Ministry of Public Health of Ukraine

National O.O.Bohomolets Medical University

Oncology Department

Study Guide

of the Lecture Course “Oncology”

Part II

For the students of medical faculties

Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD, DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.

Kyiv - 2008

Ministry of Public Health of Ukraine

National O.O.Bohomolets Medical University

Oncology Department

“APPROVED”

Vice-Rector for Educational Affairs

Professor O. Yavorovskiy

______________

“___” __________ 2008

Study Guide

of the Lecture Course “Oncology”

Part II

For the students of medical faculties

Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD, DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.

Kyiv - 2008

The texts of the lectures are approved by the methodical counsel

of Oncology Department.

Protocol № 19 « 17 » march 2008.

CONTENTS

Lecture 8

Gastric cancer

Lecture 9

Colorectal cancer

Lecture 10

Pancreatic Cancer. Liver cancer. Gallbladder cancer.

Lecture 11

Tumors of the bones

Lecture 8

Gastric cancer

Incidence

· The crude incidence of gastric cancer in the European Union has been decreasing during the last decades and currently is approximately 18.9/100 000 per year, the mortality 14.7/100 000 per year with about 1.5 times higher rates for males than females and with a peak incidence in the seventh decade.

· The most higher incidence of gastric cancer was observed in Japan (59/100 000 per year ) and Finland (49/100 000 per year )

· In Ukraine gastric cancer takes third place in males and forth place in females among all oncology diseases.

· In Ukraine 27/100 000 per year, 35/100 000 per year for males and 20/100 000 per year for females. The mortality 21.7/100 000 per year, 28,4/100 000 per year for males and 15/100 000 per year for females.

Etiology

· Infection with Helicobacter pylori enhances the risk of gastric cancer. Other risk factors include:

· Male sex

· Daly intake food with large concentration of nitrites, nitrates and salt

· Pernicious anemia

· Smoking

· Menetrier’s disease

· Genetic factors such as hereditary non-polyposis colon cancer

· Patients after surgical treatment of gastric ulcer disease: resection of stomach and vagotomy.

Anatomy.

The stomach is a muscular organ that functions in storage and digestion. It has three parts and two sphincteric mechanisms (gastroesophageal, pylorus). In accordance with Japanes classification, stomach is divaded into three part –upper (C), medium (M), lower (A).

Fig. 1. Parts of the stomach.

· 1. Cardia

· 2. Fundus –C part

· 3. Body– M-part

· 4. Antrum – A-part

· 5. Pilorus

Microscopic anatomy.

The stomach has four layers and three distinct mucosal areas.

The layers of the stomach wall are serosa, muscularis, muscularis mucosae, and mucosa. The layers of muscle fibers are longitudinal, oblique, and circular.

The divisions of the mucosa correspond to the gross divisions of cardia, body, and antrum.

1. The cardiac gland area js a glands secrete mucus.

2. The parietal cell area comprises the proximal three-quarters of the stomach. Four types of cells are found in its glands:

· Mucous cells secrete an alkaline mucous coating for the epithelium. This 1mm-thick coating primarily facilitates food passage. It also provides some mucosal protection.

· Zygomatic or chief cells secrete pepsinogen. They are found deep in the fundic glands. Pepsinogen is the precursor to pepsin, which is active in protein digestion. Chief cells are stimulated by cholinergic impulses, by gastrin, and by secretin.

· Oxyntic or parietal cells produce hydrochloric acid and intrinsic factor. They are found exclusively in the fundus and body of the stomach. They are stimulated to produce hydrochloric acid by gastrin.

· Argentaffin cells are scattered throughout the stomach. Their function is unclear

3. The pyloroantral mucosa is found in the antrum of the stomach.

· Parietal and chief cells are absent here.

· C cells, which secrete gastrin, are found in this area. They are part of the amine precursor uptake and decarboxylase (APUD) system of endocrine cells. Gastrin is a hormone that causes the secretion of hydrochloric acid and pepsinogen in the stomach. It also influences gastric motility.

Innervation. The nervous supply of the stomach is via parasympathetic and sympathetic fibers.

· The parasympathetic supply is through the vagus nerves. The anterior or left vagus supplies the anterior portion of the stomach. The posterior or right vagus supplies the posterior stomach. The vagi contribute to gastric acid secretion both by direct action on parietal cell secretion and by stimulating the antrum to release gastrin. They also contribute to gastric motility.

· The sympathetic innervation is via the greater splanchnic nerves. These terminate in the celiac ganglion, and postganglionic fibers travel with the gastric arteries to the stomach. The sympathetic afferent fibers are the pathway for perception of visceral pain.

Vasculature

Arterial supply to the stomach is via the right and left gastric arteries, the right and left gastroepiploic arteries, and the vasa brevia.

1. The right gastric artery is a branch of the common hepatic artery and supplies the lesser curvature.

2. The left gastric artery is a branch of the celiac axis and supplies the lesser curvature.

3. The right gastroepiploic artery is a branch of the gastroduodenal artery and supplies the greater curvature.

4. The left gastroepiploic artery is a branch of the splenic artery and supplies the greater curvature.

5. The vasa brevia arise from either the splenic artery or the left gastroepiploic artery . and supply the fundus.

Venous drainage of the stomach is both portal and systemic.

1. The right and left gastric and gastroepiploic veins accompany their corresponding arteries. They drain into the portal system.

2. The left gastric vein also has multiple anastomoses with the lower esophageal venous plexus. These drain systemically into the azygous vein.

Fig. 2. Regional lymph nodes of the stomach (part 1)

Lymphatic drainage of the stomach is extensive. Lymph nodes that drain the

stomach are found at the cardia (1,2) along the lesser and greater curvatures (3,4a,b), supra and infra pyloric (5,6). This is perigastric stations.

Fig. 3. Additional Regional lymph nodes of the stomach (part 2)

Additional regional lymph nodes stations are also: along left gastric artery (7), common hepatic artery (8), Lineal (splenic) artery (10,11), celiac

Trunk (9) and hepatica-duodenal lymph nodes (12).

Histology

Approximately 90%-95% of gastric tumors are malignant and of the

malignancies, 95% are carcinomas.

Gastric adenocarcinoma is divided on two types: intestinal and diffuse

1. intestinal (epidemic) type is retained glandular structure and cellular polarity, it usually has a sharp margin. It arises from the gastric mucosa and is associated with chronic gastritis, atrophy and intestinal metaplasia. It correspond with papillary and tubular groups

2. Diffuse type has little glandular formation. Mucin production is common. It correspond with mucinous and signet ring cell groups.

Gastric carcinoma is classified according to its gross characteristics.

