Disorders of the Tissue Growth. Neoplasm.

Case 1 (N 62)

A 48-year-old patient N. who has been smoking for 25 years works at
the chemical plant where he deals with dyes and organic solvents. He
visited his primary care physician with complaints of malaise, weakness,
decreased appetite, and persistent cough without secretions. During the
previous 3 weeks he noted the presence of blood in the urine, burning
sensation in the lower abdomen aggravated by urination. The results of
computer tomography scanning, x-ray, and ultrasonography attest against
renal or ureter pathology in the patient. Cystoscopy shows proliferation of
the bladder's mucosa with erosion of its surface. Biopsy of the lesion in the
bladder shows the presence of malignant cells.

Questions:
1. What factors could be a potential cause of cancer of the bladder mucosa
in this case? Substantiate your answer.
2. What mechanisms of the anticancer defence system could have been
deficient in this patient and failed to prevent the development of tumor?
3. Characterize stages of carcinogenesis after the first contact
of the bladder mucosa with carcinogen and up to the emergence of the tumor
cells.
4. Can you exclude the possibility of metastases of the lung cancer in the
bladder? Substantiate your opinion.

Answers:
1. 2 sources of carcinogens:
a) tobacco smoke (Smoking potential can also cause cancer of the
bladder but usually causes cancer of the lungs)
b) varnish and dyes
- More important! Because liver cancer is more for those working
with dyes.
Localization of cancer:
- Substances are inhaled and enter the blood
- With general circulation, enter organs that are involved in
detoxification of substances, i.e. liver and kidneys.
- Liver and kidneys are rich in microsomes with cytochrome P450.
- And so first these procarcinogens are first activated to
carcinogens, but then they are immediately neutralized in
reaction of addition to glucuronide and conjugation.
- Glucuronides and other conjugates are released into general
circulation and filtered in the kidneys and excreted with urine.
Substances that are excreted are neutral (chemically inert).
- Point: Some microbes, especially those present in intestine and
also some arteriole cells may release an enzyme called beta
glucuronidase that can split glucuronides with release of active
carcinogens.
- Since urine is stored in urinary bladder for some time, and even
can be partially concentrated if urine bladder also contain this
enzyme, it may lead to active carcinogen that can affect the
cells of the bladder mucosa and cause cancer. (Called
professional cancer)
- Normally cancer develops at the place where concentration of
carcinogens is the highest, in this case, highest in urinary
bladder.
- While in smoke is highest in lungs because smoke is the
suspension of particles of tar, and these particles sediment on
the surface of the lungs and induce the monocytes-macrophage
reaction. They come to sites of sedimentation and try to absorb
these particles. After that, the carcinogens that are release from
the particles of tar are then converted to active carcinogens and
affect the epithelium.
2. Anticarcinogenic mechanism. Because of the great load of carcinogens
for the body.
3. Events that occur during initiation stage:
- Active carcinogen if not neutralized may enter the cell or may be
formed inside the cell and interacts with DNA. in addition
reactions, modify nucleotide bases in many genes but also
including prooncogenes or antioncogenes, etc.
- Modification of the genes may render cell more prone to division
! cell start to proliferate ! more mutations ! tumor cell
- Tumor cell is not formed at once, its a process that takes time. It
accumulation mutations (8-10 mutations).
4. Yes. Its a very complex route. Enter general circulation ! find artery
that goes to wall of bladder ! reach wall of bladder ! vessel wall !
muscle wall ! form on surface ! make implant ! development.

Case 2 (N 63)

Seven months after a patient had undergone a surgical removal of the
stomach carcinoma and completed a course of chemotherapy he presented
with an enlargement of a supraclavial lymph node. Biopsy of the swelled
lymph node showed the presence of malignant cells. Some of these cells
were similar to the removed tumor cells by their morphology.

Questions:
1. Can you attribute the appearance of the tumor cells in the lymph node to
the tumor progression phenomenon? Substantiate your answer and
characterize the phenomenon of tumor progression (its mechanisms and
biological significance).
2. Do you think that the presence of the tumor cells in the lymph node is the
result of the primary tumor metastases?
- a multicentered tumor growth?
- recidivation of the stomach carcinoma?
- a new tumor growth?
Substantiate your opinion.
3. What factors of the anticancer defence system were ineffective in this
case? What are the possible mechanisms of their action?
Answers:
Notes: Tumor progression:
- An acquisition of initially benign tumor more and more malignant
properties.
- In general, malignalization of benign tumor.
Properties of malignant:
- Invasive growth
- Infiltration
- More rapid growth
- Poor differentiation
- Ability to metastatize
- Ability to cause cachexia
*Properties not acquire at once. Its a step wise, progressive fashion.
Moreover, they are acquired randomly, so its difficult to determine
which property is acquired first. Because progression is based on
mutation; and mutation is a random process.
*In general, changes of tumor follow the process of evolution of living
matter, that is first variability in the biological properties (based on
mutations in this case), and selection.
*Factors of selection that affects the tumor cells can be recognized by
the immune system and eliminated. It may grow in adverse
environment, for example, if it invades the surrounding tissue, it may be
adverse environment (Eg: if you take a normal hepatocyte and implant
it into normal kidneys, it will die, because kidney cells will not endure
alien cells unlike hepatocytes same for this tissue).
*So it means that cells of primary tumor benign tumor which is
monoclinic (all cells have similar genetic properties) may undergo
mutations with formation of different clones, different mutations. These
clones are under the effect of selective factors. So those that have
more ability to survive may remain and proliferate; those that have less
ability to survive will eliminate.
*In general, this is called progression to more malignant, aggressive
tissue.

