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

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

o change in the quality of stools

o change in consistency of stools

Bloody stools or rectal bleeding

Stools with mucus

Tarry stools (melena) (more likely related to upper gastrointestinal eg

stomach or duodenal disease)

Feeling of incomplete defecation (tenesmus) (usually associated with

rectal cancer)

Reduction in diameter of feces

Bowel obstruction (rare)

Constitutional symptoms

Especially in the cases of cancer in the ascending colon, sometimes only the

less specific constitutional symptoms will be found:

Anemia, with symptoms such as dizziness, malaise and palpitations.

Clinically there will be pallor and a complete blood picture will confirm the low

hemoglobin level.

Anorexia

Asthenia, weakness

Unexplained weight loss.

Metastatic symptoms

There may also be symptoms attributed to distant metastasis:

Shortness of breath as in lung metastasis

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

Risk factors

The lifetime risk of developing colon cancer in the United States is about 7%.

Certain factors increase a person's risk of developing the disease. These include:

Age. The risk of developing colorectal cancer increases with age. Most

cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a

family history of early colon cancer is present.

Polyps of the colon, particularly adenomatous polyps, are a risk factor

for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the

subsequent risk of colon cancer.

History of cancer. Individuals who have previously been diagnosed and

treated for colon cancer are at risk for developing colon cancer in the future. Women

who have had cancer of the ovary, uterus, or breast are at higher risk of developing

colorectal cancer.

Heredity:

o Family history of colon cancer, especially in a close relative before the

age of 55 or multiple relatives

o Familial adenomatous polyposis (FAP) carries a near 100% risk of

developing colorectal cancer by the age of 40 if untreated

o Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome

Long-standing ulcerative colitis or Crohn's disease of the colon,

approximately 30% after 25 years if the entire colon is involved

Smoking. Smokers are more likely to die of colorectal cancer than non-

smokers. An American Cancer Society study found that "Women who smoked were

more than 40% more likely to die from colorectal cancer than women who never had

smoked. Male smokers had more than a 30% increase in risk of dying from the

disease compared to men who never had smoked."

Diet. Studies show that a diet high in red meat and low in fresh fruit,

vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a

study by the European Prospective Investigation into Cancer and Nutrition suggested

that diets high in red and processed meat, as well as those low in fiber, are associated

with an increased risk of colorectal cancer. Individuals who frequently ate fish

showed a decreased risk. However, other studies have cast doubt on the claim that

diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was

associated with other risk factors, leading to confounding. The nature of the

relationship between dietary fiber and risk of colorectal cancer remains controversial.

Physical inactivity. People who are physically active are at lower risk of

developing colorectal cancer.

Virus. Exposure to some viruses (such as particular strains of human

papilloma virus) may be associated with colorectal cancer.

Alcohol. See the subsection below.

Primary sclerosing cholangitis offers a risk independent to ulcerative

colitis

Low selenium.

Inflammatory Bowel Disease. About one percent of colorectal cancer

patients have a history of chronic ulcerative colitis. The risk of developing colorectal

cancer varies inversely with the age of onset of the colitis and directly with the extent

of colonic involvement and the duration of active disease. Patients with colorectal

Crohn's disease have a more than average risk of colorectal cancer, but less than that

of patients with ulcerative colitis.

Environmental Factors. Industrialized countries are at a relatively

increased risk compared to less developed countries or countries that traditionally had

high-fiber/low-fat diets. Studies of migrant populations have revealed a role for

environmental factors, particularly dietary, in the etiology of colorectal cancers.

Genetic factors and inflammatory bowel disease also place certain individuals at

increased risk.

Exogenous Hormones. The differences in the time trends in colorectal

cancer in males and females could be explained by cohort effects in exposure to some

sex-specific risk factor; one possibility that has been suggested is exposure to

estrogens. There is, however, little evidence of an influence of endogenous hormones

on the risk of colorectal cancer. In contrast,there is evidence that exogenous estrogens

such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might

be associated with colorectal tumors.

Alcohol

One study found that "People who drink more than 30 grams of alcohol per day

(and especially those who drink more than 45 grams per day) appear to have a

slightly higher risk for colorectal cancer." Another found that "The consumption of

one or more alcoholic beverages a day at baseline was associated with approximately

a 70% greater risk of colon cancer."

One study found that "While there was a more than twofold increased risk of

significant colorectal neoplasia in people who drink spirits and beer, people who

drank wine had a lower risk. In our sample, people who drank more than eight

servings of beer or spirits per week had at least a one in five chance of having

significant colorectal neoplasia detected by screening colonoscopy.".

Other research suggests that "to minimize your risk of developing colorectal

cancer, it's best to drink in moderation"

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

Diagnosis, screening and monitoring

Endoscopic image of colon cancer identified in sigmoid colon on screening

colonoscopy in the setting of Crohn's disease.