1. Fungating. These are the least common lesions and have a better prognosis.

2. Ulcerating. These are the commonest.

3. Diffusely infiltrating (linitis plastica). The tumor causes extensive submucosal infiltration.

Other malignances of the stomach

Gastric lymphoma can be primary or can occur as part of disseminated disease. The stomach is the commonest site of primary intestinal lymphoma. The tumors may be bulky with central ulceration.

Diagnosis preoperatively is crucial since the surgical approach differs markedly from that used with gastric cancer.

Surgical treatment involves local resection (partial gastrectomy). Most lesions also require treatment with radiation therapy, chemotherapy, or both.

Prognosis is good with 5-year survival up to 90%.

Leiomyosarcomas are bulky, well-localized tumors. They are slow to metastasize and can be treated with partial gastrectomy.

Benign tumors

1. Leiomyomas are the commonest benign gastric tumors. They are usually asymptomatic but may undergo hemorrhage or cause a mass effect. They are submucosal and well encapsulated.

2. Gastric polips are of two tipes. They often can be excised via endoscope.

· Hyperplastic polips are the commonest and are not premalignant

· Adenomatous polips are associated with a high risk of malignancy, especially those greater then 1.5 cm.

3. Other benign tumors are fibromas, neurofibromas, aberrant pancreas, and angiomas.

TNM – classification.

Fig. 4. T – tumor, T1- tumor involve mucosa and submucosa, T-2 tumor invade the muscularis propria

Fig. 5. TNM – classification. T – tumor, T2

· Tumor invasion of mucosa and muscularis layers

· T2a –up to muscularic

· T2b –up to serosa

Fig. 6. TNM – classification. T – tumor, T3

· Tumor invasion of mucosa, muscularic and serosa layers

Fig. 7. TNM – classification. T – tumor, T3

Tumor invasion of mucosa, muscularic and serosa layers

Fig. 8. TNM – classification. T – tumor, T3,4

· T3 - Tumor invasion of mucosa, muscularic and serosa layers

· T4 – tumor invasion up to adjusting organs

Fig. 9. TNM – classification. N – nodules, N-1

· N1- 1-6 lymph nodes with tumor

Fig. 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 tumor

Fig. 12. TNM – classification. M – metastases, M-1

· M0- no metastases

· M1 – obtained distant metastases

Table 1. TNM 2002 (5-th edition) and AJCC stage grouping

Stage

T

N

M

I A

T1

N0

M0

I B

T1

N1

M0

T2a,T2b

N0

M0

II

T1

N2

M0

T2a,T2b

N1

M0

T3

N0

M0

IIIA

T2a,T2b

N2

M0

T3

N1

M0

T4

N0

M0

IIIB

T3

N2

M0

IV

T4

N1,N2,N3

M0

T1,T2,T3

N3

M0

Any T

Any N

M1

Clinical manifestations

Due to the fact that both the stomach and abdominal cavity

are large to distention the symptoms of gastric cancer are obtained at

an advanced stage.

Early symptoms such us vague gastrointestinal distress, nausea,

vomiting and anorexia are common for different diseases.

The most common symptoms at diagnosis are

· Abdominal pain (65%)

· Weight loss (40%)

· Anemia (17%)

· Dysphagia in patients with proximal cancer localization

· Early satiety

· Gastrointestinal bleeding

Diagnosis

· Physical examination

· laboratory stadies, endoscopic ultrasonography

· Endoscopies with biopsy

· chest X-ray and barium swallow (Fig. 13,14)

· CT-scan of the abdomen

· laparoscopy

· CEA, CA-125

Fig. 13. Radiologic examination of the stomach. Double contrast study. The arrows outline the area of irregular mucosa which was caused by an invasive gastric carcinoma.

The stomach is temporarily paralyzed by administration of glucagon, filled with dense barium, and distended with gas using effervescent granules. Hence both barium and air are used for contrast. Images are obtained as the patient rolls in various positions to coat the gastric mucosa with contrast. Double-contrast technique provides improved visualization of the gastric mucosa.

Fig. 14. Radiologic examination of the stomach. Single contrast study from the same patient showing the apple core appearance of the stomach due to the invasive gastric adenocarcinoma

The stomach is filled and distended with dilute barium or a water-soluble contrast agent. Water-soluble contrast should be used when perforation or post-operative anastomotic failure is suspected. The stomach is compressed either manually or by positioning to allow for adequate x-ray penetration in the evaluation of each anatomical segment. Single-contrast technique assesses thickness of the gastric folds and evaluation of gastric emptying. Large luminal defects can be detected.

· Diagnosis should be made from a gastroscopic or surgical biopsy and the histology given according to the World Health Organisation criteria.

Fig. 15. Gastroscopic examination of the stomach.

Staging and risk assessment

· Staging consists of clinical examination, blood counts, liver and renal function tests, chest X-ray and CT-scan of the abdomen, as well as of endoscopy. Endoscopic ultrasound and laparoscopy may help to optimally determine resectability. The stage is to be given according to the TNM 2002 system and the AJCC stage grouping, as shown in Table 1.

Surgery

· Multi-disciplinary treatment planning is mandatory. Surgical resection is the only potentially curative option and is recommended for stages Tis-T3N0-N2M0 or T4N0M0.

· The choice for gastric resection include segmental resection, distal subtotal, total and proximal subtotal gastrectomy and is dependent upon the location of the tumor, its histologic type and stage of desease.

· Endoscopic mucosal resection is recommended for very early cancers without nodal involvement

· The extent of regional lymphadenectomy required for optimal results is still debated. Randomized trials have failed to prove the superiority of D2 over D1 resection but a minimum of 14, optimally at least 25 lymph nodes should be recovered.

Fig. 16. Total and subtotal gastrectomy

Fig. 17. Gastrojejunostomy after subtotal gastrectomy

Fig. 18. Reconstruction after total gastrectomy with Roux limb

Fig. 19. Reconstruction after total gastrectomy splenectomy and distal pancreatectomy 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, ECF

Treatment of locally advanced disease (stage III: T3-4, N1)

· Some patients with locally advanced disease may benefit from preoperative chemotherapy with down-staging and higher rates of resectability but the results of phase II trials are conflicting and no optimal regimen has yet been defined.

· Other patients may be treated as those with localized disease (see above).

· Therapy for patients with incomplete resection remains palliative.

Treatment of metastatic disease (stage IV)

· Patients with stage IV disease should be considered for palliative chemotherapy. Combination regimens incorporating cisplatin, 5-fluorouracil with or without anthracyclines are generally used.

· Epirubicin 50 mg/m2, cisplatin 60 mg/m2 and protracted venous infusion 5-fluorouracil 200 mg/m2/day (ECF) is one among the most active and well tolerated combination chemotherapy regimens.

