Test 3- Neoplasia Part 2

Question 1

Experimentally-induced

Answer 1

Experimentally-induced (Nude Mice) – able to accept grafting: no rejection (no only allografts but also xenograftstissue from other species)

• nude mice lack T- lymphocytes(which are the main cells for defense against tumors

USED AS MODELS SINCE THEY CAN ACCEPT GRAFTING FROM MULTIPLE SPECIES

Question 2

Naturally occurring

Answer 2

– Age-adjusted cancer incidence in dogs is similar to humans (381 per 100,000). Dogs present many advantages to study human neoplastic diseases, specially now that including the canine genome has been mapped.

Question 3

Molecular Basis of Cancer

Answer 3

“The genetic alterations that contribute to cancer development include inheritable changes (present in all cells within the organism) and somatic changes that accumulate in individual cells over time” – Kusewitt & Rush in McGavin et al.

“Non-lethal genetic damage lies at the heart of carcinogenesis. Such genetic damage (or mutation) may be acquired (environmental agents) or may be inherited in the germ line” – Robbins & Cotran

“Genetic damage per se does not constitute mutation, mutation occurs during DNA replication”  the alteration in DNA sequence caused by genetic damage needs to be imprinted in the genome

Question 4

In addition to DNA mutations,

Answer 4

In addition to DNA mutations, epigenetic changes & chromosomal alterations are also observed in tumor cells.

Question 5

Epigenetic changes

Answer 5

Refers to heritable changes in gene expression in somatic cells resulting from something other than a change in the DNA sequence (most common ones are DNA methylation and histone modification)”.

MODIFYS FUNCTION OF GENES

Question 6

Carcinogenesis

Answer 6

Carcinogenesis is a multistep process at both the phenotypic and the genetic level”…“Tumor progression”

“Each mutation provides the cell with a growth advantage of some kind that

enriches the ability of the cell and its clones to escape normal host regulation”

Question 7

Four classes of normal regulatory genes are the main target of genetic damage and play a significant role in carcinogenesis:

Answer 7

Four classes of normal regulatory genes are the main target of genetic damage and play a significant role in carcinogenesis:

1. growth-promoting proto-oncogenes
2. growth-inhibiting tumor suppressor genes
3. genes that regulate programmed cell death (apoptosis), and
4. genes involved in DNA repair

Question 8

A tumor is formed by the

Answer 8

A tumor is formed by the clonal expansion of a single precursor cell that has incurred in genetic damage (tumors are monoclonal)”…

Question 9

p53 gene

Answer 9

This growth-inhibiting tumor suppressor gene deserves a special mention:

“Guardian of the Genome”acts as a

“molecular policeman” when facing damage to the genome…

stops cellular replication

Question 10

Molecular Basis of Cancer:

Answer 10

Molecular Basis of Cancer: Changes in cell physiology that together determine malignant phenotype:

1. self-sufficiency in growth signals
2. insentitivty to growth inhibitory signals
3. evasiono of apoptosis
4. defects in DNA repair
5. limitless replicative potential
6. sustained agniogenesis
7. ability to invade and metastasize
8. ability to escape from immunity and repair

Question 11

Tumor immunity/ immune surveillance

Answer 11

The increase incidence of cancer in immuno-suppressed people and animals is the strongest argument for the existence of tumor immune surveillance.

Unfortunately tumor immune surveillance mechanisms are not as effective as they should be. The reason is that tumor cells have the capability to develop mechanisms to evade the immune system of the immunocompetent host.

Question 12

Tumor antigens:

Answer 12

Tumor antigens:
– Tumor-specific antigens- molecules expressed on the surface of only tumor cells
– Tumor-associated antigens- expressed on neoplasic cell, but they are also expressed on normal cells

Tumor antigens can serve as the targets of effective immunosurveillance

Tumor antigens can be use for diagnosis, monitoring or immunotherapy

Question 13

Immune surveillance

Answer 13

CD8 + Cytotoxic T lymphocytes (CTLs) are the major immune defense mechanism against tumors.

