of the colorectal mucosa. It invades the wall, infiltratingthe muscularis mucosae, the submucosa and thence the muscularis propria. Tumorcells describe irregular tubular structures, harboring pluristratification, multiplelumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells arediscohesive and secrete mucus, which invades the interstitium producing large poolsof mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma,poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleusat the periphery - "signet-ring cell." Depending on glandular architecture, cellularpleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma maypresent three degrees of differentiation: well, moderately, and poorly differentiated. Staging Colon cancer staging is an estimate of the amount of penetration of a particularcancer. It is performed for diagnostic and research purposes, and to determine thebest method of treatment. The systems for staging colorectal cancers largely dependon the extent of local invasion, the degree of lymph node involvement and whetherthere is distant metastasis. Definitive staging can only be done after surgery has been performed andpathology 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 (fortumors/nodes/metastases) system, though many doctors still use the older Dukessystem. 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 fromthe TNM value grouped by prognosis; a higher number indicates a more advancedcancer 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 thegastrointestinal 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 tomalignancy. Treatment The treatment depends on the staging of the cancer. When colorectal cancer iscaught at early stages (with little spread) it can be curable. However when it isdetected at later stages (when distant metastases are present) it is less likely to becurable. Surgery remains the primary treatment while chemotherapy and/orradiotherapy may be recommended depending on the individual patients staging andother medical factors.
Surgery Surgeries can be categorised into curative, palliative, bypass, fecal diversion, oropen-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 theprimary tumor is still offered in order to reduce further morbidity caused by tumorbleeding, invasion, and its catabolic effect. Surgical removal of isolated livermetastases is, however, common and may be curative in selected patients; improvedchemotherapy has increased the number of patients who are offered surgical removalof isolated liver metastases. If the tumor invaded into adjacent vital structures which makes excisiontechnically difficult, the surgeons may prefer to bypass the tumor (ileotransversebypass) or to do a proximal fecal diversion through a stoma. The worst case would be an open-and-close surgery, when surgeons find thetumor unresectable and the small bowel involved; any more procedures would domore harm than good to the patient. This is uncommon with the advent oflaparoscopy and better radiological imaging. Most of these cases formerly subjectedto "open and close" procedures are now diagnosed in advance and surgery avoided.
Laparoscopic-assisted colectomy is a minimally-invasive technique that canreduce 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 complicationsincluding • 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, shrinktumor size, or slow tumor growth. Chemotherapy is often applied after surgery(adjuvant), before surgery (neo-adjuvant), or as the primary therapy if surgery is notindicated (palliative). The treatments listed here have been shown in clinical trials toimprove survival and/or reduce mortality rate and have been approved for use by theUS 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 targetspecific portions of the colon. It is more common for radiation to be used in rectalcancer, since the rectum does not move as much as the colon and is thus easier totarget. 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 Dukes 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 ofradiation 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 ofdiagnosis, and up to 25% of this group will have isolated liver metastasis that ispotentially resectable. Lesions which undergo curative resection have demonstrated5-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 visualizationduring resection. Lesions confined to the right lobe are amenable to en bloc removalwith a right hepatectomy (liver resection) surgery. Smaller lesions of the central orleft liver lobe may sometimes be resected in anatomic "segments", while large lesionsof left hepatic lobe are resected by a procedure called hepatic trisegmentectomy.Treatment of lesions by smaller, non-anatomic "wedge" resections is associated withhigher recurrence rates. Some lesions which are not initially amenable to surgicalresection may become candidates if they have significant responses to preoperativechemotherapy or immunotherapy regimines. Lesions which are not amenable tosurgical resection for cure can be treated with modalities including radio-frequencyablation (RFA), cryoablation, and chemoembolization. Patients with colon cancer and metastatic disease to the liver may be treated ineither a single surgery or in staged surgeries (with the colon tumor traditionallyremoved first) depending upon the fitness of the patient for prolonged surgery, thedifficulty expected with the procedure with either the colon or liver resection, and thecomfort 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 anymetastasis 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 6months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen bloodlevel measurements follow the same timing, but are only advised for patients with T2or 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 whoare at high risk of recurrence (for example, patients who had poorly differentiatedtumors or venous or lymphatic invasion) and are candidates for curative surgery (withthe aim to cure). A colonoscopy can be done after 1 year, except if it could not bedone during the initial staging because of an obstructing mass, in which case it shouldbe performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or highgrade dysplasia is found, it can be repeated after 3 years, then every 5 years. For otherabnormalities, the colonoscopy can be repeated after 1 year. Routine PET or ultrasound scanning, chest X-rays, complete blood count orliver 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 bedetected and removed during colonoscopy. Studies show this procedure woulddecrease by > 80% the risk of cancer death, provided it is started by the age of 50,and repeated every 5 or 10 years.
Lecture 10Pancreatic 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 ofcigarette smoking. The excess risk levels off 10 to 15 years after cessation ofsmoking. The risk is ascribed to tobacco-specific nitrosamines.2. Diet. A high intake of fat, meat, or both is associated with increased risk, whereasthe 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 thanexpected incidence of pancreatic cancer 15 to 20 years later. The increased formationof N-nitroso compounds by bacteria that produce nitrate reductase and proliferate inthe hypoacidic stomach has been proposed to account for the increased occurrence ofgastric and pancreatic cancer after partial gastrectomy.
4. Cholecystokinin is the primary hormone that causes growth of exocrine pancreaticcells; others include epidermal growth factor and insulin-like growth factors.Pancreatic cancer has been induced experimentally by long-term duodenogastricreflux, which is associated with increased cholecystokinin levels. Some clinicalevidence suggests that cholecystectomy, which also increases the circulatingcholecystokinin, may increase the risk for pancreatic cancer.5. Diabetes mellitus may be an early manifestation of pancreatic cancer or apredisposing factor. It is found in 13% of patients with pancreatic cancer and in only2% 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 pancreaticcancer.7. Toxic substances. Occupational exposure to 2-naphthylamine, benzidine, andgasoline derivatives is associated with a five-fold increased risk for pancreatic cancer.Prolonged exposure to DDT and two DDT derivatives (ethylan and DDD) isassociated with a four-fold to seven-fold increased risk for pancreatic cancer.8. Socioeconomic status. Pancreatic cancer occurs in a slightly higher frequency inpopulations of lower socioeconomic status.9. Coffee. Analysis of 30 epidemiologic studies showed that only one case-controlstudy and none of the prospective studies confirmed a statistically significantassociation between coffee consumption and pancreatic cancer.10. Idiopathic deep-vein thrombosis is statistically correlated with the subsequentdevelopment of mucinous carcinomas (including pancreatic cancer), especiallyamong patients in whom venous thrombosis recurs during follow-up.11. Dermatomyositis and polymyositis are paraneoplastic syndromes associatedwith pancreatic cancer and other cancers.12. Familial pancreatic cancer. It is estimated that 3% of pancreatic cancers arelinked to inherited predisposition to the disease.Pathology Nonepithelial tumors (sarcomas and lymphomas) are rare.