· Alternate regimens including oxaliplatin, irinotecan, docetaxel, and oral fluoropyrimidines can be considered.

Follow-up

· There is no evidence that regular intensive follow up after initial therapy improves the outcome. Symptom-driven visits are recommended for most cases.

· History, physical examination, blood tests should be performed, if symptoms of relapse occur. Radiological investigations should be considered for patients who are candidates for palliative chemotherapy. Note Levels of Evidence and Grades of Recommendation as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.

Prognosis

Prognosis depends largely on the depth of invasion of the gastric wall, involvement of regional nodes and the presents of distant metastases but still remains poor. Tumor not penetrating the serosa and not involving the regional nodes are associated with approximately 70% 5-year survival. This number drops dramatically if the tumor is through the serosa or into regional nodes. Only 40% of patients have potentially curable disease at the time of diagnosis.

5-year survival

· Stage I – 75%

· Stage II – 46%

· Stage III – 28%

· Stage IV – 12%

Lecture 9

Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. It is the third most common form of cancer and the second leading cause of cancer-related death in the Western world. Colorectal cancer causes 655,000 deaths worldwide per year. Many colorectal cancers are thought to arise from adenomatous polyps in the colon. These mushroom-like growths are usually benign, but some may develop into cancer over time. The majority of the time, the diagnosis of localized colon cancer is through colonoscopy. Therapy is usually through surgery, which in many cases is followed by chemotherapy.

Symptoms

Colon cancer often causes no symptoms until it has reached a relatively advanced stage. Thus, many organizations recommend periodic screening for the disease with fecal occult blood testing and colonoscopy. When symptoms do occur, they depend on the site of the lesion. Generally speaking, the nearer the lesion is to the anus, the more bowel symptoms there will be, such as:

· Change in bowel habits

· change in frequency (constipation and/or diarrhea),

· change in the quality of stools

· change in consistency of stools

· Bloody stools or rectal bleeding

· Stools with mucus

· Tarry stools (melena) (more likely related to upper gastrointestinal eg stomach or duodenal disease)

· Feeling of incomplete defecation (tenesmus) (usually associated with rectal cancer)

· Reduction in diameter of feces

· Bowel obstruction (rare)

Constitutional symptoms

Especially in the cases of cancer in the ascending colon, sometimes only the less specific constitutional symptoms will be found:

· Anemia, with symptoms such as dizziness, malaise and palpitations. Clinically there will be pallor and a complete blood picture will confirm the low hemoglobin level.

· Anorexia

· Asthenia, weakness

· Unexplained weight loss.

Metastatic symptoms

There may also be symptoms attributed to distant metastasis:

· Shortness of breath as in lung metastasis

· Epigastric or right upper quadrant pain, as in liver metastasis.

Risk factors

The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person's risk of developing the disease. These include:

· Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.

· Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.

· History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.

· Heredity:

· Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives

· Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated

· Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome

· Long-standing ulcerative colitis or Crohn's disease of the colon, approximately 30% after 25 years if the entire colon is involved

· Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that "Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked."

· Diet. Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently ate fish showed a decreased risk. However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding. The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.

· Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.

· Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.

· Alcohol. See the subsection below.

· Primary sclerosing cholangitis offers a risk independent to ulcerative colitis

· Low selenium.

· Inflammatory Bowel Disease. About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.

· Environmental Factors. Industrialized countries are at a relatively increased risk compared to less developed countries or countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk.

· Exogenous Hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens. There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast,there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.

Alcohol

One study found that "People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer." Another found that "The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer."

One study found that "While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.".

Other research suggests that "to minimize your risk of developing colorectal cancer, it's best to drink in moderation"

Drinking may be a cause of earlier onset of colorectal cancer.

Diagnosis, screening and monitoring

Endoscopic image of colon cancer identified in sigmoid colon on screening colonoscopy in the setting of Crohn's disease.

Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the chances of a cure. Therefore, screening for the disease is recommended in individuals who are at increased risk. There are several different tests available for this purpose.

· Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.

· Fecal occult blood test (FOBT): a test for blood in the stool.

· Endoscopy:

· Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and lower colon to check for polyps and other abnormalities.

· Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be immediately removed. Tissue can also be taken for biopsy.

Other screening methods

· Double contrast barium enema (DCBE): First, an overnight preparation is taken to cleanse the colon. An enema containing barium sulfate is administered, then air is insufflated into the colon, distending it. The result is a thin layer of barium over the inner lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can be detected this way. This technique can miss the (less common) flat polyp.

· Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above) with a special computed tomography scan and requires special workstation software in order for the radiologist to interpret. This technique is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.

· Standard computed axial tomography is an x-ray method that can be used to determine the degree of spread of cancer, but is not sensitive enough to use for screening. Some cancers are found in CAT scans performed for other reasons.

· Blood tests: Measurement of the patient's blood for elevated levels of certain proteins can give an indication of tumor load. In particular, high levels of carcinoembryonic antigen (CEA) in the blood can indicate metastasis of adenocarcinoma. These tests are frequently false positive or false negative, and are not recommended for screening, it can be useful to assess disease recurrence.

· Genetic counseling and genetic testing for families who may have a hereditary form of colon cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP).

· Positron emission tomography (PET) is a 3-dimensional scanning technology where a radioactive sugar is injected into the patient, the sugar collects in tissues with high metabolic activity, and an image is formed by measuring the emission of radiation from the sugar. Because cancer cells often have very high metabolic rate, this can be used to differentiate benign and malignant tumors. PET is not used for screening and does not (yet) have a place in routine workup of colorectal cancer cases.

· Whole-Body PET imaging is the most accurate diagnostic test for detection of recurrent colorectal cancer, and is a cost-effective way to differentiate resectable from non-resectable disease. A PET scan is indicated whenever a major management decision depends upon accurate evaluation of tumour presence and extent.

· Stool DNA testing is an emerging technology in screening for colorectal cancer. Pre-malignant adenomas and cancers shed DNA markers from their cells which are not degraded during the digestive process and remain stable in the stool. Capture, followed by Polymerase Chain Reaction amplifies the DNA to detectable levels for assay. Clinical studies have shown a cancer detection sensitivity of 71%-91%.

Pathology

Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.

The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.

Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.

Histopathology: Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.

Staging

Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is performed for diagnostic and research purposes, and to determine the best method of treatment. The systems for staging colorectal cancers largely depend on the extent of local invasion, the degree of lymph node involvement and whether there is distant metastasis.

Definitive staging can only be done after surgery has been performed and pathology reports reviewed.