From Colgate immunology, web image

Natural killer cells (specific type of lymphocytes) and macrophages also play a role. Interferon-gamma (IFN-γ), a cytokine produced by T-cells and NK cells, is a potent activator of macrophages.

Antibodies against tumor antigens are also part of the defense mechanisms of the host but there is little evidence that humoral immunity is effective against tumors.

Question 14

Tumor antigens Recognized by CTLs.

Answer 14

normally, you are identifiying cells as self

tumors express particular antigens on the surface

Question 15

Cells involved
in immune- surveillance against tumors.

Answer 15

Question 16

Mechanisms by which tumors evade the immune system

Answer 16

Question 17

Tumor etiology

Answer 17

1. Macro-environmental (extrinsic) causes: e.g.: UV light, ionizing radiation, chemical carcinogens, oncoviruses.
2. Micro-environmental (intrinsic) causes: e.g.: heritable genetic changes, byproducts of normal metabolism including reactive oxygen species.

Question 18

Many of the familial cancer syndromes are due to

Answer 18

Many of the familial cancer syndromes are due to mutation in recessive tumor suppressor genes

Question 19

Chemical carcinogens are

Answer 19

Chemical carcinogens are widespread in the environment. E.g. The toxin of the bracken fern plant causes urinary bladder cancer in cattle grazing pastures containing the plant.

Tobacco smoke contains potent carcinogens.

Question 20

Answer 20

Cow, ocular squamous cell carcinoma (SCCa)

Question 21

Answer 21

Hereford cow

Question 22

Answer 22

“UV radiation causes dimerization and protein cross- links in DNA molecules. Also UV light induces formation of a carcinogen (cholesterol alpha oxide) from natural sterols in unpigmented skin”.

squamous cell carcinoma, conjuctiva, Hereford cow

slow to metasizes—- carcinomas mostly metasizes through the lymphatics

Question 23

Answer 23

SCCa are common in cats,
especially white cats, and may
be preceded by actinic (solar) keratosis,

Question 24

Clinical Oncology

Answer 24

All tumors, even benign ones may cause morbidity and mortality”

“Every neoplasm requires careful appraisal”

“Although clinical evaluation may suggest one or the other, the only unequivocally benign breast mass is the one that has been excised and anatomically diagnosed”

Question 25

Effects of tumors on the host.

Answer 25

• Local&hormonal effect
• Paraneoplastic syndromes

– “Indirect and usually remote effects caused by tumor cell products rather than the primary tumor and its metastases” – McGavin

– “Symptom complexes in cancer-bearing patients that can not readily be explained, either by the local or distant spread of the tumor, or the elaboration of hormones indigenous to the tissue of origin” – cited in Robbins & Cotran (N Engl J Med 349: 1543, 2003).

Question 26

Answer 26

2 yr old QH gelding with fibrosarcoma of the maxilla,

Question 27

“Cancer cachexia

Answer 27

progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia and anemia”

 TNF, IL-1, IL-6, IFN-gamma, prostaglandins and PIF (proteolysis inducing factor are apparently involved in the pathogenesis of cancer cachexia).

Question 28

Paraneoplastic syndromes

Answer 28

There is a long list of paraneoplastic syndromes in humans and domestic animals.

In humans they occur in approximately 75% (10% if cachexia(ie of paraneoplastic syndrome is not included) of patients with malignant disease.

They are quite important because:

– They may represent the earliest manifestation of an occult neoplasm.

– In affected patients they may represent significant clinical problems and may even be lethal.

Question 29

Paraneoplastic syndromes

Answer 29

• Examples of paraneoplastic syndromes in domestic animals are:

Cachexia
Hypercalcemia of malignancy.
Hypoglycemia
Thrombotic disease
Peripheral neuropathy
Nodular dermatofibrosis (German Shepherd dogs) Hypertrophic osteoarthropathy

Question 30

Hypercalcemia of malignancy:

Answer 30

 Most frequently observed paraneoplastic syndrome – primarily in dogs

 Due to the production of calcemic humoral substances (parathyroid hormone-related protein, PTHRP) by neoplastic cells from extra- osseous neoplasms.