Colorectal cancer can take many years to develop and early detection of

colorectal cancer greatly improves the chances of a cure. Therefore, screening for the

disease is recommended in individuals who are at increased risk. There are several

different tests available for this purpose.

Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger

into the rectum to feel for abnormal areas. It only detects tumors large enough to be

felt in the distal part of the rectum but is useful as an initial screening test.

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

Endoscopy:

o Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the

rectum and lower colon to check for polyps and other abnormalities.

o Colonoscopy: A lighted probe called a colonoscope is inserted into the

rectum and the entire colon to look for polyps and other abnormalities that may be

caused by cancer. A colonoscopy has the advantage that if polyps are found during

the procedure they can be immediately removed. Tissue can also be taken for biopsy.

Other screening methods

Double contrast barium enema (DCBE): First, an overnight preparation

is taken to cleanse the colon. An enema containing barium sulfate is administered,

then air is insufflated into the colon, distending it. The result is a thin layer of barium

over the inner lining of the colon which is visible on X-ray films. A cancer or a

precancerous polyp can be detected this way. This technique can miss the (less

common) flat polyp.

Virtual colonoscopy replaces X-ray films in the double contrast barium

enema (above) with a special computed tomography scan and requires special

workstation software in order for the radiologist to interpret. This technique is

approaching colonoscopy in sensitivity for polyps. However, any polyps found must

still be removed by standard colonoscopy.

Standard computed axial tomography is an x-ray method that can be

used to determine the degree of spread of cancer, but is not sensitive enough to use

for screening. Some cancers are found in CAT scans performed for other reasons.

Blood tests: Measurement of the patient's blood for elevated levels of

certain proteins can give an indication of tumor load. In particular, high levels of

carcinoembryonic antigen (CEA) in the blood can indicate metastasis of

adenocarcinoma. These tests are frequently false positive or false negative, and are

not recommended for screening, it can be useful to assess disease recurrence.

Genetic counseling and genetic testing for families who may have a

hereditary form of colon cancer, such as hereditary nonpolyposis colorectal cancer

(HNPCC) or familial adenomatous polyposis (FAP).

Positron emission tomography (PET) is a 3-dimensional scanning

technology where a radioactive sugar is injected into the patient, the sugar collects in

tissues with high metabolic activity, and an image is formed by measuring the

emission of radiation from the sugar. Because cancer cells often have very high

metabolic rate, this can be used to differentiate benign and malignant tumors. PET is

not used for screening and does not (yet) have a place in routine workup of colorectal

cancer cases.

Whole-Body PET imaging is the most accurate diagnostic test for

detection of recurrent colorectal cancer, and is a cost-effective way to differentiate

resectable from non-resectable disease. A PET scan is indicated whenever a major

management decision depends upon accurate evaluation of tumour presence and

extent.

Stool DNA testing is an emerging technology in screening for colorectal

cancer. Pre-malignant adenomas and cancers shed DNA markers from their cells

which are not degraded during the digestive process and remain stable in the stool.

Capture, followed by Polymerase Chain Reaction amplifies the DNA to detectable

levels for assay. Clinical studies have shown a cancer detection sensitivity of 71%-

91%.

Pathology

Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.

The pathology of the tumor is usually reported from the analysis of tissue taken

from a biopsy or surgery. A pathology report will usually contain a description of cell

type and grade. The most common colon cancer cell type is adenocarcinoma which

accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell

carcinoma.

Cancers on the right side (ascending colon and cecum) tend to be exophytic,

that is, the tumour grows outwards from one location in the bowel wall. This very

rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-

sided tumours tend to be circumferential, and can obstruct the bowel much like a

napkin ring.

Histopathology: Adenocarcinoma is a malignant epithelial tumor, originating

from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating

the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor

cells describe irregular tubular structures, harboring pluristratification, multiple

lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are

discohesive and secrete mucus, which invades the interstitium producing large pools

of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma,

poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus

at the periphery - "signet-ring cell." Depending on glandular architecture, cellular

pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may

present three degrees of differentiation: well, moderately, and poorly differentiated.

Staging

Colon cancer staging is an estimate of the amount of penetration of a particular

cancer. It is performed for diagnostic and research purposes, and to determine the

best method of treatment. The systems for staging colorectal cancers largely depend

on the extent of local invasion, the degree of lymph node involvement and whether

there is distant metastasis.

Definitive staging can only be done after surgery has been performed and

pathology reports reviewed.