Dukes' system

Dukes' classification, first proposed by Dr Cuthbert E. Dukes in 1932, identifies the stages as:

· A - Tumour confined to the intestinal wall

· B - Tumour invading through the intestinal wall

· C - With lymph node(s) involvement

· D - With distant metastasis

TNM system

Main article: TNM

The most common current staging system is the TNM (for tumors/nodes/metastases) system, though many doctors still use the older Dukes system. The TNM system assigns a number:

· T - The degree of invasion of the intestinal wall

· T0 - no evidence of tumor

· Tis- cancer in situ (tumor present, but no invasion)

· T1 - invasion through submucosa into lamina propria (basement membrane invaded)

· T2 - invasion into the muscularis propria (i.e. proper muscle of the bowel wall)

· T3 - invasion through the subserosa

· 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

· N0 - no lymph nodes involved

· N1 - one to three nodes involved

· N2 - four or more nodes involved

· M - the degree of metastasis

· M0 - no metastasis

· M1 - metastasis present

AJCC stage groupings

The stage of a cancer is usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and likely a worse outcome.

· Stage 0

· Tis, N0, M0

· Stage I

· T1, N0, M0

· T2, N0, M0

· Stage IIA

· T3, N0, M0

· Stage IIB

· T4, N0, M0

· Stage IIIA

· T1, N1, M0

· T2, N1, M0

· Stage IIIB

· T3, N1, M0

· T4, N1, M0

· Stage IIIC

· Any T, N2, M0

· Stage IV

· Any T, Any N, M1

Pathogenesis

Colorectal cancer is a disease originating from the epithelial cells lining the gastrointestinal tract. Hereditary or somatic mutations in specific DNA sequences, among which are included DNA replication or DNA repair genes, and also the APC, K-Ras, NOD2 and p53 genes, lead to unrestricted cell division. The exact reason why (and whether) a diet high in fiber might prevent colorectal cancer remains uncertain. Chronic inflammation, as in inflammatory bowel disease, may predispose patients to malignancy.

Treatment

The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However when it is detected at later stages (when distant metastases are present) it is less likely to be curable.

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient's staging and other medical factors.

Surgery

Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.

Curative Surgical treatment can be offered if the tumor is localized.

· Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.

· In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.

· Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.

In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.

If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.

The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures would do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to "open and close" procedures are now diagnosed in advance and surgery avoided.

Laparoscopic-assisted colectomy is a minimally-invasive technique that can reduce the size of the incision, minimize the risk of infection, and reduce post-operative pain.

As with any surgical procedure, colorectal surgery may result in complications including

· wound infection, Dehiscence (bursting of wound) or hernia

· anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis

· bleeding with or without hematoma formation

· adhesions resulting in bowel obstruction (especially small bowel)

· blind loop syndrome as in bypass surgery.

· adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder

· Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc

Chemotherapy

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy if surgery is not indicated (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration.

· Adjuvant (after surgery) chemotherapy. One regimen involves the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)

· 5-fluorouracil (5-FU) or Capecitabine

· Leucovorin (LV, Folinic Acid)

· 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

· 5-fluorouracil (5-FU) or Capecitabine

· Leucovorin (LV, Folinic Acid)

· Irinotecan (Camptosar)

· Oxaliplatin (Eloxatin)

· Bevacizumab (Avastin)

· Cetuximab (Erbitux)

· Panitumumab (Vectibix)

· In clinical trials for treated/untreated metastatic disease.

· Bortezomib (Velcade)

· Oblimersen (Genasense, G3139)

· Gefitinib and Erlotinib (Tarceva)

· Topotecan (Hycamtin)

Radiation therapy

Radiotherapy is not used routinely in colon cancer and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:

· Colon cancer

· pain relief and palliation - targeted at metastatic tumor deposits if they compress vital structures and/or cause pain

· Rectal cancer

· 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)

· adjuvant - where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke's B or C tumors)

· palliative - to decrease the tumor burden in order to relieve or prevent symptoms

Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.

Treatment of colorectal cancer metastasis to the liver

According to the American Cancer Society statistics in 2006 greater than 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.

Resectability of a liver met is determined using preoperative imaging studies (Ct or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic "segments", while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic "wedge" resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimines. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.

Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.

Poor pronostic factors of patients with liver metastasis include

· Synchronous (diagnosed simultaneously) liver and primary colorectal tumors

· A short time between detecting the primary cancer and subsequent development of liver mets

· Multiple metastatic lesions

· High blood levels of the tumor marker, carcino-embryonic antigen (CEA), in the patient prior to resection

· Larger size metastatic lesions

Follow-up

The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that develop later but did not originate from the original cancer (metachronous lesions).

A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.

Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. These guidelines are based on recent meta-analyses showing that intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.

Surveillance

Most colorectal cancer arise from adenomatous polyps. These lesions can be detected and removed during colonoscopy. Studies show this procedure would decrease by > 80% the risk of cancer death, provided it is started by the age of 50, and repeated every 5 or 10 years.

Lecture 10

Pancreatic Cancer. Liver cancer. Gallbladder cancer.

I. Pancreatic Cancer

Epidemiology

Incidence

· The crude incidence and mortality of pancreatic cancer in the European Union is about 11/100 000 per year.

· In around 5% of patients some genetic basis for the disease can be found.

· In the United States, the incidence of pancreatic cancer is 9 cases per 100,000 population.

· In theUkraine, the incidence of pancreatic cancer is 9,7 cases per 100,000 population.

· Pancreatic cancer is primarily a disease associated with advanced age, with 80% of cases occurring between the ages of 60 and 80.

· Men are almost twice as likely to develop this disease than women.

· Countries with the highest frequencies of pancreatic cancer include the US, New Zealand, Western European nations, and Scandinavia.

· The lowest occurrences of the disease are reported in India, Kuwait and Singapore.

Etiology and risk factors.

1. Cigarette smoking. The risk increases with increasing duration and amount of cigarette smoking. The excess risk levels off 10 to 15 years after cessation of smoking. The risk is ascribed to tobacco-specific nitrosamines.

2. Diet. A high intake of fat, meat, or both is associated with increased risk, whereas the intake of fresh fruits and vegetables appears to have a protective effect.

3. Partial gastrectomy appears to correlate with a two to five times higher than expected incidence of pancreatic cancer 15 to 20 years later. The increased formation of N-nitroso compounds by bacteria that produce nitrate reductase and proliferate in the hypoacidic stomach has been proposed to account for the increased occurrence of gastric and pancreatic cancer after partial gastrectomy.

4. Cholecystokinin is the primary hormone that causes growth of exocrine pancreatic cells; others include epidermal growth factor and insulin-like growth factors. Pancreatic cancer has been induced experimentally by long-term duodenogastric reflux, which is associated with increased cholecystokinin levels. Some clinical evidence suggests that cholecystectomy, which also increases the circulating cholecystokinin, may increase the risk for pancreatic cancer.