Ductal adenocarcinoma makes up 75% to 90% of malignant pancreaticneoplasms: 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 butreasonably 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 ofpancreas. Reported cases of pure epidermoid carcinoma (a variant of adenosquamouscarcinoma) probably are associated with hypercalcemia. Cystadenocarcinomas have an indolent course and may remain localized formany years. Ampullary cancer (which carries a significantly better prognosis),duodenal cancer, and distal bile duct cancer may be difficult to distinguish frompancreatic adenocarcinoma. Metastatic tumors. Autopsy studies show that for every primary tumor of thepancreas, four metastatic tumors are found. The most common tumors of origin arethe breast, lung, cutaneous melanoma, and non-Hodgkin’s lymphoma. Genetic abnormalities. Mutant c-K-ras genes have been found in mostspecimens 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 theliver in 45%, to the lungs in 30%, and to the bones in 3%. Carcinomas of the distal pancreas do not produce jaundice until theymetastasize 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 cancerappears 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 thepancreas. Methodes of diagnostic:1. Ultrasonography2. CT3. MRI4. Endoscopic retrograde cholangiography5.Percutaneous fine-needle aspiration cytology6. Angiography7.Laparoscopy
8.Tumor markers: a. CA 19-9 b. CEAStagingStage Primary Lymph Distant 5-year tumor nodes mets survivalStage 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 <1% TREATMENT Surgery.Only 5% to 20% of patients with pancreatic cancer have resectable tumors at the timeof presentation Pancreaticoduodenectomy, the Whipple’s procedure, is the standardsurgical treatment for adenocarcinoma of the head of the pancreas when the lesion iscurable by resection. Resectability is determined at surgery from several criteria: • There are no metastases outside the abdomen. • The tumor has not involved the porta hepatis, the portal vein as it passes behind the body of the pancreas, and the superior mesenteric artery region. • The tumor has not spread to the liver or other peritoneal structures. The Whipple’s procedure involves removal of the head of the pancreas,duodenum, distal common bile duct, gallbladder, and distal stomach. The gastrointestinal tract is then reconstructed with creation of agastrojejunostomy, choledochojejunostomy, and pancreaticojejunostomy.
The operative mortality rate with this extensive operation can be as high as15%. The complication rate is also considerable, the commonest complications beinghemorrhage, abscess, and pancreatic ductal leakage. Distal pancreatectomy, usually with splenectomy and lymphadenectomy, is theprocedure performed for carcinoma of the midbody and tail of the pancreas. Total pancreatectomy has been proposed for the treatment of pancreaticcancer. The procedure has two potential advantages: Removal of a possible multicentric tumor (present in up to 40% of patients) Avoidance of pancreatic duct anastomotic leaks However, survival rates are not markedly better, and the operation hasnot been widely adopted. In addition, it has resulted in a particularly brittle type of diabetes,making for an unpleasant postoperative life. Regional pancreatectomy Palliative procedures are performed more frequently than curative ones becauseso many of these tumors are incurable. Palliative procedures attempt to relieve biliaryobstruction by using either the common bile duct or the gallbladder as a conduit fordecompression into the intestinal tract: gastrojejunostomy with choledochojejunostomy percutaneous transhepatic biliary stents Chemotherapy 5-FU Gemcitabine Multidrug regimens that include 5-fluorouracil (5-FU) have produced aresponse (temporary tumor regression or, rarely, cure) in about 20%-25% of thepatients with metastases. Radiation therapy
is sometimes used to shrink a tumor before surgery or to remove remaining cancercells after surgery. Radiation may also be used to relieve pain or digestive problemscaused by the tumor if it cannot be removed by surgery. Prognostic factors.Fewer than 20% of patients with adenocarcinoma of the pancreas survive the firstyear, and only 3% are alive 5 years after the diagnosis. Resectable disease. The 5-year survival rate of patients whose tumors were resected is poor; thereported range is 3% to 25%. The 5-year survival is 30% for patients with smalltumors (2 cm or less in diameter), 35% for patients with no residual tumor or forpatients in whom the tumor did not require dissection from major vessels, and 55%for patients without lymph node metastasis. Nonresectable or metastatic disease. The median survival of patients with such disease is 2 to 6 months. Performance status and the presence of four symptoms (dyspnea, anorexia,weight loss, and xerostomia) appear to influence survival; patients with the higherperformance status and the least number of these symptoms lived the longest.
II. Liver cancer Incidence Liver cancer is among the most common neoplasms and causes of cancer deathin the world, occurring most commonly in Africa and Asia. Up to 1 million deathsdue to hepatocellular carcinoma (HCC) occur each year worldwide. In the UnitedStates, 16,000 new cases of cancer of the liver and biliary passages develop annually.Incidence throughout the world varies dramatically with 115 cases per 100,000people noted in China and Thailand, compared with 1 to 2 cases per 100,000 inBritain. In countries with high incidence rates, there are often subpopulations withhigh incidence rates living nearby lower-risk subpopulations. HCC is 4 to 9 timesmore common in men than in women. In theUkraine, the incidence of liver cancer is5 cases per 100,000 population. Etiology Conditions predisposing to HCC :1. Hepatitis B virus (HBV).2. Cirrhosis.3. HCV infection4. Aflatoxins5. Mutations of tumor-suppressor gene p536. Sex hormones.7. Cigarette smoking, alcohol intake, diabetes, and insulin intake. Pathology 1. Liver cell adenoma has low malignant potential. True adenomas of the liverare rare and occur mostly in women taking oral contraceptives. Most adenomas aresolitary; occasionally multiple (10 or more) tumors develop in a condition known asliver cell adenomatosis. These tumors are smooth encapsulated masses and do notcontain Kupffer’s cells. Patients usually have symptoms; hemoperitoneum occurs in25% of cases. 2. Focal nodular hyperplasia (FNH) has no malignant potential. FNH occurswith a female-to-male ratio of 2:1. The relationship of oral contraceptives to FNH is
not as clear as for hepatic adenoma; only half of patients with FNH take oralcontraceptives. FNH tumors are nodular, are not encapsulated, but do containKupffer’s cells. Patients usually do not have symptoms; hemoperitoneum rarelyoccurs. 3. Bile duct adenomas are solitary in 80% of cases and may grossly resemblemetastatic carcinoma. Most are less than 1 cm in diameter and are located under thecapsule. 4. HCC (hepatocellular carcinoma) may present grossly as a single mass,multiple nodules, or as diffuse liver involvement; these are referred to as massive,nodular, and diffuse forms. The growth pattern microscopically is trabecular, solid, ortubular, and the stroma, in contrast to bile duct carcinoma, is scanty. A rare sclerosingor fibrosing form has been associated with hypercalcemia. Fibrolamellar carcinoma,another variant, occurs predominantly in young patients without cirrhosis, has afavorable prognosis, and is not associated with elevation of serum a-fetoprotein (a-FP) levels. In the United States, almost half of HCCs in patients younger than 35years of age are fibrolamellar, and more than half of them are resectable. 5. Biliary cystadenoma and cystadenocarcinoma. Benign and malignantcystic tumors of biliary origin arise in the liver more frequently than in theextrahepatic biliary system. 6. Bile duct carcinoma (cholangiocarcinoma). Malignant tumors ofintrahepatic bile ducts are less common than HCC and have no relation to cirrhosis.Mixed hepatic tumors with elements of both HCC and cholangiocarcinoma do occur;most of these cases are actually HCC with focal ductal differentiation. Natural history Most patients die from hepatic failure and not from distant metastases. Thedisease is contained within the liver in only 20% of cases. HCC invades the portal vein in 35% of cases, hepatic vein in 15%, contiguousabdominal organs in 15%, and vena cava and right atrium in 5%.
