bohomolets oncology lecture methodical #2
DESCRIPTION
By Dr.Olga Lobanova from Oncology departmentTRANSCRIPT
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.