5. Diabetes mellitus may be an early manifestation of pancreatic cancer or a predisposing factor. It is found in 13% of patients with pancreatic cancer and in only 2% of controls.

6. Chronic and hereditary pancreatitis are associated with pancreatic cancer. Chronic pancreatitis is associated with a 15-fold increase in the risk for pancreatic cancer.

7. Toxic substances. Occupational exposure to 2-naphthylamine, benzidine, and gasoline derivatives is associated with a five-fold increased risk for pancreatic cancer. Prolonged exposure to DDT and two DDT derivatives (ethylan and DDD) is associated with a four-fold to seven-fold increased risk for pancreatic cancer.

8. Socioeconomic status. Pancreatic cancer occurs in a slightly higher frequency in populations of lower socioeconomic status.

9. Coffee. Analysis of 30 epidemiologic studies showed that only one case-control study and none of the prospective studies confirmed a statistically significant association between coffee consumption and pancreatic cancer.

10. Idiopathic deep-vein thrombosis is statistically correlated with the subsequent development of mucinous carcinomas (including pancreatic cancer), especially among patients in whom venous thrombosis recurs during follow-up.

11. Dermatomyositis and polymyositis are paraneoplastic syndromes associated with pancreatic cancer and other cancers.

12. Familial pancreatic cancer. It is estimated that 3% of pancreatic cancers are linked to inherited predisposition to the disease.

Pathology

Nonepithelial tumors (sarcomas and lymphomas) are rare.

Ductal adenocarcinoma makes up 75% to 90% of malignant pancreatic neoplasms: 57% occur in the head of the pancreas, 9% in the body, 8% in the tail, 6% in overlapping sites, and 20% in unknown anatomic subsites. Uncommon but reasonably distinctive variants of pancreatic cancer include adenosquamous, oncocytic, clear cell, giant cell, signet ring, mucinous, and anaplastic carcinoma. Anaplastic carcinomas often involve the body and tail rather than the head of pancreas. Reported cases of pure epidermoid carcinoma (a variant of adenosquamous carcinoma) probably are associated with hypercalcemia.

Cystadenocarcinomas have an indolent course and may remain localized for many years. Ampullary cancer (which carries a significantly better prognosis), duodenal cancer, and distal bile duct cancer may be difficult to distinguish from pancreatic adenocarcinoma.

Metastatic tumors. Autopsy studies show that for every primary tumor of the pancreas, four metastatic tumors are found. The most common tumors of origin are the breast, lung, cutaneous melanoma, and non-Hodgkin’s lymphoma.

Genetic abnormalities. Mutant c-K-ras genes have been found in most specimens of human pancreatic carcinoma and their metastases.

Diagnosis

Symptoms.

Most patients with pancreatic cancer have symptoms at the time of diagnosis.

Predominant initial symptoms include

· abdominal pain (80%);

· anorexia (65%);

· weight loss (60%);

· early satiety (60%);

· jaundice (50%);

· easy fatigability (45%);

· xerostomia and sleep problems (55%);

· weakness, nausea, or constipation (40%);

· depression (40%); dyspepsia (35%);

· vomiting (30%); hoarseness (25%);

· taste change, bloating, or belching (25%);

· dyspnea, dizziness, or edema (20%);

· cough, diarrhea because of fat malabsorption, hiccup, or itching (15%);

· dysphagia (5%).

Clinical findings.

· At presentation, patients with pancreatic cancer have cachexia (44%),

· palpable abdominal mass (35%),

· ascites (25%),

· supraclavicular adenopathy (5%).

· serum albumin concentration of less than 3.5 g/dL (35%),

Metastases are present to at least one major organ in 65% of patients: to the liver in 45%, to the lungs in 30%, and to the bones in 3%.

Carcinomas of the distal pancreas do not produce jaundice until they metastasize and may remain painless until the disease is advanced.

Occasionally, acute pancreatitis is the first manifestation of pancreatic cancer.

Paraneoplastic syndromes.

Panniculitis-arthritis-eosinophilia syndrome that occurs with pancreatic cancer appears to be caused by the release of lipase from the tumor. Dermatomyositis, polymyositis, recurrent Trousseau’s syndrome or idiopathic deep-vein thrombosis, and Cushing’s syndrome have been reported to be associated with cancer of the pancreas.

Methodes of diagnostic:

1. Ultrasonography

2. CT

3. MRI

4. Endoscopic retrograde cholangiography

5.Percutaneous fine-needle aspiration cytology

6. Angiography

7.Laparoscopy

8.Tumor markers:

a. CA 19-9

b. CEA

Staging

Stage

Primary

tumor

Lymph

nodes

Distant

mets

5-year

survival

Stage 0

Tis

N0

M0

–

Stage I

T1-2

N0

M0

5–35%

Stage II

T3

N0

M0

2–15%

Stage III

T1-3

N1

M0

2–15%

Stage IVA

T4

Any N

M0

1–5%

Stage IVB

Any T

Any N

M1

<1%

TREATMENT

Surgery.

Only 5% to 20% of patients with pancreatic cancer have resectable tumors at the time of presentation

Pancreaticoduodenectomy, the Whipple’s procedure, is the standard surgical treatment for adenocarcinoma of the head of the pancreas when the lesion is curable 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 a gastrojejunostomy, choledochojejunostomy, and pancreaticojejunostomy.

The operative mortality rate with this extensive operation can be as high as 15%.

The complication rate is also considerable, the commonest complications being hemorrhage, abscess, and pancreatic ductal leakage.

Distal pancreatectomy, usually with splenectomy and lymphadenectomy, is the procedure performed for carcinoma of the midbody and tail of the pancreas.

Total pancreatectomy has been proposed for the treatment of pancreatic cancer.

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 has not 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 because so many of these tumors are incurable. Palliative procedures attempt to relieve biliary obstruction by using either the common bile duct or the gallbladder as a conduit for decompression 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 a response (temporary tumor regression or, rarely, cure) in about 20%-25% of the patients with metastases.

Radiation therapy

is sometimes used to shrink a tumor before surgery or to remove remaining cancer cells after surgery. Radiation may also be used to relieve pain or digestive problems caused by the tumor if it cannot be removed by surgery.

Prognostic factors.