HCC metastasizes to the lung in 35% of cases, abdominal lymph nodes in 20%,thoracic or cervical lymph nodes in 5%, vertebrae in 5%, and kidney or adrenal glandin 5%. Clinical presentation Symptoms : Pain in the right subcostal area or on top of the shoulder from phrenic irritationis common (95%). Severe symptoms of fatigue (31%), anorexia (27%), and weight loss (35%)and unexplained fever (30% to 40%) are not uncommon. Many patients have vague abdominal pain, fever, and anorexia for up to 2years before the diagnosis of carcinoma is made. Hemorrhage into the peritoneal cavity is often seen in patients with HCC andmay be fatal. Ascites or the presence of an upper abdominal mass noticeable by the patientare ominous prognostic signs. Physical findings hepatomegaly (90%), splenomegaly (65%), ascites (52%), fever (38%), jaundice (41%), hepatic bruit (28%), cachexia (15%). Associated paraneoplastic syndromes fever, erythrocytosis, hypercholesterolemia, gynecomastia, hypercalcemia, hypoglycemia,
virilization (precocious puberty). Diagnosis1. LFTs (serum bilirubin, lactate dehydrogenase, serum albumin, serum g-glutamyltransferase (GGT))2. Biopsy of liver nodules.3. Serum tumor markers.4. Radiologic studies. a.Ultrasound. b. CT. c. MRI d. Selective hepatic, celiac, and superior mesenteric angiography e. Radionuclide scans: • Liver-spleen scan • Gallium scan Surgical treatment lobectomy wedge resection segmentectomy hepatic resections Liver transplantation Removal of the entire liver (total hepatectomy) and liver transplantation can beused to treat liver cancer.However, there is a high risk of tumor recurrence andmetastases after transplantation. Treatment of nonresectable and metastatic disease1. Systemic chemotherapy has a response rate of 20% and does not affect mediansurvival (3 to 6 months). Doxorubicin as a single agent or in combination with otherdrugs has been used. Mitoxantrone is as effective as doxorubicin but is associatedwith less toxicity. 5-FU intravenously and FUDR intraarterially have also been usedwith similar results.
2. Tamoxifen.3. Radiation therapy is the use of high–energy rays or x rays to kill cancer cells or to shrink tumors. Its use in liver cancer, however, is only to give short–term relief from some of the symptoms. Liver cancers are not sensitive to radiation, andradiation therapy will not prolong the patient’s life.4. Recombinant interferon-a2α Other Therapies• Hepatic artery embolization with chemotherapy (chemoembolization).• Alcohol ablation via ultrasound-guided percutaneous injection.• Ultrasound-guided cryoablation.• Immunotherapy with monoclonal antibodies tagged with cytotoxic agents.• Gene therapy with retroviral vectors containing genes expressing cytotoxic agents. Prognosis Liver cancer has a very poor prognosis because it is often not diagnosed until ithas metastasized. Fewer than 10% of patients survive three years after the initialdiagnosis; the overall five-year survival rate for patients with hepatomas is around4%. Most patients with primary liver cancer die within several months of diagnosis. Patients with liver cancers that metastasized from cancers in the colon liveslightly longer than those whose cancers spread from cancers in the stomach orpancreas.
III. Gallbladder cancer Epidemiology Incidence. Primary gallbladder carcinoma (GBC) is the most common malignant tumor ofthe biliary tract and the fifth most common cancer of the digestive tract. There are 6000 to 7000 cases annually in the United States. GBCs were foundin 1% to 2% of operations on the biliary tract. In theUkraine, the incidence of GBC is 2.1 cases per 100,000 population. Risk factors:1. Sex.2. Race.3. Older age.4. Chronic cholecystitis and cholelithiasis .5. Benign neoplasms.6. Ulcerative colitis Morphology Most GBCs are adenocarcinomas (80%) showing varying degrees ofdifferentiation. The mucus secreted by this cancer is typically of the sialomucin type,in contrast to the sulfomucin type secreted by the normal or inflamed mucus-secreting glands. Other types of GBC include adenoacarcinoma, adenosquamouscarcinomas, and undifferentiated (anaplastic, pleomorphic, sarcomatoid) carcinomas.Some adenocarcinomas have choriocarcinoma-like elements, and others havemorphology equivalent to small cell carcinoma. Natural history GBC has a propensity to involve the liver, stomach, and duodenum by directextension. The common sites of metastasis are the liver (60%), adjacent organs(55%), regional lymph nodes (35%), peritoneum (25%), and distant visceral organs(30%). Clinical presentation GBC may present as one of the following clinical syndromes:
1.Acute cholecystitis (15% of patients). These patients appear to have less advancedcarcinoma, a higher rate of resectability, and longer survival.2. Chronic cholecystitis (45%)3. Symptoms suggestive of malignant disease (e.g., jaundice, weight loss,generalized weakness, anorexia, or persistent right upper quadrant pain; 35%)4. Benign nonbiliary manifestations (e.g., GI bleeding or obstruction; 5%) Diagnosis Symptoms. The lack of specific symptoms prevents detection of GBC at an early stage.Consequently, the diagnosis is usually made unexpectedly at the time of surgerybecause the clinical signs commonly mimic benign gallbladder disease.Pain is present in 79% of patients;jaundice, anorexia, or nausea and vomiting in 45% to 55%;weight loss or fatigue in 30%. Physical examination. Certain combinations of symptoms and signs may suggest the diagnosis, suchas an elderly woman with a history of chronic biliary symptoms that have changed infrequency or severity. A right upper quadrant mass or hepatomegaly andconstitutional symptoms suggest GBC. Laboratory examination.Elevated serum alkaline phosphatase is present in 65% of patients, anemia in 55%,elevated bilirubin in 40%, leukocytosis in 40%, and leukemoid reaction in 1% ofpatients with GBC. The association of elevated alkaline phosphatase without elevatedbilirubin is consistent with GBC. Radiologic examination : Abdominal ultrasound CT of the abdomen MRI Percutaneous transhepatic cholangiography Laparoscopic exploration
StagingStage I: An intramuscular lesion or muscular invasion unrecognized at operation andlater discovered by the pathologist.Stage II: Transmural invasion.Stage III: Lymph node involvement.Stage IV: Involvement of two or more adjacent organs, or more than 2 cm invasion ofliver, or distant metastasis. Treatment Cholecystectomy is the only effective treatment. The best chance for long-term survival is the serendipitous discovery of an early cancer at the time ofcholecystectomy. Radical cholecystectomy or resection of adjacent structure has notresulted in better survival. Chemotherapy. The data on adjuvant systemic chemotherapy are anecdotal. 5-FU–basedcombinations are most commonly used, but the response rates are poor. Anecdotalreports of hepatic arterial infusion of chemotherapy have also claimed benefit inhighly selected patients Prognostic factors The overall median survival of patients with GBC is 6 months. After surgicalresection, only 27% are alive at 1 year, 19% at 3 years, and 13% at 5 years. Disease stage is the most significant prognostic factor. The 5-year survival rateafter surgical resection is 65% to 100% for stage I, 30% for stage II, 15% for stageIII, and 0% for stage IV disease. Poorly differentiated (higher-grade) tumors and the presence of jaundice areassociated with poorer survival. Ploidy patterns do not correlate with survival.