Dukes' system

Dukes' classification, first proposed by Dr Cuthbert E. Dukes in 1932,

identifies the stages as:

A - Tumour confined to the intestinal wall

B - Tumour invading through the intestinal wall

C - With lymph node(s) involvement

D - With distant metastasis

TNM system

Main article: TNM

The most common current staging system is the TNM (for

tumors/nodes/metastases) system, though many doctors still use the older Dukes

system. The TNM system assigns a number:

T - The degree of invasion of the intestinal wall

o T0 - no evidence of tumor

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

o T1 - invasion through submucosa into lamina propria (basement

membrane invaded)

o T2 - invasion into the muscularis propria (i.e. proper muscle of the

bowel wall)

o T3 - invasion through the subserosa

o T4 - invasion of surrounding structures (e.g. bladder) or with tumour

cells on the free external surface of the bowel

N - the degree of lymphatic node involvement

o N0 - no lymph nodes involved

o N1 - one to three nodes involved

o N2 - four or more nodes involved

M - the degree of metastasis

o M0 - no metastasis

o M1 - metastasis present

AJCC stage groupings

The stage of a cancer is usually quoted as a number I, II, III, IV derived from

the TNM value grouped by prognosis; a higher number indicates a more advanced

cancer and likely a worse outcome.

Stage 0

o Tis, N0, M0

Stage I

o T1, N0, M0

o T2, N0, M0

Stage IIA

o T3, N0, M0

Stage IIB

o T4, N0, M0

Stage IIIA

o T1, N1, M0

o T2, N1, M0

Stage IIIB

o T3, N1, M0

o T4, N1, M0

Stage IIIC

o Any T, N2, M0

Stage IV

o Any T, Any N, M1

Pathogenesis

Colorectal cancer is a disease originating from the epithelial cells lining the

gastrointestinal tract. Hereditary or somatic mutations in specific DNA sequences,

among which are included DNA replication or DNA repair genes, and also the APC,

K-Ras, NOD2 and p53 genes, lead to unrestricted cell division. The exact reason why

(and whether) a diet high in fiber might prevent colorectal cancer remains uncertain.

Chronic inflammation, as in inflammatory bowel disease, may predispose patients to

malignancy.

Treatment

The treatment depends on the staging of the cancer. When colorectal cancer is

caught at early stages (with little spread) it can be curable. However when it is

detected at later stages (when distant metastases are present) it is less likely to be

curable.

Surgery remains the primary treatment while chemotherapy and/or

radiotherapy may be recommended depending on the individual patient's staging and

other medical factors.

Surgery

Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or

open-and-close.

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

Very early cancer that develops within a polyp can often be cured by

removing the polyp (i.e., polypectomy) at the time of colonoscopy.

In colon cancer, a more advanced tumor typically requires surgical

removal of the section of colon containing the tumor with sufficient margins, and

radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence

(i.e., colectomy). If possible, the remaining parts of colon are anastomosed together

to create a functioning colon. In cases when anastomosis is not possible, a stoma

(artificial orifice) is created.

Curative surgery on rectal cancer includes total mesorectal excision

(lower anterior resection) or abdominoperineal excision.

In case of multiple metastases, palliative (non curative) resection of the

primary tumor is still offered in order to reduce further morbidity caused by tumor

bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver

metastases is, however, common and may be curative in selected patients; improved

chemotherapy has increased the number of patients who are offered surgical removal

of isolated liver metastases.

If the tumor invaded into adjacent vital structures which makes excision

technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse

bypass) or to do a proximal fecal diversion through a stoma.

The worst case would be an open-and-close surgery, when surgeons find the

tumor unresectable and the small bowel involved; any more procedures would do

more harm than good to the patient. This is uncommon with the advent of

laparoscopy and better radiological imaging. Most of these cases formerly subjected

to "open and close" procedures are now diagnosed in advance and surgery avoided.

Laparoscopic-assisted colectomy is a minimally-invasive technique that can

reduce the size of the incision, minimize the risk of infection, and reduce post-

operative pain.

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

including

wound infection, Dehiscence (bursting of wound) or hernia

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

peritonitis

bleeding with or without hematoma formation

adhesions resulting in bowel obstruction (especially small bowel)

blind loop syndrome as in bypass surgery.

adjacent organ injury; most commonly to the small intestine, ureters,

spleen, or bladder

Cardiorespiratory complications such as myocardial infarction,

pneumonia, arrythmia, pulmonary embolism etc

Chemotherapy

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink

tumor size, or slow tumor growth. Chemotherapy is often applied after surgery

(adjuvant), before surgery (neo-adjuvant), or as the primary therapy if surgery is not

indicated (palliative). The treatments listed here have been shown in clinical trials to

improve survival and/or reduce mortality rate and have been approved for use by the

US Food and Drug Administration.