Fewer than 20% of patients with adenocarcinoma of the pancreas survive the first year, 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; the reported range is 3% to 25%. The 5-year survival is 30% for patients with small tumors (2 cm or less in diameter), 35% for patients with no residual tumor or for patients 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 higher performance 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 death in the world, occurring most commonly in Africa and Asia. Up to 1 million deaths due to hepatocellular carcinoma (HCC) occur each year worldwide. In the United States, 16,000 new cases of cancer of the liver and biliary passages develop annually. Incidence throughout the world varies dramatically with 115 cases per 100,000 people noted in China and Thailand, compared with 1 to 2 cases per 100,000 in Britain. In countries with high incidence rates, there are often subpopulations with high incidence rates living nearby lower-risk subpopulations. HCC is 4 to 9 times more common in men than in women. In theUkraine, the incidence of liver cancer is 5 cases per 100,000 population.

Etiology

Conditions predisposing to HCC :

1. Hepatitis B virus (HBV).

2. Cirrhosis.

3. HCV infection

4. Aflatoxins

5. Mutations of tumor-suppressor gene p53

6. Sex hormones.

7. Cigarette smoking, alcohol intake, diabetes, and insulin intake.

Pathology

1. Liver cell adenoma has low malignant potential. True adenomas of the liver are rare and occur mostly in women taking oral contraceptives. Most adenomas are solitary; occasionally multiple (10 or more) tumors develop in a condition known as liver cell adenomatosis. These tumors are smooth encapsulated masses and do not contain Kupffer’s cells. Patients usually have symptoms; hemoperitoneum occurs in 25% of cases.

2. Focal nodular hyperplasia (FNH) has no malignant potential. FNH occurs with 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 oral contraceptives. FNH tumors are nodular, are not encapsulated, but do contain Kupffer’s cells. Patients usually do not have symptoms; hemoperitoneum rarely occurs.

3. Bile duct adenomas are solitary in 80% of cases and may grossly resemble metastatic carcinoma. Most are less than 1 cm in diameter and are located under the capsule.

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, or tubular, and the stroma, in contrast to bile duct carcinoma, is scanty. A rare sclerosing or fibrosing form has been associated with hypercalcemia. Fibrolamellar carcinoma, another variant, occurs predominantly in young patients without cirrhosis, has a favorable 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 35 years of age are fibrolamellar, and more than half of them are resectable.

5. Biliary cystadenoma and cystadenocarcinoma. Benign and malignant cystic tumors of biliary origin arise in the liver more frequently than in the extrahepatic biliary system.

6. Bile duct carcinoma (cholangiocarcinoma). Malignant tumors of intrahepatic 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. The disease is contained within the liver in only 20% of cases.

HCC invades the portal vein in 35% of cases, hepatic vein in 15%, contiguous abdominal 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 gland in 5%.

Clinical presentation

Symptoms :

Pain in the right subcostal area or on top of the shoulder from phrenic irritation is 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 2 years before the diagnosis of carcinoma is made.

Hemorrhage into the peritoneal cavity is often seen in patients with HCC and may be fatal.

Ascites or the presence of an upper abdominal mass noticeable by the patient are 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).

Diagnosis

1. LFTs (serum bilirubin, lactate dehydrogenase, serum albumin, serum g-glutamyl transferase (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 be used to treat liver cancer.

However, there is a high risk of tumor recurrence and

metastases after transplantation.

Treatment of nonresectable and metastatic disease

1. Systemic chemotherapy has a response rate of 20% and does not affect median survival (3 to 6 months). Doxorubicin as a single agent or in combination with other drugs has been used. Mitoxantrone is as effective as doxorubicin but is associated with less toxicity. 5-FU intravenously and FUDR intraarterially have also been used with 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, and radiation 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 it has metastasized. Fewer than 10% of patients survive three years after the initial diagnosis; the overall five-year survival rate for patients with hepatomas is around 4%. Most patients with primary liver cancer die within several months of diagnosis.

Patients with liver cancers that metastasized from cancers in the colon live slightly longer than those whose cancers spread from cancers in the stomach or pancreas.

III. Gallbladder cancer

Epidemiology

Incidence.

Primary gallbladder carcinoma (GBC) is the most common malignant tumor of the 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 found in 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 of differentiation. 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, adenosquamous carcinomas, and undifferentiated (anaplastic, pleomorphic, sarcomatoid) carcinomas. Some adenocarcinomas have choriocarcinoma-like elements, and others have morphology equivalent to small cell carcinoma.

Natural history

GBC has a propensity to involve the liver, stomach, and duodenum by direct extension. 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 advanced carcinoma, 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 surgery because 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, such as an elderly woman with a history of chronic biliary symptoms that have changed in frequency or severity. A right upper quadrant mass or hepatomegaly and constitutional 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% of patients with GBC. The association of elevated alkaline phosphatase without elevated bilirubin is consistent with GBC.

Radiologic examination :

· Abdominal ultrasound

· CT of the abdomen

· MRI

· Percutaneous transhepatic cholangiography

· Laparoscopic exploration

Staging

Stage I: An intramuscular lesion or muscular invasion unrecognized at operation and later 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 of liver, 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 of cholecystectomy. Radical cholecystectomy or resection of adjacent structure has not resulted in better survival.

Chemotherapy.

The data on adjuvant systemic chemotherapy are anecdotal. 5-FU–based combinations are most commonly used, but the response rates are poor. Anecdotal reports of hepatic arterial infusion of chemotherapy have also claimed benefit in highly selected patients

Prognostic factors

The overall median survival of patients with GBC is 6 months. After surgical resection, 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 rate after surgical resection is 65% to 100% for stage I, 30% for stage II, 15% for stage III, and 0% for stage IV disease.

Poorly differentiated (higher-grade) tumors and the presence of jaundice are associated with poorer survival. Ploidy patterns do not correlate with survival.

Lecture 11

Tumors of the bones

Bone is the supporting framework of the body. Most bones are hollow. The outer part of bones consists of a network of fibrous tissue called matrix onto which calcium salts are deposited. At each end of the bone is a zone of cartilage, a softer form of bone-like tissue. Cartilage is made of a fibrous tissue matrix mixed with a gel-like substance. Unlike bone, cartilage does not contain much calcium.

Cartilage acts as a cushion between bones and, together with ligaments and some other tissues, forms the joints between bones. The bone itself is very hard and strong. Some bone is able to support as much as 12,000 pounds per square inch. It takes 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 called periosteum. The bone itself contains 2 kinds of cells. The osteoblast is the cell responsible for forming bone, and the osteoclast is the cell responsible for dissolving bone. Although bone looks to be a very unchanging organ, the truth is that it is very active. 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 some bones consists only of fatty tissue. The marrow of other bones is a mixture of fat cells and blood-forming (hematopoietic) cells. These blood-forming cells produce red blood cells, white blood cells, and blood platelets. There are some other cells in the marrow such as plasma cells, fibroblasts, and reticuloendothelial cells.