Lecture 11Tumors of the bones Bone is the supporting framework of the body. Most bones are hollow. Theouter part of bones consists of a network of fibrous tissue called matrix onto whichcalcium salts are deposited. At each end of the bone is a zone of cartilage, a softerform of bone-like tissue. Cartilage is made of a fibrous tissue matrix mixed with agel-like substance. Unlike bone, cartilage does not contain much calcium. Cartilage acts as a cushion between bones and, together with ligaments andsome other tissues, forms the joints between bones. The bone itself is very hard andstrong. Some bone is able to support as much as 12,000 pounds per square inch. Ittakes as much as 1,200 to 1,800 pounds of pressure to break a femur (thigh bone). The outside of the bone is covered with a layer of fibrous tissue calledperiosteum. The bone itself contains 2 kinds of cells. The osteoblast is the cellresponsible for forming bone, and the osteoclast is the cell responsible for dissolvingbone. Although bone looks to be a very unchanging organ, the truth is that it is veryactive. New bone is constantly forming, and at the same time, old bone is dissolving. Bone marrow is the soft tissue inside the hollow bones. The marrow of somebones consists only of fatty tissue. The marrow of other bones is a mixture of fat cellsand blood-forming (hematopoietic) cells. These blood-forming cells produce redblood cells, white blood cells, and blood platelets. There are some other cells in themarrow such as plasma cells, fibroblasts, and reticuloendothelial cells. All these tissues can develop into a tumor - a lump or mass of tissue that formswhen cells divide uncontrollably. For most bone tumors, the cause is unknown. Agrowing tumor may replace healthy tissue with abnormal tissue. It may weaken thebone, causing it to break (fracture). Aggressive tumors can lead to disability or death,particularly if signs and symptoms are ignored. Most bone tumors are noncancerous (benign). Some are cancerous (malignant).Occasionally, infection, stress fractures, and other non-tumor conditions can closelyresemble tumors.
Benign tumors are usually not life threatening. Malignant tumors can spreadcancer cells throughout the body (metastasize). This happens via the blood orlymphatic system. Cancer that begins in bone (primary bone cancer) is different from cancer thatbegins somewhere else in the body and spreads to bone (secondary bone cancer). Clinical presentation Most patients with a bone tumor will experience pain in the area of the tumor.The pain is generally described as dull and achy. The pain may or may not get worsewith activity. The pain often awakens the patient at night. Although tumors are not caused by trauma, occasionally injury can cause atumor to start hurting. Injury can cause a bone that is already weakened by a tumor tobreak. This often leads to severe pain. Some tumors can cause fevers and nightsweats. Many patients will not have any symptoms, but will instead note a painlessmass. Occasionally benign tumors may be discovered incidentally when X-rays aretaken for other reasons, such as a sprained ankle or rotator cuff problem. Medical History The doctor will need to take a complete medical history. This includes learningabout any medications you take, details about any previous tumors or cancers thatyou or your family members may have had, and symptoms you are experiencing. Physical Examination Your doctor will physically examine you. The focus is on the tumor mass,tenderness in bone, and any impact on joints and/or range of motion. In some cases,the doctor may want to examine other parts of your body to rule out cancers that canspread to bone. Imaging Your doctor will probably obtain X-rays. Different types of tumors havedifferent characteristics on X-ray. Some dissolve bone or make a hole in the bone.Some cause additional bone to form. Some can have a mixture of these findings.
Some tumors have characteristic findings on X-rays. In other cases, it may behard to tell what kind of tumor is involved. More imaging studies may be needed tofurther evaluate some tumors. These may include magnetic resonance imaging (MRI)or computed tomography (CT). Tests Blood tests and/or urine tests may be done. A biopsy is another test. A biopsyremoves a sample of tissue from the tumor. The tissue sample is examined under amicroscope. There are two basic methods of doing a biopsy. Needle Biopsy The doctor inserts a needle into the tumor to remove some tissue. This may bedone in the doctors office using local anesthesia. A radiologist may do a needlebiopsy, using some type of imaging, such as an X-ray, CT, or MRI to help direct theneedle to the tumor. Open Biopsy The doctor surgically removes tissue. This is generally done in an operatingroom. The patient is given general anesthesia and a small incision is made and thetissue is removed. Treatment of Benign Tumors In many cases, benign tumors just need to be watched. Some can be treatedeffectively with medication. Some benign tumors will disappear over time. This isparticularly true for some benign tumors that occur in children. Certain benign tumors can spread or become cancerous (metastasize).Sometimes the doctor may recommend removing the tumor (excision) or some othertreatment techniques to reduce the risk of fracture and disability. Some tumors maycome back, even repeatedly, after appropriate treatment. Treatment of Malignant Tumors If the patient is diagnosed with a malignant bone tumor, the treatment teammay include several specialists. These may include an orthopaedic oncologist, a
medical oncologist, a radiation oncologist, a radiologist, and a pathologist. Treatmentgoals include curing the cancer and preserving the function of the body. Doctors often combine several methods to treat malignant bone tumors.Treatment depends upon various factors, including the stage of the cancer (whetherthe cancer has spread). Cancers have spread elsewhere in the body. Tumors at thisstage are more serious and harder to cure. Generally, the tumor is removed using surgery. Often, radiation therapy is usedin combination with surgery. Limb Salvage Surgery This surgery removes the cancerous section of bone but keeps nearby muscles,tendons, nerves, and blood vessels. If possible, the surgeon will take out the tumorand a margin of healthy tissue around it. The excised bone is replaced with a metallicimplant (prosthesis) or bone transplant. Amputation Amputation removes all or part of an arm or leg when the tumor is large and/ornerves and blood vessels are involved. Radiation Therapy Radiation therapy uses high-dose X-rays to kill cancer cells and shrink tumors. Systemic Treatment (Chemotherapy) This treatment is often used to kill tumor cells when they have spread into theblood stream but cannot yet be detected on tests and scans. Chemotherapy isgenerally used when cancerous tumors have a very high chance of spreading. After Treatment When treatment for a bone tumor is finished, the doctor may take more X-raysand other imaging studies. These can confirm that the tumor is actually gone. Regulardoctor visits and tests every few months may be needed. When the tumor disappears,it is important to monitor patient’s body for signs that is may have returned (relapse). On the Horizon