Adjuvant (after surgery) chemotherapy. One regimen involves the

combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)

o 5-fluorouracil (5-FU) or Capecitabine

o Leucovorin (LV, Folinic Acid)

o Oxaliplatin (Eloxatin)

Chemotherapy for metastatic disease. Commonly used first line

chemotherapy regimens involve the combination of infusional 5-fluorouracil,

leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-

fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab

o 5-fluorouracil (5-FU) or Capecitabine

o Leucovorin (LV, Folinic Acid)

o Irinotecan (Camptosar)

o Oxaliplatin (Eloxatin)

o Bevacizumab (Avastin)

o Cetuximab (Erbitux)

o Panitumumab (Vectibix)

In clinical trials for treated/untreated metastatic disease.

o Bortezomib (Velcade)

o Oblimersen (Genasense, G3139)

o Gefitinib and Erlotinib (Tarceva)

o Topotecan (Hycamtin)

Radiation therapy

Radiotherapy is not used routinely in colon cancer and it is difficult to target

specific portions of the colon. It is more common for radiation to be used in rectal

cancer, since the rectum does not move as much as the colon and is thus easier to

target. Indications include:

Colon cancer

o pain relief and palliation - targeted at metastatic tumor deposits if they

compress vital structures and/or cause pain

Rectal cancer

o neoadjuvant - given before surgery in patients with tumors that extend

outside the rectum or have spread to regional lymph nodes, in order to decrease the

risk of recurrence following surgery or to allow for less invasive surgical approaches

(such as a low anterior resection instead of an abdomino-perineal resection)

o adjuvant - where a tumor perforates the rectum or involves regional

lymph nodes (AJCC T3 or T4 tumors or Duke's B or C tumors)

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

symptoms

Sometimes chemotherapy agents are used to increase the effectiveness of

radiation by sensitizing tumor cells if present.

Treatment of colorectal cancer metastasis to the liver

According to the American Cancer Society statistics in 2006 greater than 20%

of patients present with metastatic (stage IV) colorectal cancer at the time of

diagnosis, and up to 25% of this group will have isolated liver metastasis that is

potentially resectable. Lesions which undergo curative resection have demonstrated

5-year survival outcomes now exceeding 50%.

Resectability of a liver met is determined using preoperative imaging studies

(Ct or MRI), intraoperative ultrasound, and by direct palpation and visualization

during resection. Lesions confined to the right lobe are amenable to en bloc removal

with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or

left liver lobe may sometimes be resected in anatomic "segments", while large lesions

of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy.

Treatment of lesions by smaller, non-anatomic "wedge" resections is associated with

higher recurrence rates. Some lesions which are not initially amenable to surgical

resection may become candidates if they have significant responses to preoperative

chemotherapy or immunotherapy regimines. Lesions which are not amenable to

surgical resection for cure can be treated with modalities including radio-frequency

ablation (RFA), cryoablation, and chemoembolization.

Patients with colon cancer and metastatic disease to the liver may be treated in

either a single surgery or in staged surgeries (with the colon tumor traditionally

removed first) depending upon the fitness of the patient for prolonged surgery, the

difficulty expected with the procedure with either the colon or liver resection, and the

comfort of the surgery performing potentially complex hepatic surgery.

Poor pronostic factors of patients with liver metastasis include

Synchronous (diagnosed simultaneously) liver and primary colorectal

tumors

A short time between detecting the primary cancer and subsequent

development of liver mets

Multiple metastatic lesions

High blood levels of the tumor marker, carcino-embryonic antigen

(CEA), in the patient prior to resection

Larger size metastatic lesions

Follow-up

The aims of follow-up are to diagnose in the earliest possible stage any

metastasis or tumors that develop later but did not originate from the original cancer

(metachronous lesions).

A medical history and physical examination are recommended every 3 to 6

months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood

level measurements follow the same timing, but are only advised for patients with T2

or greater lesions who are candidates for intervention. A CT-scan of the chest,

abdomen and pelvis can be considered annually for the first 3 years for patients who

are at high risk of recurrence (for example, patients who had poorly differentiated

tumors or venous or lymphatic invasion) and are candidates for curative surgery (with

the aim to cure). A colonoscopy can be done after 1 year, except if it could not be

done during the initial staging because of an obstructing mass, in which case it should

be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high

grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other

abnormalities, the colonoscopy can be repeated after 1 year.

Routine PET or ultrasound scanning, chest X-rays, complete blood count or

liver function tests are not recommended. These guidelines are based on recent meta-

analyses showing that intensive surveillance and close follow-up can reduce the 5-

year mortality rate from 37% to 30%.

Surveillance

Most colorectal cancer arise from adenomatous polyps. These lesions can be

detected and removed during colonoscopy. Studies show this procedure would

decrease by > 80% the risk of cancer death, provided it is started by the age of 50,

and repeated every 5 or 10 years.

Lecture 10

Pancreatic Cancer. Liver cancer. Gallbladder cancer.