All these tissues can develop into a tumor - a lump or mass of tissue that forms when cells divide uncontrollably. For most bone tumors, the cause is unknown. A growing tumor may replace healthy tissue with abnormal tissue. It may weaken the bone, 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 closely resemble tumors.

Benign tumors are usually not life threatening. Malignant tumors can spread cancer cells throughout the body (metastasize). This happens via the blood or lymphatic system.

Cancer that begins in bone (primary bone cancer) is different from cancer that begins 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 worse with activity. The pain often awakens the patient at night.

Although tumors are not caused by trauma, occasionally injury can cause a tumor to start hurting. Injury can cause a bone that is already weakened by a tumor to break. This often leads to severe pain. Some tumors can cause fevers and night sweats. Many patients will not have any symptoms, but will instead note a painless mass.

Occasionally benign tumors may be discovered incidentally when X-rays are taken 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 learning about any medications you take, details about any previous tumors or cancers that you 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 can spread to bone.

Imaging

Your doctor will probably obtain X-rays. Different types of tumors have different 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 be hard to tell what kind of tumor is involved. More imaging studies may be needed to further 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 biopsy removes a sample of tissue from the tumor. The tissue sample is examined under a microscope.

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 be done in the doctor's office using local anesthesia. A radiologist may do a needle biopsy, using some type of imaging, such as an X-ray, CT, or MRI to help direct the needle to the tumor.

Open Biopsy

The doctor surgically removes tissue. This is generally done in an operating room. The patient is given general anesthesia and a small incision is made and the tissue is removed.

Treatment of Benign Tumors

In many cases, benign tumors just need to be watched. Some can be treated effectively with medication. Some benign tumors will disappear over time. This is particularly 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 other treatment techniques to reduce the risk of fracture and disability. Some tumors may come back, even repeatedly, after appropriate treatment.

Treatment of Malignant Tumors

If the patient is diagnosed with a malignant bone tumor, the treatment team may include several specialists. These may include an orthopaedic oncologist, a medical oncologist, a radiation oncologist, a radiologist, and a pathologist. Treatment goals 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 (whether the cancer has spread). Cancers have spread elsewhere in the body. Tumors at this stage are more serious and harder to cure.

Generally, the tumor is removed using surgery. Often, radiation therapy is used in 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 tumor and a margin of healthy tissue around it. The excised bone is replaced with a metallic implant (prosthesis) or bone transplant.

Amputation

Amputation removes all or part of an arm or leg when the tumor is large and/or nerves 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 the blood stream but cannot yet be detected on tests and scans. Chemotherapy is generally 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-rays and other imaging studies. These can confirm that the tumor is actually gone. Regular doctor 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 bone tumors 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 computer technology. This is leading to better function and quality of life after amputation.

Research into new medications and new combinations of older medications will lead to continual improvements in survival from bone cancers. Your doctor may discuss clinical research trials with you. Clinical trials may involve the use of new therapies and may offer a better outcome.

Bening bone tumors.

Desmoplastic fibroma is an extremely rare tumor with less than 200 cases in the published literature. It is a slowly progressing tumor with well-differentiated cells that produce collagen. This benign tumor is characterized by aggressive local infiltration. It occurs most often in the first 3 decades and is found equally in men and women. 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 present as an effusion if near a joint. Only 12% present with a pathological fracture.

The diagnosis of desmoplastic fibroma is difficult to make radiologically. Plain xray shows an osteolytic, expansile, medullary lesion with well defined sclerotic margins. The oval tumor is often found in the metaphysis aligned with the long axis of the bone. There is usually thinned cortex and the fine intra-lesional trabeculae give a lobulated appearance that is described as "soap-bubbly". A CT scan is only useful to further demonstrate cortical breakthrough. MRI demonstrates the separation of the intraosseus tumor from the bone. The radiological differential includes non-ossifying fibroma, giant cell tumor, UBC, ABC and fibrous dysplasia.

Grossly, desmoplastic fibroma has a grayish to yellowish white color and a rubbery consistency. The edges are irregular, round and blunt. The tumor has occasional cystic foci with clear fluid.

Microscopically, the tumor has interlacing bundles of dense collagen and low cellularity. The fusiform cells that are present have no atypia and the nuclei are ovoid or elongated. The differential of the tumor includes spindle cell tumors, most specifically low grade fibrosarcoma. The desmoplastic fibroma does not have the cellularity, mitotic activity or pleomorphism of a fibrosarcoma but the distinction can be difficult and is sometimes made clinically. The edge of the tumor may resemble fibrous dysplasia, but under polarized light lamellar structures are obvious.

Treatment of desmoplastic fibroma is marginal or wide surgical excision. Rates of recurrence are 55-72% without resection and 17% with resection.

Aneurysmal bone cyst (ABC) is a solitary, expansible and erosive lesion of bone. It is found most commonly during the second decade and the ratio of female to male is 2:1. ABC's can be found in any bone in the body. The most common location is the metaphysis of the lower extremity long bones, more so than the upper extremity. The vertebral bodies or arches of the spine also may be involved.Approximately one-half of lesions in flat bones occur in the pelvis. One theory of the etiology of primary ABCs is that these lesions are secondary to increased venous pressure that leads to hemorrhage which causes osteolysis. This osteolysis can in turn promote more hemorrhage causing amplification of the cyst.

More often, ABC's are thought to be a reactive process secondary to trauma or vascular disturbance. ABC's can be secondary to an underlying lesion such as non-ossifying fibroma, chondroblastoma, osteoblastoma, UBC's, chondromyxoid fibroma and fibrous dysplasia. This association is so strong that the lesion should be examined microscopically in several places to eliminate the possibility of a primary lesion. The most common precursor lesion was giant cell tumor, (19-39%) of cases, followed by osteoblastoma, angioma, and chondroblastoma. Less common precursor lesions were fibrous dysplasia, non-ossifying fibroma, chondromyxoid fibroma, unicameral bone cyst, fibrous histiocytoma, eosinoplilic granuloma, and osteosarcoma. A translocation involving the 16q22 and 17p13 chromosomes has been identified in the solid variant and 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 lesions can cause neurological symptoms secondary to cord compression. Pathological fractures are rare due to the eccentric location of the lesion. Depending on the location, 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 and appears osteolytic. The periosteum is elevated and the cortex is eroded to a thin margin. 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 or spine where plain film imaging may be inadequate. CT scan can narrow the differential diagnosis of ABC by demonstrating multiple fluid-fluid levels within the cystic 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 precursor lesion, if any, is recommended. Some lesions may have a flocculent chondroid matrix that may be a clue to their pathogenesis.