 Hypercalcemia due to osteolysis by skeletal metastases is not a paraneoplastic syndrome

Question 31

Clinical signs of hypercalcemia

Answer 31

 Muscle weakness
 Cardiac arrhythmia (rare)

 Anorexia
 Vomiting
 Renal Failure
 Polyuria/ polydipsia

Even though neoplasia is the most common cause of persisent hypercalcemia, other causes are those listed above. Make sure to rule these out!

Question 32

Even though neoplasia is the most common cause of persistent hypercalcemia, other causes should also be considered and ruled out:

Answer 32

 Hyperparathyroidism

 Renal failure
 Hypoadrenocorticism

 Hypervitaminosis D

Question 33

Answer 33

In dogs it is primarily associated with apocrine gland carcinomas of the anal sacs (80-90% of the cases)- ass with paraneoplastic syndrome, or with lymphosarcomas

Hypercalcemia of malignancy:

Question 34

Answer 34

Hypercalcemia of malignancy:

Question 35

Answer 35

Dog –Hypertrophic Osteopathy – forelimbs.

This dog had a pulmonary tumor.

SPACE OCCUPYING LESIONS in the thoracic cavity

Also known as Marie’s Disease or Hypertrophic Pulmonary osteopathy

animals present with lameness-

Question 36

Answer 36

Hypertrophic osteopathy

pathogenesis is not clear

Periosteal bone proliferation. Occurs in dogs and cats: Often associated with space-occupying lesions in the lungs (tumors or abscesses etc..). Cornell’s files, Dr. John King.

Canine, , hypertrophic osteopathy (osteoarthropathy), Noah’s Arkive

can be associated with spiracera lupi

Question 37

Nodular Dermatofibrosis,

Answer 37

Nodular Dermatofibrosis, German Shepherd dogs (autosomal dominant)

Affected dogs developed multiple benign cutaneous lesions almost always associated with underlying bilateral renal disease: polycystic kidneys, renal cystadenomas or cystadenocarcinomas (most common). Occasionally reported in other breeds.

Question 38

9. Laboratory Diagnosis of Tumors

• Histologic & Cytologic Examination

Answer 38

– Clinical data is quite valuable for diagnosis

– “Laboratory evaluation can be only as good as the specimen available for examination”

Question 39

Immunohistochemistry.

Answer 39

The availability of monoclonal antibodies has greatly facilitated the identification of cell products or surface markers.

Question 40

Advantages of the use of Immunohistochemistry in tumor diagnosis:

Answer 40

1. Categorization of undifferentiated malignant tumors Use of antibodies against specific intermediate (cytoskeletal) filaments: Cytokeratins, Vimentin, Desmin etc..
2. Categorization of leukemias/ lymphomas
3. Determination of site of origin of metastatic tumors
4. Determination of molecules that have prognostic or therapeutic significance:

e.g.: determination of estrogen/ progesterone receptors in breast cancer cells  receptor positive breast cancers have a better prognosis/ susceptible to anti-estrogen therapy (e.g. Tamoxifen is a antagonist of the estrogen receptor in breast tissue)

Question 41

Grading

Answer 41

Grading: Gives a semi-quantitative evaluation of the degree of differentiation of the tumor. Cancers are classified from I to IV with increasing anaplasia.

Although histologic grading is useful, histologic appearance not always correlates with biologic behavior.- some tumors may look very well differentiated, but they may metasizes quickly

can be subjective

Question 42

Staging

Answer 42

It is based on the size of the primary tumor, its extend of spread to regional lymph nodes, and the presence or absence of hematogenous metastases.

Question 43

Staging from a clinical point of view has proved to be more useful

Answer 43

Staging from a clinical point of view has proved to be more useful than grading.

Question 44

TNM System:

Answer 44

T= Primary tumor, with increasing size: T1 to T4. T0= “in

situ” lesion.

N: regional LN involvement. N0= No LN involvement. N1 to N3 would denote increase number and range of nodes.

M: Blood-borne metastases. M0= No blood-borne metastases, M1 or M2 indicates the presence of blood- borne metastases and some judgment as to their number.