I. Pancreatic Cancer

Epidemiology

Incidence

The crude incidence and mortality of pancreatic cancer in the European Union

is about 11/100 000 per year.

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

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

population.

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

population.

Pancreatic cancer is primarily a disease associated with advanced age, with

80% of cases occurring between the ages of 60 and 80.

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

Countries with the highest frequencies of pancreatic cancer include the US,

New Zealand, Western European nations, and Scandinavia.

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

Singapore.

Etiology and risk factors.

1. Cigarette smoking. The risk increases with increasing duration and amount of

cigarette smoking. The excess risk levels off 10 to 15 years after cessation of

smoking. The risk is ascribed to tobacco-specific nitrosamines.

2. Diet. A high intake of fat, meat, or both is associated with increased risk, whereas

the intake of fresh fruits and vegetables appears to have a protective effect.

3. Partial gastrectomy appears to correlate with a two to five times higher than

expected incidence of pancreatic cancer 15 to 20 years later. The increased formation

of N-nitroso compounds by bacteria that produce nitrate reductase and proliferate in

the hypoacidic stomach has been proposed to account for the increased occurrence of

gastric and pancreatic cancer after partial gastrectomy.

4. Cholecystokinin is the primary hormone that causes growth of exocrine pancreatic

cells; others include epidermal growth factor and insulin-like growth factors.

Pancreatic cancer has been induced experimentally by long-term duodenogastric

reflux, which is associated with increased cholecystokinin levels. Some clinical

evidence suggests that cholecystectomy, which also increases the circulating

cholecystokinin, may increase the risk for pancreatic cancer.

5. Diabetes mellitus may be an early manifestation of pancreatic cancer or a

predisposing factor. It is found in 13% of patients with pancreatic cancer and in only

2% of controls.

6. Chronic and hereditary pancreatitis are associated with pancreatic cancer.

Chronic pancreatitis is associated with a 15-fold increase in the risk for pancreatic

cancer.

7. Toxic substances. Occupational exposure to 2-naphthylamine, benzidine, and

gasoline derivatives is associated with a five-fold increased risk for pancreatic cancer.

Prolonged exposure to DDT and two DDT derivatives (ethylan and DDD) is

associated with a four-fold to seven-fold increased risk for pancreatic cancer.

8. Socioeconomic status. Pancreatic cancer occurs in a slightly higher frequency in

populations of lower socioeconomic status.

9. Coffee. Analysis of 30 epidemiologic studies showed that only one case-control

study and none of the prospective studies confirmed a statistically significant

association between coffee consumption and pancreatic cancer.

10. Idiopathic deep-vein thrombosis is statistically correlated with the subsequent

development of mucinous carcinomas (including pancreatic cancer), especially

among patients in whom venous thrombosis recurs during follow-up.

11. Dermatomyositis and polymyositis are paraneoplastic syndromes associated

with pancreatic cancer and other cancers.

12. Familial pancreatic cancer. It is estimated that 3% of pancreatic cancers are

linked to inherited predisposition to the disease.

Pathology

Nonepithelial tumors (sarcomas and lymphomas) are rare.

Ductal adenocarcinoma makes up 75% to 90% of malignant pancreatic

neoplasms: 57% occur in the head of the pancreas, 9% in the body, 8% in the tail, 6%

in overlapping sites, and 20% in unknown anatomic subsites. Uncommon but

reasonably distinctive variants of pancreatic cancer include adenosquamous,

oncocytic, clear cell, giant cell, signet ring, mucinous, and anaplastic carcinoma.

Anaplastic carcinomas often involve the body and tail rather than the head of

pancreas. Reported cases of pure epidermoid carcinoma (a variant of adenosquamous

carcinoma) probably are associated with hypercalcemia.

Cystadenocarcinomas have an indolent course and may remain localized for

many years. Ampullary cancer (which carries a significantly better prognosis),

duodenal cancer, and distal bile duct cancer may be difficult to distinguish from

pancreatic adenocarcinoma.

Metastatic tumors. Autopsy studies show that for every primary tumor of the

pancreas, four metastatic tumors are found. The most common tumors of origin are

the breast, lung, cutaneous melanoma, and non-Hodgkin’s lymphoma.

Genetic abnormalities. Mutant c-K-ras genes have been found in most

specimens of human pancreatic carcinoma and their metastases.

Diagnosis

Symptoms.

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

Predominant initial symptoms include

abdominal pain (80%);

anorexia (65%);

weight loss (60%);

early satiety (60%);

jaundice (50%);

easy fatigability (45%);

xerostomia and sleep problems (55%);

weakness, nausea, or constipation (40%);

depression (40%); dyspepsia (35%);

vomiting (30%); hoarseness (25%);

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

dyspnea, dizziness, or edema (20%);

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

dysphagia (5%).