Enchondroma is a solitary, benign, intramedullary cartilage tumor that is usually found in the short tubular bones of the hands and feet. The peak incidence is in 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 the diaphysis. The mature hyaline cartilage located centrally within short tubular bones usually presents clinically as a fracture due to an enlarging lesion. Enchondromas are also found incidentally in long bones and undergo malignant transformation in less than 1% of cases.

Multiple enchondromatosis is a non-heritable condition also known as Ollier's disease. Multiple enchondromas and hemangiomas of soft tissue are otherwise known as Maffucci's Syndrome. In both conditions, males are affected more than women and the disease process often only affects one side of the body. In both diseases, there is a 30% risk of malignant transformation of the enchondromas.  Enchondromas are difficult to differentiate from low grade chondrosarcoma by radiology. Lesions located near the shoulder or the pelvis may have a higher risk of sarcomatous degeneration. Chondrosarcoma is much more common in older patients, so large enchondromas in older individuals demand a careful work-up.

Enchondromas are usually long and oval and have well-defined margins. In larger lesions, the lucent defect has endosteal scalloping and the cortex is expanded and thinned. Calcifications throughout the lesion can range from punctate to rings. CT is useful for detecting matrix mineralization and cortex integrity. MRI is helpful for describing the non-mineralized portion of the lesion and visualizing any aggressive or destructive features.

Radiographic and imaging features of enchondroma that are considered worrisome due to the potential for malignancy include large size, a large unmineralized component, significant thinning of the adjacent cortex, and bone scan activity greater than that of the anterior superior iliac spine. Features of enchondroma that are very strongly associated with malignant transformation are progressive destruction of the chondroid matrix by an expanding, non-mineralized component, an enlarging lesion associated with pain, or an expansile soft tissue mass.

On gross examination, an enchondroma consists of bluish-gray lobules of fine translucent tissue. The degree of calcification of the lesion determines if the consistency is gritty. Under the microscope, a thin layer of lamellar bone surrounding the cartilage nodules is a positive sign that the lesion is benign. At low power, there are lobules of different sizes. Blood vessels are surrounded by osteoid. Enchondromas have chondrocytes without atypia inside hyaline cartilage. The nuclei are small, round and pyknotic. The cellularity varies between lesions and within the same lesion.

Each potential enchondroma needs to be evaluated for cellularity, nuclear atypia, double nucleated chondrocytes and mitotic activity in a viable area without calcifications to distinguish it from low-grade chondrosarcoma. Small peripheral lesions are more likely to be benign than large axial lesions. The pathologic diagnosis is so difficult it always needs to be made in conjunction with the radiologist and the surgeon.

A solitary painless enchondroma may be observed. Painful or worrisome lesions should be treated with biopsy followed by intralesional resection. Large defects can be filled with bone graft. All specimens must be analyzed carefully for malignancy.

Adamantinoma of the long bones, or extragnathic adamantinoma, is an extremely rare, low-grade malignant tumor of epithelial origin. It is not related to adamantinoma or ameloblastoma of the mandible and maxilla which is derived from Rathke's pouch. Adamantinoma is a locally aggressive osteolytic tumor.

The site 90% of the time in the diaphysis of the tibia with the remaining lesions found in the fibula and long tubular bones. The tumor usually occurs in the second to fifth decade of life but may affect patients from ages 3 to 73. In 20% of cases there are metastases late in the course of the disease. There is often a history of trauma associated with adamantinoma but its role in the development of this lesion remains unclear. The patient usually has swelling that may be painful. The duration of symptoms can vary from a few weeks to years.

Adamantinoma appears as an eccentric, well-circumscribed, and lytic lesion on plain x-ray. The anterior cortex of the tibia is by far the most common location. The lesion usually has several lytic defects separated by sclerotic bone which gives a "soap-bubble" appearance. There is cortical thinning but little periosteal reaction. The lesion may break through the cortex and extend into soft tissue. There may be multiple adjacent lesions with normal intervening bone. MRI helps demonstrate the intraosseus and extraosseous involvement. The differential diagnosis radiologically includes osteofibrous dysplasia, fibrous dysplasia, ABC, chondromyxoid fibroma and chondrosarcoma .

On gross examination, adamantinoma is well demarcated and lobulated. The gray 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 a bland reactive fibrous stroma. The stroma consists of spindle shaped collagen producing cells. The nests of malignant cells are columnar and have peripheral palisading. Squamous differentiation and keratin production are rare. The tumor is positive on immunohistochemical staining with keratin antibody. The epithelial origin is confirmed when basal membranes, desmosomes and ton filaments are seen under the electron microscope.

Osteofibrous dysplasia, or ossifying fibroma, is another lesion with a striking predilection for the tibia that has a well documented association with adamantinoma and may be a benign precursor to it.

Adamantinoma is treated by wide surgical excision. This tumor is insensitive to radiation and may metastasize to lungs, lymph nodes and abdominal organs by both hematogenous and lymphatic routes. Chemotherapy is not used.

Benign Fibrous Histiocytoma. This tumor has been given the names benign fibrous hystiocytoma, fibrous histiocytoma, xanthofibroma, fibroxanthoma of bone, and primary xanthoma of bone. Clinically, patients report pain from the lesion, often of months or years duration. Pain may be associated with pathological fracture. There may be some local tenderness, but no swelling or mass is seen, and there are no systemic symptoms. There it is normally no impairment of the function of the nearby joint. Spinal lesions may cause neurologic defect by pressing on the spinal cord.

In some cases there is a primary underlying disorder of cholesterol metabolism or other lipid abnormalities. In these cases the lytic bone lesions are analogous to those seen in storage diseases such as Gaucher's disease. These multiple lesions are termed "xanthoma disseminatum". One reported case is of a 10 year old boy with lytic lesions in the pelvis, femur, and humerus, as well as yellow and brown papules and plaques on the face and trunk. This patient also had polyuria and polydipsia, and was found to have diabetes insipidus.

Radiographically, the lesion occur commonly in the ribs, pelvis, including the sacrum and ilium, or in the epiphysis or diaphysis of tubular bones. These tumors have been reported in the jaw and associated soft tissues. In another report this tumor occurred commonly around the knee. It has a lytic, loculated appearance with prominent sclerosis of the edges of the lesion. There is no matrix mineralization. The zone 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 the patients are older and have pain, and these lesions have more promenent marginal sclerosis. Some authors have report a periosteal reaction, but others do not. There is prominent marginal sclerosis which may have the appearance of periosteal reaction in lesions that are juxtacortical.

CT scan shows a moderately irregular lytic area with an prominent trabecular pattern and surrounding sclerotic bone.

On gross examination, the tumor tissue consists of a mixture of firm but unmi