Genetic research is leading to a better understanding of the types of bonetumors and their behaviors. Researchers are studying the design of metallic implants.This allows better function and durability after limb salvage surgery. Advancements in the development of prosthetic limbs include computertechnology. This is leading to better function and quality of life after amputation. Research into new medications and new combinations of older medicationswill lead to continual improvements in survival from bone cancers. Your doctor maydiscuss clinical research trials with you. Clinical trials may involve the use of newtherapies and may offer a better outcome. Bening bone tumors. Desmoplastic fibroma is an extremely rare tumor with less than 200 cases inthe published literature. It is a slowly progressing tumor with well-differentiated cellsthat produce collagen. This benign tumor is characterized by aggressive localinfiltration. It occurs most often in the first 3 decades and is found equally in men andwomen. The most common site is the mandible, followed by the femur and pelvis.Clinical findings include pain late in the clinical course and swelling. It may presentas an effusion if near a joint. Only 12% present with a pathological fracture. The diagnosis of desmoplastic fibroma is difficult to make radiologically. Plainxray shows an osteolytic, expansile, medullary lesion with well defined scleroticmargins. The oval tumor is often found in the metaphysis aligned with the long axisof the bone. There is usually thinned cortex and the fine intra-lesional trabeculae givea lobulated appearance that is described as "soap-bubbly". A CT scan is only usefulto further demonstrate cortical breakthrough. MRI demonstrates the separation of theintraosseus tumor from the bone. The radiological differential includes non-ossifyingfibroma, giant cell tumor, UBC, ABC and fibrous dysplasia. Grossly, desmoplastic fibroma has a grayish to yellowish white color and arubbery consistency. The edges are irregular, round and blunt. The tumor hasoccasional cystic foci with clear fluid.
Microscopically, the tumor has interlacing bundles of dense collagen and lowcellularity. The fusiform cells that are present have no atypia and the nuclei are ovoidor elongated. The differential of the tumor includes spindle cell tumors, mostspecifically low grade fibrosarcoma. The desmoplastic fibroma does not have thecellularity, mitotic activity or pleomorphism of a fibrosarcoma but the distinction canbe difficult and is sometimes made clinically. The edge of the tumor may resemblefibrous dysplasia, but under polarized light lamellar structures are obvious. Treatment of desmoplastic fibroma is marginal or wide surgical excision. Ratesof recurrence are 55-72% without resection and 17% with resection. Aneurysmal bone cyst (ABC) is a solitary, expansible and erosive lesion ofbone. It is found most commonly during the second decade and the ratio of female tomale is 2:1. ABCs can be found in any bone in the body. The most common locationis the metaphysis of the lower extremity long bones, more so than the upperextremity. The vertebral bodies or arches of the spine also may beinvolved.Approximately one-half of lesions in flat bones occur in the pelvis. Onetheory of the etiology of primary ABCs is that these lesions are secondary toincreased venous pressure that leads to hemorrhage which causes osteolysis. Thisosteolysis can in turn promote more hemorrhage causing amplification of the cyst. More often, ABCs are thought to be a reactive process secondary to trauma orvascular disturbance. ABCs can be secondary to an underlying lesion such as non-ossifying fibroma, chondroblastoma, osteoblastoma, UBCs, chondromyxoid fibromaand fibrous dysplasia. This association is so strong that the lesion should be examinedmicroscopically in several places to eliminate the possibility of a primary lesion. Themost common precursor lesion was giant cell tumor, (19-39%) of cases, followed byosteoblastoma, angioma, and chondroblastoma. Less common precursor lesions werefibrous dysplasia, non-ossifying fibroma, chondromyxoid fibroma, unicameral bonecyst, fibrous histiocytoma, eosinoplilic granuloma, and osteosarcoma. A translocationinvolving the 16q22 and 17p13 chromosomes has been identified in the solid variantand extraosseous forms of aneurysmal bone cyst.
The clinical presentation of an ABC is swelling, tenderness and pain.Occasionally there is limited range of motion due to joint obstruction. Spinal lesionscan cause neurological symptoms secondary to cord compression. Pathologicalfractures are rare due to the eccentric location of the lesion. Depending on thelocation, the differential includes UBC, chondromyxoid fibroma, giant cell tumor,osteoblastoma and the highly malignant telangiectatic osteosarcoma. On plain film, an ABC is normally placed eccentrically in the metaphysis andappears osteolytic. The periosteum is elevated and the cortex is eroded to a thinmargin. The expansible nature of the lesion is often reflected by a "blow-out" or"soap bubble" appearance. CT scan can also help delineate lesions in the pelvis orspine where plain film imaging may be inadequate. CT scan can narrow thedifferential diagnosis of ABC by demonstrating multiple fluid-fluid levels within thecystic spaces. MRI can also confirm the multiple fluid-fluid levels and the non-homogeneity of the lesion. A careful search for radiological signs of the precursorlesion, if any, is recommended. Some lesions may have a flocculent chondroid matrixthat may be a clue to their pathogenesis. Enchondroma is a solitary, benign, intramedullary cartilage tumor that isusually found in the short tubular bones of the hands and feet. The peak incidence isin the third decade and is equal between men and women. It is the most common primary tumor in the hand and is normally found in thediaphysis. The mature hyaline cartilage located centrally within short tubular bonesusually presents clinically as a fracture due to an enlarging lesion. Enchondromas arealso found incidentally in long bones and undergo malignant transformation in lessthan 1% of cases. Multiple enchondromatosis is a non-heritable condition also known as Olliersdisease. Multiple enchondromas and hemangiomas of soft tissue are otherwise knownas Maffuccis Syndrome. In both conditions, males are affected more than women andthe disease process often only affects one side of the body. In both diseases, there is a30% risk of malignant transformation of the enchondromas. Enchondromas aredifficult to differentiate from low grade chondrosarcoma by radiology. Lesions
located near the shoulder or the pelvis may have a higher risk of sarcomatousdegeneration. Chondrosarcoma is much more common in older patients, so largeenchondromas in older individuals demand a careful work-up. Enchondromas are usually long and oval and have well-defined margins. Inlarger lesions, the lucent defect has endosteal scalloping and the cortex is expandedand thinned. Calcifications throughout the lesion can range from punctate to rings.CT is useful for detecting matrix mineralization and cortex integrity. MRI is helpfulfor describing the non-mineralized portion of the lesion and visualizing anyaggressive or destructive features. Radiographic and imaging features of enchondroma that are consideredworrisome due to the potential for malignancy include large size, a largeunmineralized component, significant thinning of the adjacent cortex, and bone scanactivity greater than that of the anterior superior iliac spine. Features of enchondromathat are very strongly associated with malignant transformation are progressivedestruction of the chondroid matrix by an expanding, non-mineralized component, anenlarging lesion associated with pain, or an expansile soft tissue mass. On gross examination, an enchondroma consists of bluish-gray lobules of finetranslucent tissue. The degree of calcification of the lesion determines if theconsistency is gritty. Under the microscope, a thin layer of lamellar bone surroundingthe cartilage nodules is a positive sign that the lesion is benign. At low power, thereare lobules of different sizes. Blood vessels are surrounded by osteoid.Enchondromas have chondrocytes without atypia inside hyaline cartilage. The nucleiare small, round and pyknotic. The cellularity varies between lesions and within thesame lesion. Each potential enchondroma needs to be evaluated for cellularity, nuclearatypia, double nucleated chondrocytes and mitotic activity in a viable area withoutcalcifications to distinguish it from low-grade chondrosarcoma. Small peripherallesions are more likely to be benign than large axial lesions. The pathologic diagnosisis so difficult it always needs to be made in conjunction with the radiologist and thesurgeon.