Clinical findings.

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

palpable abdominal mass (35%),

ascites (25%),

supraclavicular adenopathy (5%).

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

Metastases are present to at least one major organ in 65% of patients: to the

liver in 45%, to the lungs in 30%, and to the bones in 3%.

Carcinomas of the distal pancreas do not produce jaundice until they

metastasize and may remain painless until the disease is advanced.

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

Paraneoplastic syndromes.

Panniculitis-arthritis-eosinophilia syndrome that occurs with pancreatic cancer

appears to be caused by the release of lipase from the tumor. Dermatomyositis,

polymyositis, recurrent Trousseau’s syndrome or idiopathic deep-vein thrombosis,

and Cushing’s syndrome have been reported to be associated with cancer of the

pancreas.

Methodes of diagnostic:

1. Ultrasonography

2. CT

3. MRI

4. Endoscopic retrograde cholangiography

5.Percutaneous fine-needle aspiration cytology

6. Angiography

7.Laparoscopy

8.Tumor markers:

a. CA 19-9

b. CEA

Staging

Stage Primary

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

unmineralized yellow-tan tissue and partially hemorrhagic red-brown tissue. The

yellow-tan tissue contains predominantly xanthic material. Histologically , the tumor

consists of fibroblasts and mononuclear or multinucleated cells that have the

appearance of histiocytes. The tumor may contain large areas of "foam cells", lipid-

filled cells with abundant vacuolated cytoplasm, interspersed with small fibrovascular

septations, as well as masses of cholesterol. No mitotic activity, cellular atypia, or

pleomorphism is present.

Treatment consists of careful and complete curettage and filling of the defect

with graft material, bone cement, or other suitable bone void filler. The risk of

recurrence is variable depending on which series is consulted.

Chondromyxoid Fibroma (CMF) is a benign cartilage tumor that also has

myxoid and fibrous elements. It is extremely rare and accounts for less that 1% of all

bone tumors. CMF is found most often in the metaphysis around the knee in the

proximal tibia, proximal fibula, or distal femur. It presents in the second to third

decade and has a male to female ratio of 2 to 1. The clinical presentation is usually

chronic pain, swelling and possibly a palpable soft tissue mass or restriction of

movement. Only 5% of patients with CMF present with a pathological fractureю

Radiological findings demonstrate an eccentrically placed lytic lesion with well

defined margins in the metaphysis of the lower extremity. The lesion usually has a

sclerotic margin of bone and a lobulated contour. Ridges and grooves that appear in

the margins secondary to scalloping falsely appear to be trabeculae. CT helps define

cortical integrity and confirms that there is no mineralization of the matrix, unlike

other cartilage tumors. CMF has the same appearance on MRI as other cartilage

tumors which is decreased signal on T 1 weighted images and increased signal on T2

weighted images. MRI is helpful in preoperative planning and staging. The radiologic

differential diagnosis includes giant cell tumor, aneurysmal bone cyst, unicameral

bone cyst, chondroblastoma and fibrous dysplasia.

CMF resembles fibrocartilage grossly. It has a sharp border often with an outer

surface of thin bone or periosteum. The glistening grayish white lesion is firm and

lobulated. It may also have small cystic foci or areas of hemorrhage.

Histologically, CMF appears very similar to chondrosarcoma. They are so

close in histology that often radiology helps to make the final diagnosis. The

predominant features of CMF are the zonal architecture and lobular pattern. Nodules

of cartilage are found in between fibromyxoid areas. In some fields the loose myxoid

dominates and in other the dense chondroid dominates. The chondrocytes are plump

to spindly in shape and have indistinct cell borders in sparsely cellular lobules of

myxoid or chondroid matrix. There are also more cellular zones of the tumor with

some giant cells at the edges. The sharp borders of each lobule and the lesion itself

help to differentiate it from chondrosarcoma.

Treatment of CMF is en bloc excision. Recurrences after curettage are

common.

Giant cell tumor of bone: This type of primary bone tumor has benign and

malignant forms. The benign (non-cancerous) form is most common. These tumors

typically 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 and

spread 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 cell

bone 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 cells

of the bone marrow (the soft inner part of some bones). Although it causes bone

destruction, it is no more a bone cancer than is leukemia. It is treated as a widespread

disease. At times, myeloma can be first found as a single tumor in a single bone, but

most of the time it will go on to spread to the marrow of other bones. Multiple

myeloma is the most common primary bone cancer. It is a malignant tumor of bone

marrow. 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 bone

can be involved.

Osteosarcoma

Osteosarcoma is the second most common bone cancer. It occurs in two or

three new people per million people each year. Most cases occur in teenagers. Other

common locations include the hip and shoulder. Although osteosarcoma most often

occurs in young people between the age of 10 and 30, about 10% of cases develop in

people in their 60s and 70s. This cancer is rare during middle age. More males than

females get this cancer. These tumors develop most often in bones of the arms, legs,

or pelvis. Most tumors occur around the knee.