1. Yes. If it develops property of metastatizing.
2. Metastasis.
Polyfocal tumor growth is not a common disorder. May be seen in
disease multiple endocrine neoplasia. In this case, tumors
develop simultaneously in many endocrine glands.
Some types of lymphoma that may appear in several lymph nodes
at the same time because of the multifocal growth and not because
of metastasis. In this case we have gastric cancer and something
in lymph node that is similar to gastric cancer.
So its unlikely that it is polyfocal growth.
Recidivation of the stomach carcinoma cannot be in the lymph
node. It is not possible.
A new tumor growth. Theoretically it is possible but if there is new
tumor growth there would be tumor cells of lymphocytic origin, of
another epithelial gastric origin. So it can only be metastasis.
3. Intercellular. See notes.
Case 3 (N 64)
A 56-year-old patient M., who has been suffering from gastric atrophy and
hypoacidity for more than 20 years, complains of fatigability, weakness, pain
in the epigastrium, decreased appetite, rapid satiety during meal, nausea, a
great loss of body mass during the last 4 months, and a persistent fever.
Laboratory tests showed anemia, leukocytosis, hypochlorhydria, and a
decreased activity of gastric juice enzymes. Gastroscopy revealed flattening
of the mucosal folds in the pyloric area, and the presence of a saucer-like
tumor with ulcerative alterations in the center.

Questions:
1. Why does chronic gastric atrophy promote the development of a
gastric tumor?
2. Can we suspect the insufficiency of the antineoplastic mechanisms in this
case? If we can, describe these mechanisms.
3. What are the possible causes and mechanisms of fever and anemia in this
patient?
4. What are the possible causes of cachexia in this patient?
Answers:
1. Chronic gastritis trophic gastritis. The other type may be hypertrophic
and hyperacidic but in this case is hypotrophic and hypoacidic. Under
microscopical examination, can find areas of pathological metaplasia.
Intestinal or colonic metaplasia. Cancer develops from this areas. In
general, pathologic metaplasia is a precancerous change in the tissue.
Other factors that promote cancer:
- Atrophic gastritis means loss of production of gastric juice that is
protective.
- It is antineoplastic mechanism; anticarcinogenic
- Carcinogens that are neutralized by gastric juice: microbes
indirectly promote cancer because they can destroy epithelial
cells and stimulate regeneration. Any excessive regeneration
can be associated with mutations and cancer. In the course of
microbes metabolism, there can be production of carcinogenice
substances, like microbes in intestine produce phenols, indoles
or amines, etc (carcinogenic substances).
- Highly acidic media of the gastric juice also neutralizes chemical
carcinogens. So, gastric juice is anticarcinogenic factor.
2. See notes.
3. See notes.
4. Fever is pyrogens. Source of pyrogens:
- Microbes that populate the gastric mucosa, for example,
helicobacter pylori.
- Decomposing tumor itself because sources like cancer is one of
the ulcerative forms of cancer. Ulceration means disruption
process of tissue. Necrotic tissue may give rise to pyrogens that
may absorb and evoke an acute phase response fever.
Anemia. Cancer especially with ulceration lead to loss of blood, minor
portions but persistent. Small proportions of blood will not disturb
hemodynamics but they may cause depletion of iron stores and so
produces signs of anemia. Moreover, trophic gastritis is associated with
elimination of parietal cells that produce HCl and intrinsic factor (protein
necessary for absorption of Vitamin B12; lack of B12 also causes
anemia). 2 factors: deficiency of iron and vitamin B12.
5. Causes of cachexia:
- wasting of body mass associated with malignant tumors
- tumor of gastric intestinal tract ! disturb digestion
- for example if present in pyloric area, close to outlet of stomach,
it may block the channels and disturb evacuation of food
- food that is retained in stomach may undergo decay,
fermentation ! nausea, loss of appetite
- Causes of cachexia:
(a) Production of tumor necrosis factor in response to tumors
2 types of TNF: alpha (signal molecule; a cytokine) and beta
(also called cachexia; it affects metabolism, for eg
stimulates triglyceride lipase in adipose tissue and leads to
loss of mass of adipose tissue). Can also directly affect
hypothalamus and affect appetite.