A solitary painless enchondroma may be observed. Painful or worrisomelesions should be treated with biopsy followed by intralesional resection. Largedefects can be filled with bone graft. All specimens must be analyzed carefully formalignancy. Adamantinoma of the long bones, or extragnathic adamantinoma, is anextremely rare, low-grade malignant tumor of epithelial origin. It is not related toadamantinoma or ameloblastoma of the mandible and maxilla which is derived fromRathkes pouch. Adamantinoma is a locally aggressive osteolytic tumor. The site 90% of the time in the diaphysis of the tibia with the remaining lesionsfound in the fibula and long tubular bones. The tumor usually occurs in the second tofifth decade of life but may affect patients from ages 3 to 73. In 20% of cases thereare metastases late in the course of the disease. There is often a history of traumaassociated with adamantinoma but its role in the development of this lesion remainsunclear. The patient usually has swelling that may be painful. The duration ofsymptoms can vary from a few weeks to years. Adamantinoma appears as an eccentric, well-circumscribed, and lytic lesion onplain x-ray. The anterior cortex of the tibia is by far the most common location. Thelesion usually has several lytic defects separated by sclerotic bone which gives a"soap-bubble" appearance. There is cortical thinning but little periosteal reaction. Thelesion may break through the cortex and extend into soft tissue. There may bemultiple adjacent lesions with normal intervening bone. MRI helps demonstrate theintraosseus and extraosseous involvement. The differential diagnosis radiologicallyincludes osteofibrous dysplasia, fibrous dysplasia, ABC, chondromyxoid fibroma andchondrosarcoma . On gross examination, adamantinoma is well demarcated and lobulated. Thegray or white tumor is rubbery and may have focal areas of hemorrhage and necrosis.Bone spicules and cysts filled with blood or straw-colored fluid may also be present.Adamantinoma is a biphasic tumor with islands of epithelioid cells surrounded by abland reactive fibrous stroma. The stroma consists of spindle shaped collagenproducing cells. The nests of malignant cells are columnar and have peripheral
palisading. Squamous differentiation and keratin production are rare. The tumor ispositive on immunohistochemical staining with keratin antibody. The epithelialorigin is confirmed when basal membranes, desmosomes and ton filaments are seenunder the electron microscope. Osteofibrous dysplasia, or ossifying fibroma, is another lesion with a strikingpredilection for the tibia that has a well documented association with adamantinomaand may be a benign precursor to it. Adamantinoma is treated by wide surgical excision. This tumor is insensitiveto radiation and may metastasize to lungs, lymph nodes and abdominal organs byboth hematogenous and lymphatic routes. Chemotherapy is not used. Benign Fibrous Histiocytoma. This tumor has been given the names benignfibrous hystiocytoma, fibrous histiocytoma, xanthofibroma, fibroxanthoma of bone,and primary xanthoma of bone. Clinically, patients report pain from the lesion, oftenof months or years duration. Pain may be associated with pathological fracture. Theremay be some local tenderness, but no swelling or mass is seen, and there are nosystemic symptoms. There it is normally no impairment of the function of the nearbyjoint. Spinal lesions may cause neurologic defect by pressing on the spinal cord. In some cases there is a primary underlying disorder of cholesterol metabolismor other lipid abnormalities. In these cases the lytic bone lesions are analogous tothose seen in storage diseases such as Gauchers disease. These multiple lesions aretermed "xanthoma disseminatum". One reported case is of a 10 year old boy withlytic lesions in the pelvis, femur, and humerus, as well as yellow and brown papulesand plaques on the face and trunk. This patient also had polyuria and polydipsia, andwas found to have diabetes insipidus. Radiographically, the lesion occur commonly in the ribs, pelvis, including thesacrum and ilium, or in the epiphysis or diaphysis of tubular bones. These tumorshave been reported in the jaw and associated soft tissues. In another report this tumoroccurred commonly around the knee. It has a lytic, loculated appearance withprominent sclerosis of the edges of the lesion. There is no matrix mineralization. Thezone of transition of the lesion is narrow. Cortical expansion and soft tissue invasion
are rarely seen. The tumor may resemble non-ossifying fibroma, except that thepatients are older and have pain, and these lesions have more promenent marginalsclerosis. Some authors have report a periosteal reaction, but others do not. There isprominent marginal sclerosis which may have the appearance of periosteal reaction inlesions that are juxtacortical. CT scan shows a moderately irregular lytic area with an prominent trabecularpattern and surrounding sclerotic bone. On gross examination, the tumor tissue consists of a mixture of firm butunmineralized yellow-tan tissue and partially hemorrhagic red-brown tissue. Theyellow-tan tissue contains predominantly xanthic material. Histologically , the tumorconsists of fibroblasts and mononuclear or multinucleated cells that have theappearance of histiocytes. The tumor may contain large areas of "foam cells", lipid-filled cells with abundant vacuolated cytoplasm, interspersed with small fibrovascularseptations, as well as masses of cholesterol. No mitotic activity, cellular atypia, orpleomorphism is present. Treatment consists of careful and complete curettage and filling of the defectwith graft material, bone cement, or other suitable bone void filler. The risk ofrecurrence is variable depending on which series is consulted. Chondromyxoid Fibroma (CMF) is a benign cartilage tumor that also hasmyxoid and fibrous elements. It is extremely rare and accounts for less that 1% of allbone tumors. CMF is found most often in the metaphysis around the knee in theproximal tibia, proximal fibula, or distal femur. It presents in the second to thirddecade and has a male to female ratio of 2 to 1. The clinical presentation is usuallychronic pain, swelling and possibly a palpable soft tissue mass or restriction ofmovement. Only 5% of patients with CMF present with a pathological fractureюRadiological findings demonstrate an eccentrically placed lytic lesion with welldefined margins in the metaphysis of the lower extremity. The lesion usually has asclerotic margin of bone and a lobulated contour. Ridges and grooves that appear inthe margins secondary to scalloping falsely appear to be trabeculae. CT helps definecortical integrity and confirms that there is no mineralization of the matrix, unlike