Ewing's sarcoma is named after Dr. James Ewing, who first described it in

1921, most commonly occurs between 5 and 20 years of age. The most common

locations are the upper and lower leg, pelvis, upper arm, and ribs. Ewing tumors

usually develop in bones, and less than 10% arise in other tissues and organs. They

most often arise in the long bones of the legs and arms but may also develop in the

pelvis 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. This

cancer usually appears in children and teenagers and is uncommon in adults over age

30. Ewing tumors occur most often in white people and are rare among African

Americans 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 indolent

course and the prognosis remains good.  The second presentation is that of single or

multiple rapidly progressive lesions that  metastasize to other bones or to the lung this

form 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 focal

destruction of the cortex. They have a very aggressive appearance but there is no

periosteal reaction and very little soft-tissue extension, similar to what might be seen

in metastatic lesions from lung. They tend to occur as multiple lesions in the same

bone or contiguous bones, as shown in this case.

Chondroblastoma is a rare, benign tumor derived from chondroblasts. It is

found in the epiphysis of long bones, usually of the lower extremity. The most

common site is the distal femur followed by the proximal femur, proximal humerus

and proximal tibia. The tumor has a preference for males over females and the mean

age of presentation is approximately 20 years old. The tumor may have behavior not

normally associated with benign tumors including pulmonary metastases as well as

local invasion of bone and soft tissue.

Clinically, chondroblastoma presents as pain near a joint without history of

trauma. A secondary synovitis can be induced by the tumor, but pathological fracture

is extremely rare.

The diagnosis of chondroblastoma can usually be made by radiograph. when

the age of the patient and location of the lesion are considered. The most common

site for chondroblastoma is the epiphysis. The lesion is lytic with well defined

margins and can be from 1-6cm in size. Scalloping or expansion of cortical bone may

be present. Fine calcifications, either punctate or in rings, may be visible. Cysts are

present about 20% of the time and both MRI and CT can define the fluid levels. CT is

also useful for defining the relationship of the tumor to the joint, integrity of the

cortex, and intralesional calcifications. The differential diagnosis includes

enchondroma, central chondrosarcoma and aneurysmal bone cyst. On gross

examination, a chondroblastoma has a lobulated, round form and is made up of

friable, soft, grayish pink tissue that may be gritty. If present, the cystic fluid is rust

or straw-colored. Chondroblastoma is made up of uniform, polygonal cells that are

closely packed. These primitive cells are derived from the epiphyseal cartilage plate

and have abundant cytoplasm. There is little mitotic activity. A scant chondroid

matrix may be superimposed by a pericellular deposit of calcification that appears

like "chicken-wire". The rapid proliferation of immature chondrocytes does not create

lacunae or formal cartilage matrix. Giant cells are often present.

Treatment of chondroblastoma is biopsy and curettage with possible use of

adjuvant liquid nitrogen or phenol, or a mechanical burr. It may be necessary to

reconstruct articular surfaces due to subchondral erosion. Any joint invasion is

usually secondary to previous instrumentation. All pulmonary nodules should be

excised.

Fibrosarcoma is an uncommon, malignant spindle cell neoplasm. It appears in

the metaphysis or metadiaphysis of long bones. Fibrosarcoma is found most

commonly around the knee in the distal femur and proximal tibia followed by the

pelvis. The tumor produces a collagen matrix but does not produce osteoid or

chondroid. Fibrosarcoma can be primary or secondary due to Paget's disease, fibrous

dysplasia, irradiated giant cell tumor, bone infarct or chronic osteomyelitis.

Fibrosarcoma occurs both as an intramedullary and periosteal lesion. It presents in

adults age 30 to 60 years old and affects men and women equally. The most common

clinical presentation is that of a localized, painful mass. The radiologic picture of

fibrosarcoma is that of an osteolytic lesion. The margins can range from well-defined

to ragged and moth-eaten. Periosteal reaction is seen with cortical destruction.

Extension into the soft tissue is common. MRI helps define intraosseus spread and

soft tissue extension. Bone scan demonstrates increased uptake. The differential

diagnosis includes leiomyosarcoma, metastatic carcinoma, melanoma, malignant

fibrous histiocytoma and multiple myeloma.

On gross examination the tumor is tan to grayish white with a rubbery

consistency. Larger tumors may have hemorrhagic and necrotic foci.

As with plain x-ray, the microscopic appearance of fibrosarcoma varies with

the level of differentiation. A well differentiated, low grade tumor has homogeneous

spindle shaped fibroblasts with ovoid nuclei. There is little pleom orphism and

infrequent mitoses in this slow growing form. The "herring bone pattern" of fascicles

of cells is prominent. Poorly differentiated or high grade tumors have pleomorphic

cells, abundant mitoses and hyperchromic nuclei. They metastasize early. The

cellularity 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 high

grades carrying a worse prognosis.

Treatment of fibrosarcoma includes radical surgical excision and adjuvant

radiation therapy. Prognosis is largely dependent on the tumor grade. Fibrosarcoma

and malignant fibrous histiocytoma is another type of cancer that develops more

often in "soft tissues" than it does from bones. Fibrosarcoma usually occurs in elderly

and 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, it

usually affects the legs (often around the knees) or arms. This cancer usually occurs

in elderly and middle-aged adults and is rare among children. Malignant fibrous

histiocytoma (often abbreviated as MFH) tends to grow quickly. It often spreads to

other parts of the body, most often to lymph nodes and to the lungs.

Chondrosarcoma occurs most commonly in patients between 40 and 70 years

of age. Most cases occur around the hip and pelvis or the shoulder. Chondrosarcomas

are classified by their grades, a measure of how fast growing they are. This is

determined by the pathologist (a doctor specially trained to examine and diagnose

tissue samples under a microscope) who examines the chondrosarcoma under the

microscope. Most chondrosarcomas are low grade (grade I), meaning they are not

likely 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 of

these variants of chondrosarcoma tend to have a better prognosis (outlook for

survival) than usual chondrosarcomas, and others tend to be more aggressive.

Dedifferentiated chondrosacromas start out as typical chondrosarcomasbut then some

parts of the tumor change into cells that closely resemble those of an osteosarcoma or

fibrosarcoma. This variant of chondrosarcoma tends to occur in older patients and is

more aggressive than usual chondrosarcomas. In contrast, clear cell chondrosarcoma

is a rare variant that grows slowly and rarely spreads to other parts of the body unless

it has already recurrent several times in the original location. Mesenchymal

chondrosarcoma shares some similarities with Ewing tumor. Although these tumors

can grow rapidly, they are sensitive to radiotherapy and chemotherapy.

Chondrosarcoma. This is a cancer of cartilage cells and is the second most

common primary bone cancer. This cancer is uncommon in people younger than 20.

After age 20, the risk of developing chondrosarcoma continues to rise until reaching

about 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 with

the highest prevalence in the fifth to seventh decade. The ratio of male to female is

two to one. Due to their origin in the notochord, chordomas occur in the mid-line of

the axial skeleton. One half of cases occur in the sacrococcygeal region and one third

occur at the base of the skull. Other rare sites include transverse processes of

vertebrae and the paranasal sinuses.

The clinical presentation depends on the location of the tumor. Sacrococcygeal

tumors often present as low back pain with no characteristic pattern or time course.

Sacrococcygeal tumors can also present as bowel and bladder dysfunction. Presacral

tumors can sometimes be palpated on rectal exam. Sacral tumors are often large at

presentation as a large volume of tumor can be accommodated within the pelvis.

Anterior cervical tumors can present as dysphagia and posterior cervical tumors can

cause neurological deficits. Tumors at the base of the skull may present with

headaches.

On plain X-ray, chordomas appear as a solitary mid-line lesion with bony

destruction. There is often an accompanying soft tissue mass. Approximately half of

the time focal calcifications are present. CT and MRI scans help demonstrate the soft

tissue component, calcifications and epidural extension. MRI is helpful in identifying

local recurrences. Chordomas have reduced uptake on bone scan.

On gross examination, chordomas are soft, blue-gray, lobulated tumors. There

are gelatinous translucent areas and often a capsule is present. The lesion often tracks

along nerve roots in the sacral plexus or out the sciatic notch in planes of least

resistance.

Under the microscope, the chordomas are characterized by lobules and fibrous

septa. The malignant cell has eosinophilic cytoplasm. Prominent vacuoles of mucus

push the nuclei to the side resulting in "physaliphorous" cells from the Greek word

for bubble or drop.

During the fourth to sixth week of fetal development mesenchymal cells from

individual sclerotomes merge to surround the notochord and form the vertebral

bodies. The notochord normally degenerates and remnants form the nucleus pulposus

of the vertebral disc. The prevailing theory is that in chordomas the notochord fails to

degenerate and then undergoes malignant transformation. The major failing of this

theory is that normal notochord remnants have never been observed.

The treatment of chordomas is difficult. Wide surgical excision is desirable but

rarely feasible based on the anatomic location of the tumor. With sacrococcygeal

tumors, sexual function and sphincter control may be compromised after surgery.

Radiation is used if complete resection is impossible. Chordomas metastasize to

lymph nodes, lungs, liver and bone. Chemotherapy can be used for late stage disease.