other cartilage tumors. CMF has the same appearance on MRI as other cartilagetumors which is decreased signal on T 1 weighted images and increased signal on T2weighted images. MRI is helpful in preoperative planning and staging. The radiologicdifferential diagnosis includes giant cell tumor, aneurysmal bone cyst, unicameralbone cyst, chondroblastoma and fibrous dysplasia. CMF resembles fibrocartilage grossly. It has a sharp border often with an outersurface of thin bone or periosteum. The glistening grayish white lesion is firm andlobulated. It may also have small cystic foci or areas of hemorrhage. Histologically, CMF appears very similar to chondrosarcoma. They are soclose in histology that often radiology helps to make the final diagnosis. Thepredominant features of CMF are the zonal architecture and lobular pattern. Nodulesof cartilage are found in between fibromyxoid areas. In some fields the loose myxoiddominates and in other the dense chondroid dominates. The chondrocytes are plumpto spindly in shape and have indistinct cell borders in sparsely cellular lobules ofmyxoid or chondroid matrix. There are also more cellular zones of the tumor withsome giant cells at the edges. The sharp borders of each lobule and the lesion itselfhelp to differentiate it from chondrosarcoma. Treatment of CMF is en bloc excision. Recurrences after curettage arecommon. Giant cell tumor of bone: This type of primary bone tumor has benign andmalignant forms. The benign (non-cancerous) form is most common. These tumorstypically affect the leg (usually, near the knees) or arm bones of young and middle-aged adults. Fewer than 10% of giant cell bone tumors are initially cancerous andspread to other parts of the body, but after surgery giant cell bone tumors often recur(come back) locally (in the same place where the cancer started). When giant cellbone tumors recur, they become more likely to spread to other parts of the body,especially if they recur several times. Malignant bone tumors.
Multiple myeloma. Although multiple myeloma almost always starts in bones,doctors do not consider this a bone cancer because it develops from the plasma cellsof the bone marrow (the soft inner part of some bones). Although it causes bonedestruction, it is no more a bone cancer than is leukemia. It is treated as a widespreaddisease. At times, myeloma can be first found as a single tumor in a single bone, butmost of the time it will go on to spread to the marrow of other bones. Multiplemyeloma is the most common primary bone cancer. It is a malignant tumor of bonemarrow. Multiple myeloma affects approximately 20 people per million each year.Most cases are seen in patients between the ages of 50 and 70 years old. Any bonecan be involved. Osteosarcoma Osteosarcoma is the second most common bone cancer. It occurs in two orthree new people per million people each year. Most cases occur in teenagers. Othercommon locations include the hip and shoulder. Although osteosarcoma most oftenoccurs in young people between the age of 10 and 30, about 10% of cases develop inpeople in their 60s and 70s. This cancer is rare during middle age. More males thanfemales get this cancer. These tumors develop most often in bones of the arms, legs,or pelvis. Most tumors occur around the knee. Ewings sarcoma is named after Dr. James Ewing, who first described it in1921, most commonly occurs between 5 and 20 years of age. The most commonlocations are the upper and lower leg, pelvis, upper arm, and ribs. Ewing tumorsusually develop in bones, and less than 10% arise in other tissues and organs. Theymost often arise in the long bones of the legs and arms but may also develop in thepelvis and other bones. Ewing tumor is the third most common primary bone cancer.Unlike osteosarcoma, Ewing tumors of bone form in the cavity of the bone. Thiscancer usually appears in children and teenagers and is uncommon in adults over age30. Ewing tumors occur most often in white people and are rare among AfricanAmericans and Asian Americans. High grade angiosarcoma seems to have two distinct clinical presentations.First, the lesion can present as multiple lesions in a single bone, two or more adjacent
bones, or perhaps all the bones of a limb. These lesions seem to have an indolentcourse and the prognosis remains good. The second presentation is that of single ormultiple rapidly progressive lesions that metastasize to other bones or to the lung thisform of the disease has a very poor prognosis. This case illustrated the later type. The bone lesions of high grade angiosarcoma tend to be eccentric, purely lytic,metaphyseal and diaphyseal, with no visible matrix mineralization and focaldestruction of the cortex. They have a very aggressive appearance but there is noperiosteal reaction and very little soft-tissue extension, similar to what might be seenin metastatic lesions from lung. They tend to occur as multiple lesions in the samebone or contiguous bones, as shown in this case.
Chondroblastoma is a rare, benign tumor derived from chondroblasts. It isfound in the epiphysis of long bones, usually of the lower extremity. The mostcommon site is the distal femur followed by the proximal femur, proximal humerusand proximal tibia. The tumor has a preference for males over females and the meanage of presentation is approximately 20 years old. The tumor may have behavior notnormally associated with benign tumors including pulmonary metastases as well aslocal invasion of bone and soft tissue. Clinically, chondroblastoma presents as pain near a joint without history oftrauma. A secondary synovitis can be induced by the tumor, but pathological fractureis extremely rare. The diagnosis of chondroblastoma can usually be made by radiograph. whenthe age of the patient and location of the lesion are considered. The most commonsite for chondroblastoma is the epiphysis. The lesion is lytic with well definedmargins and can be from 1-6cm in size. Scalloping or expansion of cortical bone maybe present. Fine calcifications, either punctate or in rings, may be visible. Cysts arepresent about 20% of the time and both MRI and CT can define the fluid levels. CT isalso useful for defining the relationship of the tumor to the joint, integrity of thecortex, and intralesional calcifications. The differential diagnosis includesenchondroma, central chondrosarcoma and aneurysmal bone cyst. On grossexamination, a chondroblastoma has a lobulated, round form and is made up offriable, soft, grayish pink tissue that may be gritty. If present, the cystic fluid is rustor straw-colored. Chondroblastoma is made up of uniform, polygonal cells that areclosely packed. These primitive cells are derived from the epiphyseal cartilage plateand have abundant cytoplasm. There is little mitotic activity. A scant chondroidmatrix may be superimposed by a pericellular deposit of calcification that appearslike "chicken-wire". The rapid proliferation of immature chondrocytes does not createlacunae or formal cartilage matrix. Giant cells are often present.
Treatment of chondroblastoma is biopsy and curettage with possible use ofadjuvant liquid nitrogen or phenol, or a mechanical burr. It may be necessary toreconstruct articular surfaces due to subchondral erosion. Any joint invasion isusually secondary to previous instrumentation. All pulmonary nodules should beexcised. Fibrosarcoma is an uncommon, malignant spindle cell neoplasm. It appears inthe metaphysis or metadiaphysis of long bones. Fibrosarcoma is found mostcommonly around the knee in the distal femur and proximal tibia followed by thepelvis. The tumor produces a collagen matrix but does not produce osteoid orchondroid. Fibrosarcoma can be primary or secondary due to Pagets disease, fibrousdysplasia, irradiated giant cell tumor, bone infarct or chronic osteomyelitis.Fibrosarcoma occurs both as an intramedullary and periosteal lesion. It presents inadults age 30 to 60 years old and affects men and women equally. The most commonclinical presentation is that of a localized, painful mass. The radiologic picture offibrosarcoma is that of an osteolytic lesion. The margins can range from well-definedto ragged and moth-eaten. Periosteal reaction is seen with cortical destruction.Extension into the soft tissue is common. MRI helps define intraosseus spread andsoft tissue extension. Bone scan demonstrates increased uptake. The differentialdiagnosis includes leiomyosarcoma, metastatic carcinoma, melanoma, malignantfibrous histiocytoma and multiple myeloma. On gross examination the tumor is tan to grayish white with a rubberyconsistency. Larger tumors may have hemorrhagic and necrotic foci.
As with plain x-ray, the microscopic appearance of fibrosarcoma varies withthe level of differentiation. A well differentiated, low grade tumor has homogeneousspindle shaped fibroblasts with ovoid nuclei. There is little pleom orphism andinfrequent mitoses in this slow growing form. The "herring bone pattern" of fasciclesof cells is prominent. Poorly differentiated or high grade tumors have pleomorphiccells, abundant mitoses and hyperchromic nuclei. They metastasize early. Thecellularity of the tumor is generally in inverse proportion to the collagen production.Tumors are graded from 1 to 4 on cellularity, nuclear atypia and mitoses with highgrades carrying a worse prognosis. Treatment of fibrosarcoma includes radical surgical excision and adjuvantradiation therapy. Prognosis is largely dependent on the tumor grade. Fibrosarcomaand malignant fibrous histiocytoma is another type of cancer that develops moreoften in "soft tissues" than it does from bones. Fibrosarcoma usually occurs in elderlyand middle-aged adults. Bones most often affected include those of the legs, arms,and jaw. Malignant fibrous histiocytoma. This form of cancer occurs more often in"soft tissues" (types of connective tissues other than bone, such as ligaments, tendons,fat, and muscle) but can rarely start in bones. When it does develop in bones, itusually affects the legs (often around the knees) or arms. This cancer usually occursin elderly and middle-aged adults and is rare among children. Malignant fibroushistiocytoma (often abbreviated as MFH) tends to grow quickly. It often spreads toother parts of the body, most often to lymph nodes and to the lungs. Chondrosarcoma occurs most commonly in patients between 40 and 70 yearsof age. Most cases occur around the hip and pelvis or the shoulder. Chondrosarcomasare classified by their grades, a measure of how fast growing they are. This isdetermined by the pathologist (a doctor specially trained to examine and diagnosetissue samples under a microscope) who examines the chondrosarcoma under themicroscope. Most chondrosarcomas are low grade (grade I), meaning they are notlikely to spread, or intermediate grade (grade II). High grade (grade III)chondrosarcomas, which are the most likely to spread, are less common.
Some chondrosarcomas have distinctive features under a microscope. Some ofthese variants of chondrosarcoma tend to have a better prognosis (outlook forsurvival) than usual chondrosarcomas, and others tend to be more aggressive.Dedifferentiated chondrosacromas start out as typical chondrosarcomasbut then someparts of the tumor change into cells that closely resemble those of an osteosarcoma orfibrosarcoma. This variant of chondrosarcoma tends to occur in older patients and ismore aggressive than usual chondrosarcomas. In contrast, clear cell chondrosarcomais a rare variant that grows slowly and rarely spreads to other parts of the body unlessit has already recurrent several times in the original location. Mesenchymalchondrosarcoma shares some similarities with Ewing tumor. Although these tumorscan grow rapidly, they are sensitive to radiotherapy and chemotherapy. Chondrosarcoma. This is a cancer of cartilage cells and is the second mostcommon primary bone cancer. This cancer is uncommon in people younger than 20.After age 20, the risk of developing chondrosarcoma continues to rise until reachingabout 75 years. Men and women are equally likely to get this cancer. Chordoma is a rare malignant tumor that arises from notochord remnants.Chordomas account for 1 to 4% of all bone tumors. They occur in older adults withthe highest prevalence in the fifth to seventh decade. The ratio of male to female istwo to one. Due to their origin in the notochord, chordomas occur in the mid-line ofthe axial skeleton. One half of cases occur in the sacrococcygeal region and one thirdoccur at the base of the skull. Other rare sites include transverse processes ofvertebrae and the paranasal sinuses. The clinical presentation depends on the location of the tumor. Sacrococcygealtumors often present as low back pain with no characteristic pattern or time course.Sacrococcygeal tumors can also present as bowel and bladder dysfunction. Presacraltumors can sometimes be palpated on rectal exam. Sacral tumors are often large atpresentation as a large volume of tumor can be accommodated within the pelvis.Anterior cervical tumors can present as dysphagia and posterior cervical tumors cancause neurological deficits. Tumors at the base of the skull may present withheadaches.
On plain X-ray, chordomas appear as a solitary mid-line lesion with bonydestruction. There is often an accompanying soft tissue mass. Approximately half ofthe time focal calcifications are present. CT and MRI scans help demonstrate the softtissue component, calcifications and epidural extension. MRI is helpful in identifyinglocal recurrences. Chordomas have reduced uptake on bone scan. On gross examination, chordomas are soft, blue-gray, lobulated tumors. Thereare gelatinous translucent areas and often a capsule is present. The lesion often tracksalong nerve roots in the sacral plexus or out the sciatic notch in planes of leastresistance. Under the microscope, the chordomas are characterized by lobules and fibroussepta. The malignant cell has eosinophilic cytoplasm. Prominent vacuoles of mucuspush the nuclei to the side resulting in "physaliphorous" cells from the Greek wordfor bubble or drop. During the fourth to sixth week of fetal development mesenchymal cells fromindividual sclerotomes merge to surround the notochord and form the vertebralbodies. The notochord normally degenerates and remnants form the nucleus pulposusof the vertebral disc. The prevailing theory is that in chordomas the notochord fails todegenerate and then undergoes malignant transformation. The major failing of thistheory is that normal notochord remnants have never been observed. The treatment of chordomas is difficult. Wide surgical excision is desirable butrarely feasible based on the anatomic location of the tumor. With sacrococcygealtumors, sexual function and sphincter control may be compromised after surgery.Radiation is used if complete resection is impossible. Chordomas metastasize tolymph nodes, lungs, liver and bone. Chemotherapy can be used for late stage disease.